@article {1188, title = {Candidate gene association resource (CARe): design, methods, and proof of concept.}, journal = {Circ Cardiovasc Genet}, volume = {3}, year = {2010}, month = {2010 Jun}, pages = {267-75}, abstract = {

BACKGROUND: The National Heart, Lung, and Blood Institute{\textquoteright}s Candidate Gene Association Resource (CARe), a planned cross-cohort analysis of genetic variation in cardiovascular, pulmonary, hematologic, and sleep-related traits, comprises >40,000 participants representing 4 ethnic groups in 9 community-based cohorts. The goals of CARe include the discovery of new variants associated with traits using a candidate gene approach and the discovery of new variants using the genome-wide association mapping approach specifically in African Americans.

METHODS AND RESULTS: CARe has assembled DNA samples for >40,000 individuals self-identified as European American, African American, Hispanic, or Chinese American, with accompanying data on hundreds of phenotypes that have been standardized and deposited in the CARe Phenotype Database. All participants were genotyped for 7 single-nucleotide polymorphisms (SNPs) selected based on prior association evidence. We performed association analyses relating each of these SNPs to lipid traits, stratified by sex and ethnicity, and adjusted for age and age squared. In at least 2 of the ethnic groups, SNPs near CETP, LIPC, and LPL strongly replicated for association with high-density lipoprotein cholesterol concentrations, PCSK9 with low-density lipoprotein cholesterol levels, and LPL and APOA5 with serum triglycerides. Notably, some SNPs showed varying effect sizes and significance of association in different ethnic groups.

CONCLUSIONS: The CARe Pilot Study validates the operational framework for phenotype collection, SNP genotyping, and analytic pipeline of the CARe project and validates the planned candidate gene study of approximately 2000 biological candidate loci in all participants and genome-wide association study in approximately 8000 African American participants. CARe will serve as a valuable resource for the scientific community.

}, keywords = {African Americans, Cholesterol, HDL, Cholesterol, LDL, Cohort Studies, Databases, Genetic, European Continental Ancestry Group, Genetic Association Studies, Genotype, Humans, Phenotype, Pilot Projects, Polymorphism, Single Nucleotide, Research Design, Triglycerides}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.109.882696}, author = {Musunuru, Kiran and Lettre, Guillaume and Young, Taylor and Farlow, Deborah N and Pirruccello, James P and Ejebe, Kenechi G and Keating, Brendan J and Yang, Qiong and Chen, Ming-Huei and Lapchyk, Nina and Crenshaw, Andrew and Ziaugra, Liuda and Rachupka, Anthony and Benjamin, Emelia J and Cupples, L Adrienne and Fornage, Myriam and Fox, Ervin R and Heckbert, Susan R and Hirschhorn, Joel N and Newton-Cheh, Christopher and Nizzari, Marcia M and Paltoo, Dina N and Papanicolaou, George J and Patel, Sanjay R and Psaty, Bruce M and Rader, Daniel J and Redline, Susan and Rich, Stephen S and Rotter, Jerome I and Taylor, Herman A and Tracy, Russell P and Vasan, Ramachandran S and Wilson, James G and Kathiresan, Sekar and Fabsitz, Richard R and Boerwinkle, Eric and Gabriel, Stacey B} } @article {1311, title = {Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium.}, journal = {PLoS Genet}, volume = {7}, year = {2011}, month = {2011 Jul}, pages = {e1002193}, abstract = {

Long-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from α-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases) were associated with higher levels of ALA (p = 3 x 10$^{-}$$^{6}$$^{4}$) and lower levels of eicosapentaenoic acid (EPA, p = 5 x 10$^{-}$$^{5}$$^{8}$) and docosapentaenoic acid (DPA, p = 4 x 10$^{-}${\textonesuperior}$^{5}$$^{4}$). Minor alleles of SNPs in ELOVL2 (elongase) were associated with higher EPA (p = 2 x 10$^{-}${\textonesuperior}{\texttwosuperior}) and DPA (p = 1 x 10$^{-}$$^{4}${\textthreesuperior}) and lower docosahexaenoic acid (DHA, p = 1 x 10$^{-}${\textonesuperior}$^{5}$). In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, p = 1 x 10$^{-}$$^{8}$). We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535), suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries.

}, keywords = {Alleles, Continental Population Groups, Fatty Acids, Omega-3, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1002193}, author = {Lemaitre, Rozenn N and Tanaka, Toshiko and Tang, Weihong and Manichaikul, Ani and Foy, Millennia and Kabagambe, Edmond K and Nettleton, Jennifer A and King, Irena B and Weng, Lu-Chen and Bhattacharya, Sayanti and Bandinelli, Stefania and Bis, Joshua C and Rich, Stephen S and Jacobs, David R and Cherubini, Antonio and McKnight, Barbara and Liang, Shuang and Gu, Xiangjun and Rice, Kenneth and Laurie, Cathy C and Lumley, Thomas and Browning, Brian L and Psaty, Bruce M and Chen, Yii-der I and Friedlander, Yechiel and Djouss{\'e}, Luc and Wu, Jason H Y and Siscovick, David S and Uitterlinden, Andr{\'e} G and Arnett, Donna K and Ferrucci, Luigi and Fornage, Myriam and Tsai, Michael Y and Mozaffarian, Dariush and Steffen, Lyn M} } @article {6096, title = {Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.}, journal = {Nat Genet}, volume = {43}, year = {2011}, month = {2011 Sep 25}, pages = {1082-90}, abstract = {

Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 {\texttimes} 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.

}, keywords = {Child, European Continental Ancestry Group, Genome-Wide Association Study, Humans, Pulmonary Disease, Chronic Obstructive, Respiratory Function Tests}, issn = {1546-1718}, doi = {10.1038/ng.941}, author = {Soler Artigas, Maria and Loth, Daan W and Wain, Louise V and Gharib, Sina A and Obeidat, Ma{\textquoteright}en and Tang, Wenbo and Zhai, Guangju and Zhao, Jing Hua and Smith, Albert Vernon and Huffman, Jennifer E and Albrecht, Eva and Jackson, Catherine M and Evans, David M and Cadby, Gemma and Fornage, Myriam and Manichaikul, Ani and Lopez, Lorna M and Johnson, Toby and Aldrich, Melinda C and Aspelund, Thor and Barroso, In{\^e}s and Campbell, Harry and Cassano, Patricia A and Couper, David J and Eiriksdottir, Gudny and Franceschini, Nora and Garcia, Melissa and Gieger, Christian and Gislason, Gauti Kjartan and Grkovic, Ivica and Hammond, Christopher J and Hancock, Dana B and Harris, Tamara B and Ramasamy, Adaikalavan and Heckbert, Susan R and Heli{\"o}vaara, Markku and Homuth, Georg and Hysi, Pirro G and James, Alan L and Jankovic, Stipan and Joubert, Bonnie R and Karrasch, Stefan and Klopp, Norman and Koch, Beate and Kritchevsky, Stephen B and Launer, Lenore J and Liu, Yongmei and Loehr, Laura R and Lohman, Kurt and Loos, Ruth J F and Lumley, Thomas and Al Balushi, Khalid A and Ang, Wei Q and Barr, R Graham and Beilby, John and Blakey, John D and Boban, Mladen and Boraska, Vesna and Brisman, Jonas and Britton, John R and Brusselle, Guy G and Cooper, Cyrus and Curjuric, Ivan and Dahgam, Santosh and Deary, Ian J and Ebrahim, Shah and Eijgelsheim, Mark and Francks, Clyde and Gaysina, Darya and Granell, Raquel and Gu, Xiangjun and Hankinson, John L and Hardy, Rebecca and Harris, Sarah E and Henderson, John and Henry, Amanda and Hingorani, Aroon D and Hofman, Albert and Holt, Patrick G and Hui, Jennie and Hunter, Michael L and Imboden, Medea and Jameson, Karen A and Kerr, Shona M and Kolcic, Ivana and Kronenberg, Florian and Liu, Jason Z and Marchini, Jonathan and McKeever, Tricia and Morris, Andrew D and Olin, Anna-Carin and Porteous, David J and Postma, Dirkje S and Rich, Stephen S and Ring, Susan M and Rivadeneira, Fernando and Rochat, Thierry and Sayer, Avan Aihie and Sayers, Ian and Sly, Peter D and Smith, George Davey and Sood, Akshay and Starr, John M and Uitterlinden, Andr{\'e} G and Vonk, Judith M and Wannamethee, S Goya and Whincup, Peter H and Wijmenga, Cisca and Williams, O Dale and Wong, Andrew and Mangino, Massimo and Marciante, Kristin D and McArdle, Wendy L and Meibohm, Bernd and Morrison, Alanna C and North, Kari E and Omenaas, Ernst and Palmer, Lyle J and Pietil{\"a}inen, Kirsi H and Pin, Isabelle and Pola Sbreve Ek, Ozren and Pouta, Anneli and Psaty, Bruce M and Hartikainen, Anna-Liisa and Rantanen, Taina and Ripatti, Samuli and Rotter, Jerome I and Rudan, Igor and Rudnicka, Alicja R and Schulz, Holger and Shin, So-Youn and Spector, Tim D and Surakka, Ida and Vitart, Veronique and V{\"o}lzke, Henry and Wareham, Nicholas J and Warrington, Nicole M and Wichmann, H-Erich and Wild, Sarah H and Wilk, Jemma B and Wjst, Matthias and Wright, Alan F and Zgaga, Lina and Zemunik, Tatijana and Pennell, Craig E and Nyberg, Fredrik and Kuh, Diana and Holloway, John W and Boezen, H Marike and Lawlor, Debbie A and Morris, Richard W and Probst-Hensch, Nicole and Kaprio, Jaakko and Wilson, James F and Hayward, Caroline and K{\"a}h{\"o}nen, Mika and Heinrich, Joachim and Musk, Arthur W and Jarvis, Deborah L and Gl{\"a}ser, Sven and Jarvelin, Marjo-Riitta and Ch Stricker, Bruno H and Elliott, Paul and O{\textquoteright}Connor, George T and Strachan, David P and London, Stephanie J and Hall, Ian P and Gudnason, Vilmundur and Tobin, Martin D} } @article {6092, title = {Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction.}, journal = {Am J Respir Crit Care Med}, volume = {186}, year = {2012}, month = {2012 Oct 01}, pages = {622-32}, abstract = {

RATIONALE: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.

OBJECTIVES: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases.

METHODS: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV(1) and its ratio to FVC (FEV(1)/FVC) both less than their respective lower limits of normal as determined by published reference equations.

MEASUREMENTS AND MAIN RESULTS: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV(1)/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis.

CONCLUSIONS: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.

}, keywords = {Aged, Female, Forced Expiratory Volume, Genome-Wide Association Study, Humans, Male, Middle Aged, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive, Receptors, Nicotinic, Receptors, Serotonin, 5-HT4, Smoking, Vital Capacity}, issn = {1535-4970}, doi = {10.1164/rccm.201202-0366OC}, author = {Wilk, Jemma B and Shrine, Nick R G and Loehr, Laura R and Zhao, Jing Hua and Manichaikul, Ani and Lopez, Lorna M and Smith, Albert Vernon and Heckbert, Susan R and Smolonska, Joanna and Tang, Wenbo and Loth, Daan W and Curjuric, Ivan and Hui, Jennie and Cho, Michael H and Latourelle, Jeanne C and Henry, Amanda P and Aldrich, Melinda and Bakke, Per and Beaty, Terri H and Bentley, Amy R and Borecki, Ingrid B and Brusselle, Guy G and Burkart, Kristin M and Chen, Ting-Hsu and Couper, David and Crapo, James D and Davies, Gail and Dupuis, Jos{\'e}e and Franceschini, Nora and Gulsvik, Amund and Hancock, Dana B and Harris, Tamara B and Hofman, Albert and Imboden, Medea and James, Alan L and Khaw, Kay-Tee and Lahousse, Lies and Launer, Lenore J and Litonjua, Augusto and Liu, Yongmei and Lohman, Kurt K and Lomas, David A and Lumley, Thomas and Marciante, Kristin D and McArdle, Wendy L and Meibohm, Bernd and Morrison, Alanna C and Musk, Arthur W and Myers, Richard H and North, Kari E and Postma, Dirkje S and Psaty, Bruce M and Rich, Stephen S and Rivadeneira, Fernando and Rochat, Thierry and Rotter, Jerome I and Soler Artigas, Maria and Starr, John M and Uitterlinden, Andr{\'e} G and Wareham, Nicholas J and Wijmenga, Cisca and Zanen, Pieter and Province, Michael A and Silverman, Edwin K and Deary, Ian J and Palmer, Lyle J and Cassano, Patricia A and Gudnason, Vilmundur and Barr, R Graham and Loos, Ruth J F and Strachan, David P and London, Stephanie J and Boezen, H Marike and Probst-Hensch, Nicole and Gharib, Sina A and Hall, Ian P and O{\textquoteright}Connor, George T and Tobin, Martin D and Stricker, Bruno H} } @article {6088, title = {Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1003098}, abstract = {

Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00{\texttimes}10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35{\texttimes}10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28{\texttimes}10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.

}, keywords = {Forced Expiratory Volume, Gene Expression, Genome, Human, Genome-Wide Association Study, HLA-DQ Antigens, HLA-DQ beta-Chains, Humans, Lung, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Potassium Channels, Inwardly Rectifying, Pulmonary Disease, Chronic Obstructive, Receptors, Cell Surface, Smoking, SOX9 Transcription Factor, Vital Capacity}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003098}, author = {Hancock, Dana B and Soler Artigas, Maria and Gharib, Sina A and Henry, Amanda and Manichaikul, Ani and Ramasamy, Adaikalavan and Loth, Daan W and Imboden, Medea and Koch, Beate and McArdle, Wendy L and Smith, Albert V and Smolonska, Joanna and Sood, Akshay and Tang, Wenbo and Wilk, Jemma B and Zhai, Guangju and Zhao, Jing Hua and Aschard, Hugues and Burkart, Kristin M and Curjuric, Ivan and Eijgelsheim, Mark and Elliott, Paul and Gu, Xiangjun and Harris, Tamara B and Janson, Christer and Homuth, Georg and Hysi, Pirro G and Liu, Jason Z and Loehr, Laura R and Lohman, Kurt and Loos, Ruth J F and Manning, Alisa K and Marciante, Kristin D and Obeidat, Ma{\textquoteright}en and Postma, Dirkje S and Aldrich, Melinda C and Brusselle, Guy G and Chen, Ting-Hsu and Eiriksdottir, Gudny and Franceschini, Nora and Heinrich, Joachim and Rotter, Jerome I and Wijmenga, Cisca and Williams, O Dale and Bentley, Amy R and Hofman, Albert and Laurie, Cathy C and Lumley, Thomas and Morrison, Alanna C and Joubert, Bonnie R and Rivadeneira, Fernando and Couper, David J and Kritchevsky, Stephen B and Liu, Yongmei and Wjst, Matthias and Wain, Louise V and Vonk, Judith M and Uitterlinden, Andr{\'e} G and Rochat, Thierry and Rich, Stephen S and Psaty, Bruce M and O{\textquoteright}Connor, George T and North, Kari E and Mirel, Daniel B and Meibohm, Bernd and Launer, Lenore J and Khaw, Kay-Tee and Hartikainen, Anna-Liisa and Hammond, Christopher J and Gl{\"a}ser, Sven and Marchini, Jonathan and Kraft, Peter and Wareham, Nicholas J and V{\"o}lzke, Henry and Stricker, Bruno H C and Spector, Timothy D and Probst-Hensch, Nicole M and Jarvis, Deborah and Jarvelin, Marjo-Riitta and Heckbert, Susan R and Gudnason, Vilmundur and Boezen, H Marike and Barr, R Graham and Cassano, Patricia A and Strachan, David P and Fornage, Myriam and Hall, Ian P and Dupuis, Jos{\'e}e and Tobin, Martin D and London, Stephanie J} } @article {1388, title = {Multi-ethnic analysis of lipid-associated loci: the NHLBI CARe project.}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e36473}, abstract = {

BACKGROUND: Whereas it is well established that plasma lipid levels have substantial heritability within populations, it remains unclear how many of the genetic determinants reported in previous studies (largely performed in European American cohorts) are relevant in different ethnicities.

METHODOLOGY/PRINCIPAL FINDINGS: We tested a set of \~{}50,000 polymorphisms from \~{}2,000 candidate genes and genetic loci from genome-wide association studies (GWAS) for association with low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) in 25,000 European Americans and 9,000 African Americans in the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe). We replicated associations for a number of genes in one or both ethnicities and identified a novel lipid-associated variant in a locus harboring ICAM1. We compared the architecture of genetic loci associated with lipids in both African Americans and European Americans and found that the same genes were relevant across ethnic groups but the specific associated variants at each gene often differed.

CONCLUSIONS/SIGNIFICANCE: We identify or provide further evidence for a number of genetic determinants of plasma lipid levels through population association studies. In many loci the determinants appear to differ substantially between African Americans and European Americans.

}, keywords = {African Americans, Cholesterol, HDL, Cholesterol, LDL, European Continental Ancestry Group, Genetic Association Studies, Genetic Loci, Humans, Polymorphism, Single Nucleotide, Triglycerides}, issn = {1932-6203}, doi = {10.1371/journal.pone.0036473}, author = {Musunuru, Kiran and Romaine, Simon P R and Lettre, Guillaume and Wilson, James G and Volcik, Kelly A and Tsai, Michael Y and Taylor, Herman A and Schreiner, Pamela J and Rotter, Jerome I and Rich, Stephen S and Redline, Susan and Psaty, Bruce M and Papanicolaou, George J and Ordovas, Jose M and Liu, Kiang and Krauss, Ronald M and Glazer, Nicole L and Gabriel, Stacey B and Fornage, Myriam and Cupples, L Adrienne and Buxbaum, Sarah G and Boerwinkle, Eric and Ballantyne, Christie M and Kathiresan, Sekar and Rader, Daniel J} } @article {6067, title = {Best practices and joint calling of the HumanExome BeadChip: the CHARGE Consortium.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e68095}, abstract = {

Genotyping arrays are a cost effective approach when typing previously-identified genetic polymorphisms in large numbers of samples. One limitation of genotyping arrays with rare variants (e.g., minor allele frequency [MAF] <0.01) is the difficulty that automated clustering algorithms have to accurately detect and assign genotype calls. Combining intensity data from large numbers of samples may increase the ability to accurately call the genotypes of rare variants. Approximately 62,000 ethnically diverse samples from eleven Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium cohorts were genotyped with the Illumina HumanExome BeadChip across seven genotyping centers. The raw data files for the samples were assembled into a single project for joint calling. To assess the quality of the joint calling, concordance of genotypes in a subset of individuals having both exome chip and exome sequence data was analyzed. After exclusion of low performing SNPs on the exome chip and non-overlap of SNPs derived from sequence data, genotypes of 185,119 variants (11,356 were monomorphic) were compared in 530 individuals that had whole exome sequence data. A total of 98,113,070 pairs of genotypes were tested and 99.77\% were concordant, 0.14\% had missing data, and 0.09\% were discordant. We report that joint calling allows the ability to accurately genotype rare variation using array technology when large sample sizes are available and best practices are followed. The cluster file from this experiment is available at www.chargeconsortium.com/main/exomechip.

}, keywords = {Aging, Alleles, Cluster Analysis, Cohort Studies, Continental Population Groups, Exome, Female, Gene Frequency, Genomics, Genotype, Heart, Humans, Male, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Sample Size, Self Report, Sequence Analysis, DNA}, issn = {1932-6203}, doi = {10.1371/journal.pone.0068095}, author = {Grove, Megan L and Yu, Bing and Cochran, Barbara J and Haritunians, Talin and Bis, Joshua C and Taylor, Kent D and Hansen, Mark and Borecki, Ingrid B and Cupples, L Adrienne and Fornage, Myriam and Gudnason, Vilmundur and Harris, Tamara B and Kathiresan, Sekar and Kraaij, Robert and Launer, Lenore J and Levy, Daniel and Liu, Yongmei and Mosley, Thomas and Peloso, Gina M and Psaty, Bruce M and Rich, Stephen S and Rivadeneira, Fernando and Siscovick, David S and Smith, Albert V and Uitterlinden, Andre and van Duijn, Cornelia M and Wilson, James G and O{\textquoteright}Donnell, Christopher J and Rotter, Jerome I and Boerwinkle, Eric} } @article {8014, title = {Common variants associated with plasma triglycerides and risk for coronary artery disease.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Nov}, pages = {1345-52}, abstract = {

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 {\texttimes} 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism{\textquoteright}s effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

}, keywords = {Biological Transport, Cholesterol, HDL, Cholesterol, LDL, Coronary Artery Disease, Humans, Polymorphism, Single Nucleotide, Risk Factors, Triglycerides}, issn = {1546-1718}, doi = {10.1038/ng.2795}, author = {Do, Ron and Willer, Cristen J and Schmidt, Ellen M and Sengupta, Sebanti and Gao, Chi and Peloso, Gina M and Gustafsson, Stefan and Kanoni, Stavroula and Ganna, Andrea and Chen, Jin and Buchkovich, Martin L and Mora, Samia and Beckmann, Jacques S and Bragg-Gresham, Jennifer L and Chang, Hsing-Yi and Demirkan, Ayse and Den Hertog, Heleen M and Donnelly, Louise A and Ehret, Georg B and Esko, T{\~o}nu and Feitosa, Mary F and Ferreira, Teresa and Fischer, Krista and Fontanillas, Pierre and Fraser, Ross M and Freitag, Daniel F and Gurdasani, Deepti and Heikkil{\"a}, Kauko and Hypp{\"o}nen, Elina and Isaacs, Aaron and Jackson, Anne U and Johansson, Asa and Johnson, Toby and Kaakinen, Marika and Kettunen, Johannes and Kleber, Marcus E and Li, Xiaohui and Luan, Jian{\textquoteright}an and Lyytik{\"a}inen, Leo-Pekka and Magnusson, Patrik K E and Mangino, Massimo and Mihailov, Evelin and Montasser, May E and M{\"u}ller-Nurasyid, Martina and Nolte, Ilja M and O{\textquoteright}Connell, Jeffrey R and Palmer, Cameron D and Perola, Markus and Petersen, Ann-Kristin and Sanna, Serena and Saxena, Richa and Service, Susan K and Shah, Sonia and Shungin, Dmitry and Sidore, Carlo and Song, Ci and Strawbridge, Rona J and Surakka, Ida and Tanaka, Toshiko and Teslovich, Tanya M and Thorleifsson, Gudmar and van den Herik, Evita G and Voight, Benjamin F and Volcik, Kelly A and Waite, Lindsay L and Wong, Andrew and Wu, Ying and Zhang, Weihua and Absher, Devin and Asiki, Gershim and Barroso, In{\^e}s and Been, Latonya F and Bolton, Jennifer L and Bonnycastle, Lori L and Brambilla, Paolo and Burnett, Mary S and Cesana, Giancarlo and Dimitriou, Maria and Doney, Alex S F and D{\"o}ring, Angela and Elliott, Paul and Epstein, Stephen E and Eyjolfsson, Gudmundur Ingi and Gigante, Bruna and Goodarzi, Mark O and Grallert, Harald and Gravito, Martha L and Groves, Christopher J and Hallmans, G{\"o}ran and Hartikainen, Anna-Liisa and Hayward, Caroline and Hernandez, Dena and Hicks, Andrew A and Holm, Hilma and Hung, Yi-Jen and Illig, Thomas and Jones, Michelle R and Kaleebu, Pontiano and Kastelein, John J P and Khaw, Kay-Tee and Kim, Eric and Klopp, Norman and Komulainen, Pirjo and Kumari, Meena and Langenberg, Claudia and Lehtim{\"a}ki, Terho and Lin, Shih-Yi and Lindstr{\"o}m, Jaana and Loos, Ruth J F and Mach, Fran{\c c}ois and McArdle, Wendy L and Meisinger, Christa and Mitchell, Braxton D and M{\"u}ller, Gabrielle and Nagaraja, Ramaiah and Narisu, Narisu and Nieminen, Tuomo V M and Nsubuga, Rebecca N and Olafsson, Isleifur and Ong, Ken K and Palotie, Aarno and Papamarkou, Theodore and Pomilla, Cristina and Pouta, Anneli and Rader, Daniel J and Reilly, Muredach P and Ridker, Paul M and Rivadeneira, Fernando and Rudan, Igor and Ruokonen, Aimo and Samani, Nilesh and Scharnagl, Hubert and Seeley, Janet and Silander, Kaisa and Stan{\v c}{\'a}kov{\'a}, Alena and Stirrups, Kathleen and Swift, Amy J and Tiret, Laurence and Uitterlinden, Andr{\'e} G and van Pelt, L Joost and Vedantam, Sailaja and Wainwright, Nicholas and Wijmenga, Cisca and Wild, Sarah H and Willemsen, Gonneke and Wilsgaard, Tom and Wilson, James F and Young, Elizabeth H and Zhao, Jing Hua and Adair, Linda S and Arveiler, Dominique and Assimes, Themistocles L and Bandinelli, Stefania and Bennett, Franklyn and Bochud, Murielle and Boehm, Bernhard O and Boomsma, Dorret I and Borecki, Ingrid B and Bornstein, Stefan R and Bovet, Pascal and Burnier, Michel and Campbell, Harry and Chakravarti, Aravinda and Chambers, John C and Chen, Yii-Der Ida and Collins, Francis S and Cooper, Richard S and Danesh, John and Dedoussis, George and de Faire, Ulf and Feranil, Alan B and Ferrieres, Jean and Ferrucci, Luigi and Freimer, Nelson B and Gieger, Christian and Groop, Leif C and Gudnason, Vilmundur and Gyllensten, Ulf and Hamsten, Anders and Harris, Tamara B and Hingorani, Aroon and Hirschhorn, Joel N and Hofman, Albert and Hovingh, G Kees and Hsiung, Chao Agnes and Humphries, Steve E and Hunt, Steven C and Hveem, Kristian and Iribarren, Carlos and Jarvelin, Marjo-Riitta and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kaprio, Jaakko and Kes{\"a}niemi, Antero and Kivimaki, Mika and Kooner, Jaspal S and Koudstaal, Peter J and Krauss, Ronald M and Kuh, Diana and Kuusisto, Johanna and Kyvik, Kirsten O and Laakso, Markku and Lakka, Timo A and Lind, Lars and Lindgren, Cecilia M and Martin, Nicholas G and M{\"a}rz, Winfried and McCarthy, Mark I and McKenzie, Colin A and Meneton, Pierre and Metspalu, Andres and Moilanen, Leena and Morris, Andrew D and Munroe, Patricia B and Nj{\o}lstad, Inger and Pedersen, Nancy L and Power, Chris and Pramstaller, Peter P and Price, Jackie F and Psaty, Bruce M and Quertermous, Thomas and Rauramaa, Rainer and Saleheen, Danish and Salomaa, Veikko and Sanghera, Dharambir K and Saramies, Jouko and Schwarz, Peter E H and Sheu, Wayne H-H and Shuldiner, Alan R and Siegbahn, Agneta and Spector, Tim D and Stefansson, Kari and Strachan, David P and Tayo, Bamidele O and Tremoli, Elena and Tuomilehto, Jaakko and Uusitupa, Matti and van Duijn, Cornelia M and Vollenweider, Peter and Wallentin, Lars and Wareham, Nicholas J and Whitfield, John B and Wolffenbuttel, Bruce H R and Altshuler, David and Ordovas, Jose M and Boerwinkle, Eric and Palmer, Colin N A and Thorsteinsdottir, Unnur and Chasman, Daniel I and Rotter, Jerome I and Franks, Paul W and Ripatti, Samuli and Cupples, L Adrienne and Sandhu, Manjinder S and Rich, Stephen S and Boehnke, Michael and Deloukas, Panos and Mohlke, Karen L and Ingelsson, Erik and Abecasis, Goncalo R and Daly, Mark J and Neale, Benjamin M and Kathiresan, Sekar} } @article {6154, title = {Discovery and refinement of loci associated with lipid levels.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Nov}, pages = {1274-1283}, abstract = {

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 {\texttimes} 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

}, keywords = {African Continental Ancestry Group, Asian Continental Ancestry Group, Cholesterol, HDL, Cholesterol, LDL, Coronary Artery Disease, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Lipids, Triglycerides}, issn = {1546-1718}, doi = {10.1038/ng.2797}, author = {Willer, Cristen J and Schmidt, Ellen M and Sengupta, Sebanti and Peloso, Gina M and Gustafsson, Stefan and Kanoni, Stavroula and Ganna, Andrea and Chen, Jin and Buchkovich, Martin L and Mora, Samia and Beckmann, Jacques S and Bragg-Gresham, Jennifer L and Chang, Hsing-Yi and Demirkan, Ayse and Den Hertog, Heleen M and Do, Ron and Donnelly, Louise A and Ehret, Georg B and Esko, T{\~o}nu and Feitosa, Mary F and Ferreira, Teresa and Fischer, Krista and Fontanillas, Pierre and Fraser, Ross M and Freitag, Daniel F and Gurdasani, Deepti and Heikkil{\"a}, Kauko and Hypp{\"o}nen, Elina and Isaacs, Aaron and Jackson, Anne U and Johansson, Asa and Johnson, Toby and Kaakinen, Marika and Kettunen, Johannes and Kleber, Marcus E and Li, Xiaohui and Luan, Jian{\textquoteright}an and Lyytik{\"a}inen, Leo-Pekka and Magnusson, Patrik K E and Mangino, Massimo and Mihailov, Evelin and Montasser, May E and M{\"u}ller-Nurasyid, Martina and Nolte, Ilja M and O{\textquoteright}Connell, Jeffrey R and Palmer, Cameron D and Perola, Markus and Petersen, Ann-Kristin and Sanna, Serena and Saxena, Richa and Service, Susan K and Shah, Sonia and Shungin, Dmitry and Sidore, Carlo and Song, Ci and Strawbridge, Rona J and Surakka, Ida and Tanaka, Toshiko and Teslovich, Tanya M and Thorleifsson, Gudmar and van den Herik, Evita G and Voight, Benjamin F and Volcik, Kelly A and Waite, Lindsay L and Wong, Andrew and Wu, Ying and Zhang, Weihua and Absher, Devin and Asiki, Gershim and Barroso, In{\^e}s and Been, Latonya F and Bolton, Jennifer L and Bonnycastle, Lori L and Brambilla, Paolo and Burnett, Mary S and Cesana, Giancarlo and Dimitriou, Maria and Doney, Alex S F and D{\"o}ring, Angela and Elliott, Paul and Epstein, Stephen E and Ingi Eyjolfsson, Gudmundur and Gigante, Bruna and Goodarzi, Mark O and Grallert, Harald and Gravito, Martha L and Groves, Christopher J and Hallmans, G{\"o}ran and Hartikainen, Anna-Liisa and Hayward, Caroline and Hernandez, Dena and Hicks, Andrew A and Holm, Hilma and Hung, Yi-Jen and Illig, Thomas and Jones, Michelle R and Kaleebu, Pontiano and Kastelein, John J P and Khaw, Kay-Tee and Kim, Eric and Klopp, Norman and Komulainen, Pirjo and Kumari, Meena and Langenberg, Claudia and Lehtim{\"a}ki, Terho and Lin, Shih-Yi and Lindstr{\"o}m, Jaana and Loos, Ruth J F and Mach, Fran{\c c}ois and McArdle, Wendy L and Meisinger, Christa and Mitchell, Braxton D and M{\"u}ller, Gabrielle and Nagaraja, Ramaiah and Narisu, Narisu and Nieminen, Tuomo V M and Nsubuga, Rebecca N and Olafsson, Isleifur and Ong, Ken K and Palotie, Aarno and Papamarkou, Theodore and Pomilla, Cristina and Pouta, Anneli and Rader, Daniel J and Reilly, Muredach P and Ridker, Paul M and Rivadeneira, Fernando and Rudan, Igor and Ruokonen, Aimo and Samani, Nilesh and Scharnagl, Hubert and Seeley, Janet and Silander, Kaisa and Stan{\v c}{\'a}kov{\'a}, Alena and Stirrups, Kathleen and Swift, Amy J and Tiret, Laurence and Uitterlinden, Andr{\'e} G and van Pelt, L Joost and Vedantam, Sailaja and Wainwright, Nicholas and Wijmenga, Cisca and Wild, Sarah H and Willemsen, Gonneke and Wilsgaard, Tom and Wilson, James F and Young, Elizabeth H and Zhao, Jing Hua and Adair, Linda S and Arveiler, Dominique and Assimes, Themistocles L and Bandinelli, Stefania and Bennett, Franklyn and Bochud, Murielle and Boehm, Bernhard O and Boomsma, Dorret I and Borecki, Ingrid B and Bornstein, Stefan R and Bovet, Pascal and Burnier, Michel and Campbell, Harry and Chakravarti, Aravinda and Chambers, John C and Chen, Yii-Der Ida and Collins, Francis S and Cooper, Richard S and Danesh, John and Dedoussis, George and de Faire, Ulf and Feranil, Alan B and Ferrieres, Jean and Ferrucci, Luigi and Freimer, Nelson B and Gieger, Christian and Groop, Leif C and Gudnason, Vilmundur and Gyllensten, Ulf and Hamsten, Anders and Harris, Tamara B and Hingorani, Aroon and Hirschhorn, Joel N and Hofman, Albert and Hovingh, G Kees and Hsiung, Chao Agnes and Humphries, Steve E and Hunt, Steven C and Hveem, Kristian and Iribarren, Carlos and Jarvelin, Marjo-Riitta and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kaprio, Jaakko and Kes{\"a}niemi, Antero and Kivimaki, Mika and Kooner, Jaspal S and Koudstaal, Peter J and Krauss, Ronald M and Kuh, Diana and Kuusisto, Johanna and Kyvik, Kirsten O and Laakso, Markku and Lakka, Timo A and Lind, Lars and Lindgren, Cecilia M and Martin, Nicholas G and M{\"a}rz, Winfried and McCarthy, Mark I and McKenzie, Colin A and Meneton, Pierre and Metspalu, Andres and Moilanen, Leena and Morris, Andrew D and Munroe, Patricia B and Nj{\o}lstad, Inger and Pedersen, Nancy L and Power, Chris and Pramstaller, Peter P and Price, Jackie F and Psaty, Bruce M and Quertermous, Thomas and Rauramaa, Rainer and Saleheen, Danish and Salomaa, Veikko and Sanghera, Dharambir K and Saramies, Jouko and Schwarz, Peter E H and Sheu, Wayne H-H and Shuldiner, Alan R and Siegbahn, Agneta and Spector, Tim D and Stefansson, Kari and Strachan, David P and Tayo, Bamidele O and Tremoli, Elena and Tuomilehto, Jaakko and Uusitupa, Matti and van Duijn, Cornelia M and Vollenweider, Peter and Wallentin, Lars and Wareham, Nicholas J and Whitfield, John B and Wolffenbuttel, Bruce H R and Ordovas, Jose M and Boerwinkle, Eric and Palmer, Colin N A and Thorsteinsdottir, Unnur and Chasman, Daniel I and Rotter, Jerome I and Franks, Paul W and Ripatti, Samuli and Cupples, L Adrienne and Sandhu, Manjinder S and Rich, Stephen S and Boehnke, Michael and Deloukas, Panos and Kathiresan, Sekar and Mohlke, Karen L and Ingelsson, Erik and Abecasis, Goncalo R} } @article {5880, title = {Genome-wide association study identifies novel loci associated with concentrations of four plasma phospholipid fatty acids in the de novo lipogenesis pathway: results from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortiu}, journal = {Circ Cardiovasc Genet}, volume = {6}, year = {2013}, month = {2013 Apr}, pages = {171-83}, abstract = {

BACKGROUND- Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n-7), and oleic acid (18:1n-9) are major saturated and monounsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis and are the main saturated and monounsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes mellitus and coronary heart disease. METHODS AND RESULTS- Genome-wide association studies were conducted in 5 population-based cohorts comprising 8961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these 4 fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of >=1 of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0 (P=2.7{\texttimes}10(-11)) and lower 18:0 (P=2.2{\texttimes}10(-18)). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7 (P=6.6{\texttimes}10(-13)) and 18:1n-9 (P=2.2{\texttimes}10(-32)) and lower 18:0 (P=1.3{\texttimes}10(-20)). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0 (P=2.8{\texttimes}10(-9)). GCKR (glucokinase regulator; P=9.8{\texttimes}10(-10)) and HIF1AN (factor inhibiting hypoxia-inducible factor-1; P=5.7{\texttimes}10(-9)) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1 (polycystic kidney disease 2-like 1; P=5.7{\texttimes}10(-15)) and a locus on chromosome 2 (not near known genes) were associated with lower 16:1n-7 (P=4.1{\texttimes}10(-8)). CONCLUSIONS- Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of 4 fatty acids in the de novo lipogenesis pathway. These results expand our knowledge of genetic factors relevant to de novo lipogenesis and fatty acid biology.

}, keywords = {Adult, Aged, Chromosomes, Human, Pair 2, Cohort Studies, Coronary Disease, Diabetes Mellitus, Type 2, Fatty Acids, Monounsaturated, Female, Genetic Loci, Genome-Wide Association Study, Genotype, Humans, Linkage Disequilibrium, Lipogenesis, Male, Middle Aged, Oleic Acid, Palmitic Acid, Polymorphism, Single Nucleotide, Stearic Acids}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.112.964619}, author = {Wu, Jason H Y and Lemaitre, Rozenn N and Manichaikul, Ani and Guan, Weihua and Tanaka, Toshiko and Foy, Millennia and Kabagambe, Edmond K and Djouss{\'e}, Luc and Siscovick, David and Fretts, Amanda M and Johnson, Catherine and King, Irena B and Psaty, Bruce M and McKnight, Barbara and Rich, Stephen S and Chen, Yii-der I and Nettleton, Jennifer A and Tang, Weihong and Bandinelli, Stefania and Jacobs, David R and Browning, Brian L and Laurie, Cathy C and Gu, Xiangjun and Tsai, Michael Y and Steffen, Lyn M and Ferrucci, Luigi and Fornage, Myriam and Mozaffarian, Dariush} } @article {6590, title = {Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Feb 06}, pages = {223-32}, abstract = {

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1\% and 2\%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.

}, keywords = {1-Alkyl-2-acetylglycerophosphocholine Esterase, Adult, African Continental Ancestry Group, Aged, Alleles, Animals, Cholesterol, HDL, Cholesterol, LDL, Cohort Studies, Coronary Disease, European Continental Ancestry Group, Female, Gene Frequency, Genetic Association Studies, Genetic Code, Genetic Variation, Humans, Linear Models, Male, Mice, Mice, Inbred C57BL, Microtubule-Associated Proteins, Middle Aged, Phenotype, Sequence Analysis, DNA, Subtilisins, Triglycerides}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.01.009}, author = {Peloso, Gina M and Auer, Paul L and Bis, Joshua C and Voorman, Arend and Morrison, Alanna C and Stitziel, Nathan O and Brody, Jennifer A and Khetarpal, Sumeet A and Crosby, Jacy R and Fornage, Myriam and Isaacs, Aaron and Jakobsdottir, Johanna and Feitosa, Mary F and Davies, Gail and Huffman, Jennifer E and Manichaikul, Ani and Davis, Brian and Lohman, Kurt and Joon, Aron Y and Smith, Albert V and Grove, Megan L and Zanoni, Paolo and Redon, Valeska and Demissie, Serkalem and Lawson, Kim and Peters, Ulrike and Carlson, Christopher and Jackson, Rebecca D and Ryckman, Kelli K and Mackey, Rachel H and Robinson, Jennifer G and Siscovick, David S and Schreiner, Pamela J and Mychaleckyj, Josyf C and Pankow, James S and Hofman, Albert and Uitterlinden, Andr{\'e} G and Harris, Tamara B and Taylor, Kent D and Stafford, Jeanette M and Reynolds, Lindsay M and Marioni, Riccardo E and Dehghan, Abbas and Franco, Oscar H and Patel, Aniruddh P and Lu, Yingchang and Hindy, George and Gottesman, Omri and Bottinger, Erwin P and Melander, Olle and Orho-Melander, Marju and Loos, Ruth J F and Duga, Stefano and Merlini, Piera Angelica and Farrall, Martin and Goel, Anuj and Asselta, Rosanna and Girelli, Domenico and Martinelli, Nicola and Shah, Svati H and Kraus, William E and Li, Mingyao and Rader, Daniel J and Reilly, Muredach P and McPherson, Ruth and Watkins, Hugh and Ardissino, Diego and Zhang, Qunyuan and Wang, Judy and Tsai, Michael Y and Taylor, Herman A and Correa, Adolfo and Griswold, Michael E and Lange, Leslie A and Starr, John M and Rudan, Igor and Eiriksdottir, Gudny and Launer, Lenore J and Ordovas, Jose M and Levy, Daniel and Chen, Y-D Ida and Reiner, Alexander P and Hayward, Caroline and Polasek, Ozren and Deary, Ian J and Borecki, Ingrid B and Liu, Yongmei and Gudnason, Vilmundur and Wilson, James G and van Duijn, Cornelia M and Kooperberg, Charles and Rich, Stephen S and Psaty, Bruce M and Rotter, Jerome I and O{\textquoteright}Donnell, Christopher J and Rice, Kenneth and Boerwinkle, Eric and Kathiresan, Sekar and Cupples, L Adrienne} } @article {6611, title = {A genetic association study of D-dimer levels with 50K SNPs from a candidate gene chip in four ethnic groups.}, journal = {Thromb Res}, volume = {134}, year = {2014}, month = {2014 Aug}, pages = {462-7}, abstract = {

INTRODUCTION: D-dimer, a fibrin degradation product, is related to risk of cardiovascular disease and venous thromboembolism. Genetic determinants of D-dimer are not well characterized; notably, few data have been reported for African American (AA), Asian, and Hispanic populations.

MATERIALS AND METHODS: We conducted a large-scale candidate gene association study to identify variants in genes associated with D-dimer levels in multi-ethnic populations. Four cohorts, comprising 6,848 European Americans (EAs), 2,192 AAs, 670 Asians, and 1,286 Hispanics in the National Heart, Lung, and Blood Institute Candidate Gene Association Resource consortium, were assembled. Approximately 50,000 genotyped single nucleotide polymorphisms (SNPs) in 2,000 cardiovascular disease gene loci were analyzed by linear regression, adjusting for age, sex, study site, and principal components in each cohort and ethnic group. Results across studies were combined within each ethnic group by meta-analysis.

RESULTS: Twelve SNPs in coagulation factor V (F5) and 3 SNPs in the fibrinogen alpha chain (FGA) were significantly associated with D-dimer level in EAs with p<2.0{\texttimes}10(-6). The signal for the most associated SNP in F5 (rs6025, factor V Leiden) was replicated in Hispanics (p=0.023), while that for the top functional SNP in FGA (rs6050) was replicated in AAs (p=0.006). No additional SNPs were significantly associated with D-dimer.

CONCLUSIONS: Our study replicated previously reported associations of D-dimer with SNPs in F5 and FGA in EAs; we demonstrated replication of the association of D-dimer with FGA rs6050 in AAs and the factor V Leiden variant in Hispanics.

}, keywords = {Adult, Aged, Cardiovascular Diseases, Ethnic Groups, Factor V, Female, Fibrin Fibrinogen Degradation Products, Fibrinogen, Genetic Association Studies, Genotype, Humans, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Young Adult}, issn = {1879-2472}, doi = {10.1016/j.thromres.2014.05.018}, author = {Weng, Lu-Chen and Tang, Weihong and Rich, Stephen S and Smith, Nicholas L and Redline, Susan and O{\textquoteright}Donnell, Christopher J and Basu, Saonli and Reiner, Alexander P and Delaney, Joseph A and Tracy, Russell P and Palmer, Cameron D and Young, Taylor and Yang, Qiong and Folsom, Aaron R and Cushman, Mary} } @article {6582, title = {Genome-wide association analysis identifies six new loci associated with forced vital capacity.}, journal = {Nat Genet}, volume = {46}, year = {2014}, month = {2014 Jul}, pages = {669-77}, abstract = {

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 {\texttimes} 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.

}, keywords = {Cohort Studies, Databases, Genetic, Follow-Up Studies, Forced Expiratory Volume, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Lung Diseases, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Prognosis, Quantitative Trait Loci, Respiratory Function Tests, Spirometry, Vital Capacity}, issn = {1546-1718}, doi = {10.1038/ng.3011}, author = {Loth, Daan W and Soler Artigas, Maria and Gharib, Sina A and Wain, Louise V and Franceschini, Nora and Koch, Beate and Pottinger, Tess D and Smith, Albert Vernon and Duan, Qing and Oldmeadow, Chris and Lee, Mi Kyeong and Strachan, David P and James, Alan L and Huffman, Jennifer E and Vitart, Veronique and Ramasamy, Adaikalavan and Wareham, Nicholas J and Kaprio, Jaakko and Wang, Xin-Qun and Trochet, Holly and K{\"a}h{\"o}nen, Mika and Flexeder, Claudia and Albrecht, Eva and Lopez, Lorna M and de Jong, Kim and Thyagarajan, Bharat and Alves, Alexessander Couto and Enroth, Stefan and Omenaas, Ernst and Joshi, Peter K and Fall, Tove and Vi{\~n}uela, Ana and Launer, Lenore J and Loehr, Laura R and Fornage, Myriam and Li, Guo and Wilk, Jemma B and Tang, Wenbo and Manichaikul, Ani and Lahousse, Lies and Harris, Tamara B and North, Kari E and Rudnicka, Alicja R and Hui, Jennie and Gu, Xiangjun and Lumley, Thomas and Wright, Alan F and Hastie, Nicholas D and Campbell, Susan and Kumar, Rajesh and Pin, Isabelle and Scott, Robert A and Pietil{\"a}inen, Kirsi H and Surakka, Ida and Liu, Yongmei and Holliday, Elizabeth G and Schulz, Holger and Heinrich, Joachim and Davies, Gail and Vonk, Judith M and Wojczynski, Mary and Pouta, Anneli and Johansson, Asa and Wild, Sarah H and Ingelsson, Erik and Rivadeneira, Fernando and V{\"o}lzke, Henry and Hysi, Pirro G and Eiriksdottir, Gudny and Morrison, Alanna C and Rotter, Jerome I and Gao, Wei and Postma, Dirkje S and White, Wendy B and Rich, Stephen S and Hofman, Albert and Aspelund, Thor and Couper, David and Smith, Lewis J and Psaty, Bruce M and Lohman, Kurt and Burchard, Esteban G and Uitterlinden, Andr{\'e} G and Garcia, Melissa and Joubert, Bonnie R and McArdle, Wendy L and Musk, A Bill and Hansel, Nadia and Heckbert, Susan R and Zgaga, Lina and van Meurs, Joyce B J and Navarro, Pau and Rudan, Igor and Oh, Yeon-Mok and Redline, Susan and Jarvis, Deborah L and Zhao, Jing Hua and Rantanen, Taina and O{\textquoteright}Connor, George T and Ripatti, Samuli and Scott, Rodney J and Karrasch, Stefan and Grallert, Harald and Gaddis, Nathan C and Starr, John M and Wijmenga, Cisca and Minster, Ryan L and Lederer, David J and Pekkanen, Juha and Gyllensten, Ulf and Campbell, Harry and Morris, Andrew P and Gl{\"a}ser, Sven and Hammond, Christopher J and Burkart, Kristin M and Beilby, John and Kritchevsky, Stephen B and Gudnason, Vilmundur and Hancock, Dana B and Williams, O Dale and Polasek, Ozren and Zemunik, Tatijana and Kolcic, Ivana and Petrini, Marcy F and Wjst, Matthias and Kim, Woo Jin and Porteous, David J and Scotland, Generation and Smith, Blair H and Viljanen, Anne and Heli{\"o}vaara, Markku and Attia, John R and Sayers, Ian and Hampel, Regina and Gieger, Christian and Deary, Ian J and Boezen, H Marike and Newman, Anne and Jarvelin, Marjo-Riitta and Wilson, James F and Lind, Lars and Stricker, Bruno H and Teumer, Alexander and Spector, Timothy D and Mel{\'e}n, Erik and Peters, Marjolein J and Lange, Leslie A and Barr, R Graham and Bracke, Ken R and Verhamme, Fien M and Sung, Joohon and Hiemstra, Pieter S and Cassano, Patricia A and Sood, Akshay and Hayward, Caroline and Dupuis, Jos{\'e}e and Hall, Ian P and Brusselle, Guy G and Tobin, Martin D and London, Stephanie J} } @article {6567, title = {Genome-wide association study of plasma N6 polyunsaturated fatty acids within the cohorts for heart and aging research in genomic epidemiology consortium.}, journal = {Circ Cardiovasc Genet}, volume = {7}, year = {2014}, month = {2014 Jun}, pages = {321-331}, abstract = {

BACKGROUND: Omega6 (n6) polyunsaturated fatty acids (PUFAs) and their metabolites are involved in cell signaling, inflammation, clot formation, and other crucial biological processes. Genetic components, such as variants of fatty acid desaturase (FADS) genes, determine the composition of n6 PUFAs.

METHODS AND RESULTS: To elucidate undiscovered biological pathways that may influence n6 PUFA composition, we conducted genome-wide association studies and meta-analyses of associations of common genetic variants with 6 plasma n6 PUFAs in 8631 white adults (55\% women) across 5 prospective studies. Plasma phospholipid or total plasma fatty acids were analyzed by similar gas chromatography techniques. The n6 fatty acids linoleic acid (LA), γ-linolenic acid (GLA), dihomo-GLA, arachidonic acid, and adrenic acid were expressed as percentage of total fatty acids. We performed linear regression with robust SEs to test for single-nucleotide polymorphism-fatty acid associations, with pooling using inverse-variance-weighted meta-analysis. Novel regions were identified on chromosome 10 associated with LA (rs10740118; P=8.1{\texttimes}10(-9); near NRBF2), on chromosome 16 with LA, GLA, dihomo-GLA, and arachidonic acid (rs16966952; P=1.2{\texttimes}10(-15), 5.0{\texttimes}10(-11), 7.6{\texttimes}10(-65), and 2.4{\texttimes}10(-10), respectively; NTAN1), and on chromosome 6 with adrenic acid after adjustment for arachidonic acid (rs3134950; P=2.1{\texttimes}10(-10); AGPAT1). We confirmed previous findings of the FADS cluster on chromosome 11 with LA and arachidonic acid, and further observed novel genome-wide significant association of this cluster with GLA, dihomo-GLA, and adrenic acid (P=2.3{\texttimes}10(-72), 2.6{\texttimes}10(-151), and 6.3{\texttimes}10(-140), respectively).

CONCLUSIONS: Our findings suggest that along with the FADS gene cluster, additional genes may influence n6 PUFA composition.

}, keywords = {Adult, Aged, Aged, 80 and over, Aging, Chromosomes, Human, Pair 10, Chromosomes, Human, Pair 16, Chromosomes, Human, Pair 6, Fatty Acid Desaturases, Fatty Acids, Omega-6, Female, Genome-Wide Association Study, Genomics, Heart Diseases, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Prospective Studies, Sequence Analysis, DNA}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.113.000208}, author = {Guan, Weihua and Steffen, Brian T and Lemaitre, Rozenn N and Wu, Jason H Y and Tanaka, Toshiko and Manichaikul, Ani and Foy, Millennia and Rich, Stephen S and Wang, Lu and Nettleton, Jennifer A and Tang, Weihong and Gu, Xiangjun and Bandinelli, Stafania and King, Irena B and McKnight, Barbara and Psaty, Bruce M and Siscovick, David and Djouss{\'e}, Luc and Chen, Yii-Der Ida and Ferrucci, Luigi and Fornage, Myriam and Mozafarrian, Dariush and Tsai, Michael Y and Steffen, Lyn M} } @article {6605, title = {Loss-of-function mutations in APOC3, triglycerides, and coronary disease.}, journal = {N Engl J Med}, volume = {371}, year = {2014}, month = {2014 Jul 3}, pages = {22-31}, abstract = {

BACKGROUND: Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype.

METHODS: We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons.

RESULTS: An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G{\textrightarrow}A and IVS3+1G{\textrightarrow}T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39\% lower than levels in noncarriers (P<1{\texttimes}10(-20)), and circulating levels of APOC3 in carriers were 46\% lower than levels in noncarriers (P=8{\texttimes}10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40\% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95\% confidence interval, 0.47 to 0.75; P=4{\texttimes}10(-6)).

CONCLUSIONS: Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.).

}, keywords = {African Continental Ancestry Group, Apolipoprotein C-III, Coronary Disease, European Continental Ancestry Group, Exome, Genotype, Heterozygote, Humans, Liver, Mutation, Risk Factors, Sequence Analysis, DNA, Triglycerides}, issn = {1533-4406}, doi = {10.1056/NEJMoa1307095}, author = {Crosby, Jacy and Peloso, Gina M and Auer, Paul L and Crosslin, David R and Stitziel, Nathan O and Lange, Leslie A and Lu, Yingchang and Tang, Zheng-Zheng and Zhang, He and Hindy, George and Masca, Nicholas and Stirrups, Kathleen and Kanoni, Stavroula and Do, Ron and Jun, Goo and Hu, Youna and Kang, Hyun Min and Xue, Chenyi and Goel, Anuj and Farrall, Martin and Duga, Stefano and Merlini, Pier Angelica and Asselta, Rosanna and Girelli, Domenico and Olivieri, Oliviero and Martinelli, Nicola and Yin, Wu and Reilly, Dermot and Speliotes, Elizabeth and Fox, Caroline S and Hveem, Kristian and Holmen, Oddgeir L and Nikpay, Majid and Farlow, Deborah N and Assimes, Themistocles L and Franceschini, Nora and Robinson, Jennifer and North, Kari E and Martin, Lisa W and DePristo, Mark and Gupta, Namrata and Escher, Stefan A and Jansson, Jan-H{\r a}kan and Van Zuydam, Natalie and Palmer, Colin N A and Wareham, Nicholas and Koch, Werner and Meitinger, Thomas and Peters, Annette and Lieb, Wolfgang and Erbel, Raimund and K{\"o}nig, Inke R and Kruppa, Jochen and Degenhardt, Franziska and Gottesman, Omri and Bottinger, Erwin P and O{\textquoteright}Donnell, Christopher J and Psaty, Bruce M and Ballantyne, Christie M and Abecasis, Goncalo and Ordovas, Jose M and Melander, Olle and Watkins, Hugh and Orho-Melander, Marju and Ardissino, Diego and Loos, Ruth J F and McPherson, Ruth and Willer, Cristen J and Erdmann, Jeanette and Hall, Alistair S and Samani, Nilesh J and Deloukas, Panos and Schunkert, Heribert and Wilson, James G and Kooperberg, Charles and Rich, Stephen S and Tracy, Russell P and Lin, Dan-Yu and Altshuler, David and Gabriel, Stacey and Nickerson, Deborah A and Jarvik, Gail P and Cupples, L Adrienne and Reiner, Alex P and Boerwinkle, Eric and Kathiresan, Sekar} } @article {6585, title = {Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes.}, journal = {PLoS Genet}, volume = {10}, year = {2014}, month = {2014 Aug}, pages = {e1004517}, abstract = {

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 {\texttimes} 10(-94)}, keywords = {African Americans, Diabetes Mellitus, Type 2, Genome-Wide Association Study, HLA-B27 Antigen, HMGA2 Protein, Humans, KCNQ1 Potassium Channel, Mutant Chimeric Proteins, Polymorphism, Single Nucleotide, Transcription Factor 7-Like 2 Protein}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1004517}, author = {Ng, Maggie C Y and Shriner, Daniel and Chen, Brian H and Li, Jiang and Chen, Wei-Min and Guo, Xiuqing and Liu, Jiankang and Bielinski, Suzette J and Yanek, Lisa R and Nalls, Michael A and Comeau, Mary E and Rasmussen-Torvik, Laura J and Jensen, Richard A and Evans, Daniel S and Sun, Yan V and An, Ping and Patel, Sanjay R and Lu, Yingchang and Long, Jirong and Armstrong, Loren L and Wagenknecht, Lynne and Yang, Lingyao and Snively, Beverly M and Palmer, Nicholette D and Mudgal, Poorva and Langefeld, Carl D and Keene, Keith L and Freedman, Barry I and Mychaleckyj, Josyf C and Nayak, Uma and Raffel, Leslie J and Goodarzi, Mark O and Chen, Y-D Ida and Taylor, Herman A and Correa, Adolfo and Sims, Mario and Couper, David and Pankow, James S and Boerwinkle, Eric and Adeyemo, Adebowale and Doumatey, Ayo and Chen, Guanjie and Mathias, Rasika A and Vaidya, Dhananjay and Singleton, Andrew B and Zonderman, Alan B and Igo, Robert P and Sedor, John R and Kabagambe, Edmond K and Siscovick, David S and McKnight, Barbara and Rice, Kenneth and Liu, Yongmei and Hsueh, Wen-Chi and Zhao, Wei and Bielak, Lawrence F and Kraja, Aldi and Province, Michael A and Bottinger, Erwin P and Gottesman, Omri and Cai, Qiuyin and Zheng, Wei and Blot, William J and Lowe, William L and Pacheco, Jennifer A and Crawford, Dana C and Grundberg, Elin and Rich, Stephen S and Hayes, M Geoffrey and Shu, Xiao-Ou and Loos, Ruth J F and Borecki, Ingrid B and Peyser, Patricia A and Cummings, Steven R and Psaty, Bruce M and Fornage, Myriam and Iyengar, Sudha K and Evans, Michele K and Becker, Diane M and Kao, W H Linda and Wilson, James G and Rotter, Jerome I and Sale, Mich{\`e}le M and Liu, Simin and Rotimi, Charles N and Bowden, Donald W} } @article {6565, title = {Quantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset.}, journal = {Hum Mol Genet}, volume = {23}, year = {2014}, month = {2014 Apr 15}, pages = {1957-63}, abstract = {

The study of genetic influences on drug response and efficacy ({\textquoteright}pharmacogenetics{\textquoteright}) has existed for over 50 years. Yet, we still lack a complete picture of how genetic variation, both common and rare, affects each individual{\textquoteright}s responses to medications. Exome sequencing is a promising alternative method for pharmacogenetic discovery as it provides information on both common and rare variation in large numbers of individuals. Using exome data from 2203 AA and 4300 Caucasian individuals through the NHLBI Exome Sequencing Project, we conducted a survey of coding variation within 12 Cytochrome P450 (CYP) genes that are collectively responsible for catalyzing nearly 75\% of all known Phase I drug oxidation reactions. In addition to identifying many polymorphisms with known pharmacogenetic effects, we discovered over 730 novel nonsynonymous alleles across the 12 CYP genes of interest. These alleles include many with diverse functional effects such as premature stop codons, aberrant splicesites and mutations at conserved active site residues. Our analysis considering both novel, predicted functional alleles as well as known, actionable CYP alleles reveals that rare, deleterious variation contributes markedly to the overall burden of pharmacogenetic alleles within the populations considered, and that the contribution of rare variation to this burden is over three times greater in AA individuals as compared with Caucasians. While most of these impactful alleles are individually rare, 7.6-11.7\% of individuals interrogated in the study carry at least one newly described potentially deleterious alleles in a major drug-metabolizing CYP.

}, keywords = {Cytochrome P-450 Enzyme System, Databases, Genetic, European Continental Ancestry Group, Exome, Humans, Pharmaceutical Preparations, Pharmacogenetics, Polymorphism, Genetic}, issn = {1460-2083}, doi = {10.1093/hmg/ddt588}, author = {Gordon, Adam S and Tabor, Holly K and Johnson, Andrew D and Snively, Beverly M and Assimes, Themistocles L and Auer, Paul L and Ioannidis, John P A and Peters, Ulrike and Robinson, Jennifer G and Sucheston, Lara E and Wang, Danxin and Sotoodehnia, Nona and Rotter, Jerome I and Psaty, Bruce M and Jackson, Rebecca D and Herrington, David M and O{\textquoteright}Donnell, Christopher J and Reiner, Alexander P and Rich, Stephen S and Rieder, Mark J and Bamshad, Michael J and Nickerson, Deborah A} } @article {6583, title = {Sequencing of SCN5A identifies rare and common variants associated with cardiac conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.}, journal = {Circ Cardiovasc Genet}, volume = {7}, year = {2014}, month = {2014 Jun}, pages = {365-73}, abstract = {

BACKGROUND: The cardiac sodium channel SCN5A regulates atrioventricular and ventricular conduction. Genetic variants in this gene are associated with PR and QRS intervals. We sought to characterize further the contribution of rare and common coding variation in SCN5A to cardiac conduction.

METHODS AND RESULTS: In Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study, we performed targeted exonic sequencing of SCN5A (n=3699, European ancestry individuals) and identified 4 common (minor allele frequency >1\%) and 157 rare variants. Common and rare SCN5A coding variants were examined for association with PR and QRS intervals through meta-analysis of European ancestry participants from CHARGE, National Heart, Lung, and Blood Institute{\textquoteright}s Exome Sequencing Project (n=607), and the UK10K (n=1275) and by examining Exome Sequencing Project African ancestry participants (n=972). Rare coding SCN5A variants in aggregate were associated with PR interval in European and African ancestry participants (P=1.3{\texttimes}10(-3)). Three common variants were associated with PR and QRS interval duration among European ancestry participants and one among African ancestry participants. These included 2 well-known missense variants: rs1805124 (H558R) was associated with PR and QRS shortening in European ancestry participants (P=6.25{\texttimes}10(-4) and P=5.2{\texttimes}10(-3), respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (P=2.82{\texttimes}10(-3)). Among European ancestry participants, 2 novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening (P=3.35{\texttimes}10(-7) and P=2.69{\texttimes}10(-4), respectively) and rs6599230 was associated with PR shortening (P=2.67{\texttimes}10(-5)).

CONCLUSIONS: By sequencing SCN5A, we identified novel common and rare coding variants associated with cardiac conduction.

}, keywords = {Adult, Aged, Aged, 80 and over, Aging, Cohort Studies, Female, Genetic Variation, Genome-Wide Association Study, Genomics, Heart Conduction System, Heart Diseases, Humans, Male, Middle Aged, NAV1.5 Voltage-Gated Sodium Channel, Polymorphism, Single Nucleotide, Sequence Analysis, DNA}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.113.000098}, author = {Magnani, Jared W and Brody, Jennifer A and Prins, Bram P and Arking, Dan E and Lin, Honghuang and Yin, Xiaoyan and Liu, Ching-Ti and Morrison, Alanna C and Zhang, Feng and Spector, Tim D and Alonso, Alvaro and Bis, Joshua C and Heckbert, Susan R and Lumley, Thomas and Sitlani, Colleen M and Cupples, L Adrienne and Lubitz, Steven A and Soliman, Elsayed Z and Pulit, Sara L and Newton-Cheh, Christopher and O{\textquoteright}Donnell, Christopher J and Ellinor, Patrick T and Benjamin, Emelia J and Muzny, Donna M and Gibbs, Richard A and Santibanez, Jireh and Taylor, Herman A and Rotter, Jerome I and Lange, Leslie A and Psaty, Bruce M and Jackson, Rebecca and Rich, Stephen S and Boerwinkle, Eric and Jamshidi, Yalda and Sotoodehnia, Nona} } @article {6577, title = {Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Feb 06}, pages = {233-45}, abstract = {

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.

}, keywords = {Adult, Aged, Apolipoproteins E, Cholesterol, LDL, Cohort Studies, Dyslipidemias, Exome, Female, Follow-Up Studies, Gene Frequency, Genetic Code, Genome-Wide Association Study, Genotype, Humans, Lipase, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Proprotein Convertase 9, Proprotein Convertases, Receptors, LDL, Sequence Analysis, DNA, Serine Endopeptidases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.01.010}, author = {Lange, Leslie A and Hu, Youna and Zhang, He and Xue, Chenyi and Schmidt, Ellen M and Tang, Zheng-Zheng and Bizon, Chris and Lange, Ethan M and Smith, Joshua D and Turner, Emily H and Jun, Goo and Kang, Hyun Min and Peloso, Gina and Auer, Paul and Li, Kuo-Ping and Flannick, Jason and Zhang, Ji and Fuchsberger, Christian and Gaulton, Kyle and Lindgren, Cecilia and Locke, Adam and Manning, Alisa and Sim, Xueling and Rivas, Manuel A and Holmen, Oddgeir L and Gottesman, Omri and Lu, Yingchang and Ruderfer, Douglas and Stahl, Eli A and Duan, Qing and Li, Yun and Durda, Peter and Jiao, Shuo and Isaacs, Aaron and Hofman, Albert and Bis, Joshua C and Correa, Adolfo and Griswold, Michael E and Jakobsdottir, Johanna and Smith, Albert V and Schreiner, Pamela J and Feitosa, Mary F and Zhang, Qunyuan and Huffman, Jennifer E and Crosby, Jacy and Wassel, Christina L and Do, Ron and Franceschini, Nora and Martin, Lisa W and Robinson, Jennifer G and Assimes, Themistocles L and Crosslin, David R and Rosenthal, Elisabeth A and Tsai, Michael and Rieder, Mark J and Farlow, Deborah N and Folsom, Aaron R and Lumley, Thomas and Fox, Ervin R and Carlson, Christopher S and Peters, Ulrike and Jackson, Rebecca D and van Duijn, Cornelia M and Uitterlinden, Andr{\'e} G and Levy, Daniel and Rotter, Jerome I and Taylor, Herman A and Gudnason, Vilmundur and Siscovick, David S and Fornage, Myriam and Borecki, Ingrid B and Hayward, Caroline and Rudan, Igor and Chen, Y Eugene and Bottinger, Erwin P and Loos, Ruth J F and S{\ae}trom, P{\r a}l and Hveem, Kristian and Boehnke, Michael and Groop, Leif and McCarthy, Mark and Meitinger, Thomas and Ballantyne, Christie M and Gabriel, Stacey B and O{\textquoteright}Donnell, Christopher J and Post, Wendy S and North, Kari E and Reiner, Alexander P and Boerwinkle, Eric and Psaty, Bruce M and Altshuler, David and Kathiresan, Sekar and Lin, Dan-Yu and Jarvik, Gail P and Cupples, L Adrienne and Kooperberg, Charles and Wilson, James G and Nickerson, Deborah A and Abecasis, Goncalo R and Rich, Stephen S and Tracy, Russell P and Willer, Cristen J} } @article {6597, title = {Association of exome sequences with plasma C-reactive protein levels in >9000 participants.}, journal = {Hum Mol Genet}, volume = {24}, year = {2015}, month = {2015 Jan 15}, pages = {559-71}, abstract = {

C-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that is associated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in \~{}25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency = 0.16\%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53\% lower mean CRP levels (P = 2.9 {\texttimes} 10(-6)). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 {\texttimes} 10(-15)). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-ε2 rs7214 with higher CRP levels. At the exome-wide significance level (P < 5.0 {\texttimes} 10(-8)), we confirmed associations for reported common variants of HNF1A, CRP, IL6R and TOMM40-APOE. In gene-based tests, a burden of rare/lower frequency variation in CRP in EAs (P <= 6.8 {\texttimes} 10(-4)) and in retinoic acid receptor-related orphan receptor α (RORA) in AAs (P = 1.7 {\texttimes} 10(-3)) were associated with CRP levels at the candidate gene level (P < 2.0 {\texttimes} 10(-3)). This inquiry did not elucidate novel genes, but instead demonstrated that variants distributed across the allele frequency spectrum within candidate genes contribute to CRP levels.

}, keywords = {Adult, African Americans, C-Reactive Protein, Cardiovascular Diseases, Cohort Studies, European Continental Ancestry Group, Exome, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Hepatocyte Nuclear Factor 1-alpha, Humans, Male, Plasma, Polymorphism, Single Nucleotide, Receptors, Interleukin-6, Risk Factors}, issn = {1460-2083}, doi = {10.1093/hmg/ddu450}, author = {Schick, Ursula M and Auer, Paul L and Bis, Joshua C and Lin, Honghuang and Wei, Peng and Pankratz, Nathan and Lange, Leslie A and Brody, Jennifer and Stitziel, Nathan O and Kim, Daniel S and Carlson, Christopher S and Fornage, Myriam and Haessler, Jeffery and Hsu, Li and Jackson, Rebecca D and Kooperberg, Charles and Leal, Suzanne M and Psaty, Bruce M and Boerwinkle, Eric and Tracy, Russell and Ardissino, Diego and Shah, Svati and Willer, Cristen and Loos, Ruth and Melander, Olle and McPherson, Ruth and Hovingh, Kees and Reilly, Muredach and Watkins, Hugh and Girelli, Domenico and Fontanillas, Pierre and Chasman, Daniel I and Gabriel, Stacey B and Gibbs, Richard and Nickerson, Deborah A and Kathiresan, Sekar and Peters, Ulrike and Dupuis, Jos{\'e}e and Wilson, James G and Rich, Stephen S and Morrison, Alanna C and Benjamin, Emelia J and Gross, Myron D and Reiner, Alex P} } @article {6687, title = {Dietary fatty acids modulate associations between genetic variants and circulating fatty acids in plasma and erythrocyte membranes: Meta-analysis of nine studies in the CHARGE consortium.}, journal = {Mol Nutr Food Res}, volume = {59}, year = {2015}, month = {2015 Jul}, pages = {1373-83}, abstract = {

SCOPE: Tissue concentrations of omega-3 fatty acids may reduce cardiovascular disease risk, and genetic variants are associated with circulating fatty acids concentrations. Whether dietary fatty acids interact with genetic variants to modify circulating omega-3 fatty acids is unclear. We evaluated interactions between genetic variants and fatty acid intakes for circulating alpha-linoleic acid, eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid.

METHODS AND RESULTS: We conducted meta-analyses (N = 11~668) evaluating interactions between dietary fatty acids and genetic variants (rs174538 and rs174548 in FADS1 (fatty acid desaturase 1), rs7435 in AGPAT3 (1-acyl-sn-glycerol-3-phosphate), rs4985167 in PDXDC1 (pyridoxal-dependent decarboxylase domain-containing 1), rs780094 in GCKR (glucokinase regulatory protein), and rs3734398 in ELOVL2 (fatty acid elongase 2)). Stratification by measurement compartment (plasma versus erthyrocyte) revealed compartment-specific interactions between FADS1 rs174538 and rs174548 and dietary alpha-linolenic acid and linoleic acid for docosahexaenoic acid and docosapentaenoic acid.

CONCLUSION: Our findings reinforce earlier reports that genetically based differences in circulating fatty acids may be partially due to differences in the conversion of fatty acid precursors. Further, fatty acids measurement compartment may modify gene-diet relationships, and considering compartment may improve the detection of gene-fatty acids interactions for circulating fatty acid outcomes.

}, keywords = {Acetyltransferases, Acyltransferases, Adaptor Proteins, Signal Transducing, Carboxy-Lyases, Diet, Docosahexaenoic Acids, Eicosapentaenoic Acid, Erythrocyte Membrane, Fatty Acid Desaturases, Fatty Acids, Fatty Acids, Omega-3, Female, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide}, issn = {1613-4133}, doi = {10.1002/mnfr.201400734}, author = {Smith, Caren E and Follis, Jack L and Nettleton, Jennifer A and Foy, Millennia and Wu, Jason H Y and Ma, Yiyi and Tanaka, Toshiko and Manichakul, Ani W and Wu, Hongyu and Chu, Audrey Y and Steffen, Lyn M and Fornage, Myriam and Mozaffarian, Dariush and Kabagambe, Edmond K and Ferruci, Luigi and Chen, Yii-Der Ida and Rich, Stephen S and Djouss{\'e}, Luc and Ridker, Paul M and Tang, Weihong and McKnight, Barbara and Tsai, Michael Y and Bandinelli, Stefania and Rotter, Jerome I and Hu, Frank B and Chasman, Daniel I and Psaty, Bruce M and Arnett, Donna K and King, Irena B and Sun, Qi and Wang, Lu and Lumley, Thomas and Chiuve, Stephanie E and Siscovick, David S and Ordovas, Jose M and Lemaitre, Rozenn N} } @article {6691, title = {Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.}, journal = {Nature}, volume = {518}, year = {2015}, month = {2015 Feb 5}, pages = {102-6}, abstract = {

Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (<=50 years in males and <=60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2\% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190~mg~dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.

}, keywords = {Age Factors, Age of Onset, Alleles, Apolipoproteins A, Case-Control Studies, Cholesterol, LDL, Coronary Artery Disease, Exome, Female, Genetic Predisposition to Disease, Genetics, Population, Heterozygote, Humans, Male, Middle Aged, Mutation, Myocardial Infarction, National Heart, Lung, and Blood Institute (U.S.), Receptors, LDL, Triglycerides, United States}, issn = {1476-4687}, doi = {10.1038/nature13917}, author = {Do, Ron and Stitziel, Nathan O and Won, Hong-Hee and J{\o}rgensen, Anders Berg and Duga, Stefano and Angelica Merlini, Pier and Kiezun, Adam and Farrall, Martin and Goel, Anuj and Zuk, Or and Guella, Illaria and Asselta, Rosanna and Lange, Leslie A and Peloso, Gina M and Auer, Paul L and Girelli, Domenico and Martinelli, Nicola and Farlow, Deborah N and DePristo, Mark A and Roberts, Robert and Stewart, Alexander F R and Saleheen, Danish and Danesh, John and Epstein, Stephen E and Sivapalaratnam, Suthesh and Hovingh, G Kees and Kastelein, John J and Samani, Nilesh J and Schunkert, Heribert and Erdmann, Jeanette and Shah, Svati H and Kraus, William E and Davies, Robert and Nikpay, Majid and Johansen, Christopher T and Wang, Jian and Hegele, Robert A and Hechter, Eliana and M{\"a}rz, Winfried and Kleber, Marcus E and Huang, Jie and Johnson, Andrew D and Li, Mingyao and Burke, Greg L and Gross, Myron and Liu, Yongmei and Assimes, Themistocles L and Heiss, Gerardo and Lange, Ethan M and Folsom, Aaron R and Taylor, Herman A and Olivieri, Oliviero and Hamsten, Anders and Clarke, Robert and Reilly, Dermot F and Yin, Wu and Rivas, Manuel A and Donnelly, Peter and Rossouw, Jacques E and Psaty, Bruce M and Herrington, David M and Wilson, James G and Rich, Stephen S and Bamshad, Michael J and Tracy, Russell P and Cupples, L Adrienne and Rader, Daniel J and Reilly, Muredach P and Spertus, John A and Cresci, Sharon and Hartiala, Jaana and Tang, W H Wilson and Hazen, Stanley L and Allayee, Hooman and Reiner, Alex P and Carlson, Christopher S and Kooperberg, Charles and Jackson, Rebecca D and Boerwinkle, Eric and Lander, Eric S and Schwartz, Stephen M and Siscovick, David S and McPherson, Ruth and Tybjaerg-Hansen, Anne and Abecasis, Goncalo R and Watkins, Hugh and Nickerson, Deborah A and Ardissino, Diego and Sunyaev, Shamil R and O{\textquoteright}Donnell, Christopher J and Altshuler, David and Gabriel, Stacey and Kathiresan, Sekar} } @article {7376, title = {Gene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans.}, journal = {Am J Hematol}, volume = {90}, year = {2015}, month = {2015 Jun}, pages = {534-40}, abstract = {

Coagulation factor VIII and von Willebrand factor (VWF) are key proteins in procoagulant activation. Higher FVIII coagulant activity (FVIII :C) and VWF antigen (VWF :Ag) are risk factors for cardiovascular disease and venous thromboembolism. Beyond associations with ABO blood group, genetic determinants of FVIII and VWF are not well understood, especially in non European-American populations. We performed a genetic association study of FVIII :C and VWF:Ag that assessed 50,000 gene-centric single nucleotide polymorphisms (SNPs) in 18,556 European Americans (EAs) and 5,047 African Americans (AAs) from five population-based cohorts. Previously unreported associations for FVIII :C were identified in both AAs and EAs with KNG1 (most significantly associated SNP rs710446, Ile581Thr, Ile581Thr, P = 5.10 {\texttimes} 10(-7) in EAs and P = 3.88 {\texttimes} 10(-3) in AAs) and VWF rs7962217 (Gly2705Arg,P = 6.30 {\texttimes} 10(-9) in EAs and P = 2.98 {\texttimes} 10(-2) in AAs. Significant associations for FVIII :C were also observed with F8/TMLHE region SNP rs12557310 in EAs (P = 8.02 {\texttimes} 10(-10) ), with VWF rs1800380 in AAs (P = 5.62 {\texttimes} 10(-11) ), and with MAT1A rs2236568 in AAs (P51.69 {\texttimes} 10(-6) ). We replicated previously reported associations of FVIII :C and VWF :Ag with the ABO blood group, VWF rs1063856(Thr789Ala), rs216321 (Ala852Gln), and VWF rs2229446 (Arg2185Gln). Findings from this study expand our understanding of genetic influences for FVIII :C and VWF :Ag in both EAs and AAs.

}, keywords = {Adult, African Americans, Aged, European Continental Ancestry Group, Factor VIII, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Methionine Adenosyltransferase, Middle Aged, Polymorphism, Single Nucleotide, Venous Thromboembolism, von Willebrand Factor}, issn = {1096-8652}, doi = {10.1002/ajh.24005}, author = {Tang, Weihong and Cushman, Mary and Green, David and Rich, Stephen S and Lange, Leslie A and Yang, Qiong and Tracy, Russell P and Tofler, Geoffrey H and Basu, Saonli and Wilson, James G and Keating, Brendan J and Weng, Lu-Chen and Taylor, Herman A and Jacobs, David R and Delaney, Joseph A and Palmer, Cameron D and Young, Taylor and Pankow, James S and O{\textquoteright}Donnell, Christopher J and Smith, Nicholas L and Reiner, Alexander P and Folsom, Aaron R} } @article {6615, title = {Genetic loci associated with circulating levels of very long-chain saturated fatty acids.}, journal = {J Lipid Res}, volume = {56}, year = {2015}, month = {2015 Jan}, pages = {176-84}, abstract = {

Very long-chain saturated fatty acids (VLSFAs) are saturated fatty acids with 20 or more carbons. In contrast to the more abundant saturated fatty acids, such as palmitic acid, there is growing evidence that circulating VLSFAs may have beneficial biological properties. Whether genetic factors influence circulating levels of VLSFAs is not known. We investigated the association of common genetic variation with plasma phospholipid/erythrocyte levels of three VLSFAs by performing genome-wide association studies in seven population-based cohorts comprising 10,129 subjects of European ancestry. We observed associations of circulating VLSFA concentrations with common variants in two genes, serine palmitoyl-transferase long-chain base subunit 3 (SPTLC3), a gene involved in the rate-limiting step of de novo sphingolipid synthesis, and ceramide synthase 4 (CERS4). The SPTLC3 variant at rs680379 was associated with higher arachidic acid (20:0 , P = 5.81 {\texttimes} 10(-13)). The CERS4 variant at rs2100944 was associated with higher levels of 20:0 (P = 2.65 {\texttimes} 10(-40)) and in analyses that adjusted for 20:0, with lower levels of behenic acid (P = 4.22 {\texttimes} 10(-26)) and lignoceric acid (P = 3.20 {\texttimes} 10(-21)). These novel associations suggest an inter-relationship of circulating VLSFAs and sphingolipid synthesis.

}, keywords = {Cohort Studies, Fatty Acids, Genetic Loci, Genetic Variation, Genome-Wide Association Study, Humans}, issn = {1539-7262}, doi = {10.1194/jlr.M052456}, author = {Lemaitre, Rozenn N and King, Irena B and Kabagambe, Edmond K and Wu, Jason H Y and McKnight, Barbara and Manichaikul, Ani and Guan, Weihua and Sun, Qi and Chasman, Daniel I and Foy, Millennia and Wang, Lu and Zhu, Jingwen and Siscovick, David S and Tsai, Michael Y and Arnett, Donna K and Psaty, Bruce M and Djouss{\'e}, Luc and Chen, Yii-der I and Tang, Weihong and Weng, Lu-Chen and Wu, Hongyu and Jensen, Majken K and Chu, Audrey Y and Jacobs, David R and Rich, Stephen S and Mozaffarian, Dariush and Steffen, Lyn and Rimm, Eric B and Hu, Frank B and Ridker, Paul M and Fornage, Myriam and Friedlander, Yechiel} } @article {6685, title = {Genetic loci associated with circulating phospholipid trans fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium.}, journal = {Am J Clin Nutr}, volume = {101}, year = {2015}, month = {2015 Feb}, pages = {398-406}, abstract = {

BACKGROUND: Circulating trans fatty acids (TFAs), which cannot be synthesized by humans, are linked to adverse health outcomes. Although TFAs are obtained from diet, little is known about subsequent influences (e.g., relating to incorporation, metabolism, or intercompetition with other fatty acids) that could alter circulating concentrations and possibly modulate or mediate impacts on health.

OBJECTIVE: The objective was to elucidate novel biologic pathways that may influence circulating TFAs by evaluating associations between common genetic variation and TFA biomarkers.

DESIGN: We performed meta-analyses using 7 cohorts of European-ancestry participants (n = 8013) having measured genome-wide variation in single-nucleotide polymorphisms (SNPs) and circulating TFA biomarkers (erythrocyte or plasma phospholipids), including trans-16:1n-7, total trans-18:1, trans/cis-18:2, cis/trans-18:2, and trans/trans-18:2. We further evaluated SNPs with genome-wide significant associations among African Americans (n = 1082), Chinese Americans (n = 669), and Hispanic Americans (n = 657) from 2 of these cohorts.

RESULTS: Among European-ancestry participants, 31 SNPs in or near the fatty acid desaturase (FADS) 1 and 2 cluster were associated with cis/trans-18:2; a top hit was rs174548 (β = 0.0035, P = 4.90 {\texttimes} 10(-15)), an SNP previously associated with circulating n-3 and n-6 polyunsaturated fatty acid concentrations. No significant association was identified for other TFAs. rs174548 in FADS1/2 was also associated with cis/trans-18:2 in Hispanic Americans (β = 0.0053, P = 1.05 {\texttimes} 10(-6)) and Chinese Americans (β = 0.0028, P = 0.002) but not African Americans (β = 0.0009, P = 0.34); however, in African Americans, fine mapping identified a top hit in FADS2 associated with cis/trans-18:2 (rs174579: β = 0.0118, P = 4.05 {\texttimes} 10(-5)). The association between rs174548 and cis/trans-18:2 remained significant after further adjustment for individual circulating n-3 and n-6 fatty acids, except arachidonic acid. After adjustment for arachidonic acid concentrations, the association between rs174548 and cis/trans-18:2 was nearly eliminated in European-ancestry participants (β-coefficient reduced by 86\%), with similar reductions in Hispanic Americans and Chinese Americans.

CONCLUSIONS: Our findings provide novel evidence for genetic regulation of cis/trans-18:2 by the FADS1/2 cluster and suggest that this regulation may be influenced/mediated by concentrations of arachidonic acid, an n-6 polyunsaturated fat.

}, keywords = {African Americans, Arachidonic Acid, Asian Americans, Biomarkers, European Continental Ancestry Group, Fatty Acids, Omega-6, Gene Frequency, Genetic Association Studies, Genetic Loci, Genotyping Techniques, Humans, Phospholipids, Polymorphism, Single Nucleotide, Trans Fatty Acids}, issn = {1938-3207}, doi = {10.3945/ajcn.114.094557}, author = {Mozaffarian, Dariush and Kabagambe, Edmond K and Johnson, Catherine O and Lemaitre, Rozenn N and Manichaikul, Ani and Sun, Qi and Foy, Millennia and Wang, Lu and Wiener, Howard and Irvin, Marguerite R and Rich, Stephen S and Wu, Hongyu and Jensen, Majken K and Chasman, Daniel I and Chu, Audrey Y and Fornage, Myriam and Steffen, Lyn and King, Irena B and McKnight, Barbara and Psaty, Bruce M and Djouss{\'e}, Luc and Chen, Ida Y-D and Wu, Jason H Y and Siscovick, David S and Ridker, Paul M and Tsai, Michael Y and Rimm, Eric B and Hu, Frank B and Arnett, Donna K} } @article {6682, title = {Genome of The Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels.}, journal = {Nat Commun}, volume = {6}, year = {2015}, month = {2015}, pages = {6065}, abstract = {

Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of The Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value <6.61 {\texttimes} 10(-4)), including a rare missense variant in ABCA6 (rs77542162, p.Cys1359Arg, frequency 0.034), which is predicted to be deleterious. The frequency of this ABCA6 variant is 3.65-fold increased in the Dutch and its effect (βLDL-C=0.135, βTC=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR.

}, keywords = {ATP-Binding Cassette Transporters, Cholesterol, Gene Frequency, Genetic Association Studies, Humans, Mutation, Missense, Netherlands}, issn = {2041-1723}, doi = {10.1038/ncomms7065}, author = {van Leeuwen, Elisabeth M and Karssen, Lennart C and Deelen, Joris and Isaacs, Aaron and Medina-G{\'o}mez, Carolina and Mbarek, Hamdi and Kanterakis, Alexandros and Trompet, Stella and Postmus, Iris and Verweij, Niek and van Enckevort, David J and Huffman, Jennifer E and White, Charles C and Feitosa, Mary F and Bartz, Traci M and Manichaikul, Ani and Joshi, Peter K and Peloso, Gina M and Deelen, Patrick and van Dijk, Freerk and Willemsen, Gonneke and de Geus, Eco J and Milaneschi, Yuri and Penninx, Brenda W J H and Francioli, Laurent C and Menelaou, Androniki and Pulit, Sara L and Rivadeneira, Fernando and Hofman, Albert and Oostra, Ben A and Franco, Oscar H and Mateo Leach, Irene and Beekman, Marian and de Craen, Anton J M and Uh, Hae-Won and Trochet, Holly and Hocking, Lynne J and Porteous, David J and Sattar, Naveed and Packard, Chris J and Buckley, Brendan M and Brody, Jennifer A and Bis, Joshua C and Rotter, Jerome I and Mychaleckyj, Josyf C and Campbell, Harry and Duan, Qing and Lange, Leslie A and Wilson, James F and Hayward, Caroline and Polasek, Ozren and Vitart, Veronique and Rudan, Igor and Wright, Alan F and Rich, Stephen S and Psaty, Bruce M and Borecki, Ingrid B and Kearney, Patricia M and Stott, David J and Adrienne Cupples, L and Jukema, J Wouter and van der Harst, Pim and Sijbrands, Eric J and Hottenga, Jouke-Jan and Uitterlinden, Andr{\'e} G and Swertz, Morris A and van Ommen, Gert-Jan B and de Bakker, Paul I W and Eline Slagboom, P and Boomsma, Dorret I and Wijmenga, Cisca and van Duijn, Cornelia M} } @article {6614, title = {Habitual sleep duration is associated with BMI and macronutrient intake and may be modified by CLOCK genetic variants.}, journal = {Am J Clin Nutr}, volume = {101}, year = {2015}, month = {2015 Jan}, pages = {135-43}, abstract = {

BACKGROUND: Short sleep duration has been associated with greater risks of obesity, hypertension, diabetes, and cardiovascular disease. Also, common genetic variants in the human Circadian Locomotor Output Cycles Kaput (CLOCK) show associations with ghrelin and total energy intake.

OBJECTIVES: We examined associations between habitual sleep duration, body mass index (BMI), and macronutrient intake and assessed whether CLOCK variants modify these associations.

DESIGN: We conducted inverse-variance weighted, fixed-effect meta-analyses of results of adjusted associations of sleep duration and BMI and macronutrient intake as percentages of total energy as well as interactions with CLOCK variants from 9 cohort studies including up to 14,906 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium.

RESULTS: We observed a significant association between sleep duration and lower BMI (β {\textpm} SE = 0.16 {\textpm} 0.04, P < 0.0001) in the overall sample; however, associations between sleep duration and relative macronutrient intake were evident in age- and sex-stratified analyses only. We observed a significant association between sleep duration and lower saturated fatty acid intake in younger (aged 20-64 y) adults (men: 0.11 {\textpm} 0.06\%, P = 0.03; women: 0.10 {\textpm} 0.05\%, P = 0.04) and with lower carbohydrate (-0.31 {\textpm} 0.12\%, P < 0.01), higher total fat (0.18 {\textpm} 0.09\%, P = 0.05), and higher PUFA (0.05 {\textpm} 0.02\%, P = 0.02) intakes in older (aged 65-80 y) women. In addition, the following 2 nominally significant interactions were observed: between sleep duration and rs12649507 on PUFA intake and between sleep duration and rs6858749 on protein intake.

CONCLUSIONS: Our results indicate that longer habitual sleep duration is associated with lower BMI and age- and sex-specific favorable dietary behaviors. Differences in the relative intake of specific macronutrients associated with short sleep duration could, at least in part, explain previously reported associations between short sleep duration and chronic metabolic abnormalities. In addition, the influence of obesity-associated CLOCK variants on the association between sleep duration and macronutrient intake suggests that longer habitual sleep duration could ameliorate the genetic predisposition to obesity via a favorable dietary profile.

}, keywords = {Adult, Body Mass Index, CLOCK Proteins, Cohort Studies, Cross-Sectional Studies, Diet, Dietary Proteins, Energy Intake, European Continental Ancestry Group, Fatty Acids, Unsaturated, Female, Gene-Environment Interaction, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Obesity, Polymorphism, Single Nucleotide, Sleep, Young Adult}, issn = {1938-3207}, doi = {10.3945/ajcn.114.095026}, author = {Dashti, Hassan S and Follis, Jack L and Smith, Caren E and Tanaka, Toshiko and Cade, Brian E and Gottlieb, Daniel J and Hruby, Adela and Jacques, Paul F and Lamon-Fava, Stefania and Richardson, Kris and Saxena, Richa and Scheer, Frank A J L and Kovanen, Leena and Bartz, Traci M and Per{\"a}l{\"a}, Mia-Maria and Jonsson, Anna and Frazier-Wood, Alexis C and Kalafati, Ioanna-Panagiota and Mikkil{\"a}, Vera and Partonen, Timo and Lemaitre, Rozenn N and Lahti, Jari and Hernandez, Dena G and Toft, Ulla and Johnson, W Craig and Kanoni, Stavroula and Raitakari, Olli T and Perola, Markus and Psaty, Bruce M and Ferrucci, Luigi and Grarup, Niels and Highland, Heather M and Rallidis, Loukianos and K{\"a}h{\"o}nen, Mika and Havulinna, Aki S and Siscovick, David S and R{\"a}ikk{\"o}nen, Katri and J{\o}rgensen, Torben and Rotter, Jerome I and Deloukas, Panos and Viikari, Jorma S A and Mozaffarian, Dariush and Linneberg, Allan and Sepp{\"a}l{\"a}, Ilkka and Hansen, Torben and Salomaa, Veikko and Gharib, Sina A and Eriksson, Johan G and Bandinelli, Stefania and Pedersen, Oluf and Rich, Stephen S and Dedoussis, George and Lehtim{\"a}ki, Terho and Ordovas, Jose M} } @article {6686, title = {Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.}, journal = {Nat Commun}, volume = {6}, year = {2015}, month = {2015}, pages = {5897}, abstract = {

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4\%) with lower FG (β=-0.09{\textpm}0.01 mmol l(-1), P=3.4 {\texttimes} 10(-12)), T2D risk (OR[95\%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07{\textpm}0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16{\textpm}0.05 mmol l(-1), P=4.3 {\texttimes} 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 {\texttimes} 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20\%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02{\textpm}0.004 mmol l(-1), P=1.3 {\texttimes} 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

}, keywords = {African Continental Ancestry Group, Blood Glucose, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Exome, Fasting, Genetic Association Studies, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Glucagon-Like Peptide-1 Receptor, Glucose-6-Phosphatase, Humans, Insulin, Mutation Rate, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide}, issn = {2041-1723}, doi = {10.1038/ncomms6897}, author = {Wessel, Jennifer and Chu, Audrey Y and Willems, Sara M and Wang, Shuai and Yaghootkar, Hanieh and Brody, Jennifer A and Dauriz, Marco and Hivert, Marie-France and Raghavan, Sridharan and Lipovich, Leonard and Hidalgo, Bertha and Fox, Keolu and Huffman, Jennifer E and An, Ping and Lu, Yingchang and Rasmussen-Torvik, Laura J and Grarup, Niels and Ehm, Margaret G and Li, Li and Baldridge, Abigail S and Stan{\v c}{\'a}kov{\'a}, Alena and Abrol, Ravinder and Besse, C{\'e}line and Boland, Anne and Bork-Jensen, Jette and Fornage, Myriam and Freitag, Daniel F and Garcia, Melissa E and Guo, Xiuqing and Hara, Kazuo and Isaacs, Aaron and Jakobsdottir, Johanna and Lange, Leslie A and Layton, Jill C and Li, Man and Hua Zhao, Jing and Meidtner, Karina and Morrison, Alanna C and Nalls, Mike A and Peters, Marjolein J and Sabater-Lleal, Maria and Schurmann, Claudia and Silveira, Angela and Smith, Albert V and Southam, Lorraine and Stoiber, Marcus H and Strawbridge, Rona J and Taylor, Kent D and Varga, Tibor V and Allin, Kristine H and Amin, Najaf and Aponte, Jennifer L and Aung, Tin and Barbieri, Caterina and Bihlmeyer, Nathan A and Boehnke, Michael and Bombieri, Cristina and Bowden, Donald W and Burns, Sean M and Chen, Yuning and Chen, Yii-DerI and Cheng, Ching-Yu and Correa, Adolfo and Czajkowski, Jacek and Dehghan, Abbas and Ehret, Georg B and Eiriksdottir, Gudny and Escher, Stefan A and Farmaki, Aliki-Eleni and Fr{\r a}nberg, Mattias and Gambaro, Giovanni and Giulianini, Franco and Goddard, William A and Goel, Anuj and Gottesman, Omri and Grove, Megan L and Gustafsson, Stefan and Hai, Yang and Hallmans, G{\"o}ran and Heo, Jiyoung and Hoffmann, Per and Ikram, Mohammad K and Jensen, Richard A and J{\o}rgensen, Marit E and J{\o}rgensen, Torben and Karaleftheri, Maria and Khor, Chiea C and Kirkpatrick, Andrea and Kraja, Aldi T and Kuusisto, Johanna and Lange, Ethan M and Lee, I T and Lee, Wen-Jane and Leong, Aaron and Liao, Jiemin and Liu, Chunyu and Liu, Yongmei and Lindgren, Cecilia M and Linneberg, Allan and Malerba, Giovanni and Mamakou, Vasiliki and Marouli, Eirini and Maruthur, Nisa M and Matchan, Angela and McKean-Cowdin, Roberta and McLeod, Olga and Metcalf, Ginger A and Mohlke, Karen L and Muzny, Donna M and Ntalla, Ioanna and Palmer, Nicholette D and Pasko, Dorota and Peter, Andreas and Rayner, Nigel W and Renstrom, Frida and Rice, Ken and Sala, Cinzia F and Sennblad, Bengt and Serafetinidis, Ioannis and Smith, Jennifer A and Soranzo, Nicole and Speliotes, Elizabeth K and Stahl, Eli A and Stirrups, Kathleen and Tentolouris, Nikos and Thanopoulou, Anastasia and Torres, Mina and Traglia, Michela and Tsafantakis, Emmanouil and Javad, Sundas and Yanek, Lisa R and Zengini, Eleni and Becker, Diane M and Bis, Joshua C and Brown, James B and Cupples, L Adrienne and Hansen, Torben and Ingelsson, Erik and Karter, Andrew J and Lorenzo, Carlos and Mathias, Rasika A and Norris, Jill M and Peloso, Gina M and Sheu, Wayne H-H and Toniolo, Daniela and Vaidya, Dhananjay and Varma, Rohit and Wagenknecht, Lynne E and Boeing, Heiner and Bottinger, Erwin P and Dedoussis, George and Deloukas, Panos and Ferrannini, Ele and Franco, Oscar H and Franks, Paul W and Gibbs, Richard A and Gudnason, Vilmundur and Hamsten, Anders and Harris, Tamara B and Hattersley, Andrew T and Hayward, Caroline and Hofman, Albert and Jansson, Jan-H{\r a}kan and Langenberg, Claudia and Launer, Lenore J and Levy, Daniel and Oostra, Ben A and O{\textquoteright}Donnell, Christopher J and O{\textquoteright}Rahilly, Stephen and Padmanabhan, Sandosh and Pankow, James S and Polasek, Ozren and Province, Michael A and Rich, Stephen S and Ridker, Paul M and Rudan, Igor and Schulze, Matthias B and Smith, Blair H and Uitterlinden, Andr{\'e} G and Walker, Mark and Watkins, Hugh and Wong, Tien Y and Zeggini, Eleftheria and Laakso, Markku and Borecki, Ingrid B and Chasman, Daniel I and Pedersen, Oluf and Psaty, Bruce M and Tai, E Shyong and van Duijn, Cornelia M and Wareham, Nicholas J and Waterworth, Dawn M and Boerwinkle, Eric and Kao, W H Linda and Florez, Jose C and Loos, Ruth J F and Wilson, James G and Frayling, Timothy M and Siscovick, David S and Dupuis, Jos{\'e}e and Rotter, Jerome I and Meigs, James B and Scott, Robert A and Goodarzi, Mark O} } @article {6568, title = {Mendelian randomization of blood lipids for coronary heart disease.}, journal = {Eur Heart J}, volume = {36}, year = {2015}, month = {2015 Mar 01}, pages = {539-50}, abstract = {

AIMS: To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization.

METHODS AND RESULTS: We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 {\texttimes} 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P <= 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95\% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95\% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95\% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95\% CI: 1.24, 2.11 and 1.61; 95\% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95\% CI: 0.59, 1.75).

CONCLUSION: The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.

}, keywords = {Case-Control Studies, Cholesterol, HDL, Coronary Artery Disease, Female, Gene Frequency, Genotype, Genotyping Techniques, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Polymorphism, Single Nucleotide, Risk Assessment, Triglycerides}, issn = {1522-9645}, doi = {10.1093/eurheartj/eht571}, author = {Holmes, Michael V and Asselbergs, Folkert W and Palmer, Tom M and Drenos, Fotios and Lanktree, Matthew B and Nelson, Christopher P and Dale, Caroline E and Padmanabhan, Sandosh and Finan, Chris and Swerdlow, Daniel I and Tragante, Vinicius and van Iperen, Erik P A and Sivapalaratnam, Suthesh and Shah, Sonia and Elbers, Clara C and Shah, Tina and Engmann, Jorgen and Giambartolomei, Claudia and White, Jon and Zabaneh, Delilah and Sofat, Reecha and McLachlan, Stela and Doevendans, Pieter A and Balmforth, Anthony J and Hall, Alistair S and North, Kari E and Almoguera, Berta and Hoogeveen, Ron C and Cushman, Mary and Fornage, Myriam and Patel, Sanjay R and Redline, Susan and Siscovick, David S and Tsai, Michael Y and Karczewski, Konrad J and Hofker, Marten H and Verschuren, W Monique and Bots, Michiel L and van der Schouw, Yvonne T and Melander, Olle and Dominiczak, Anna F and Morris, Richard and Ben-Shlomo, Yoav and Price, Jackie and Kumari, Meena and Baumert, Jens and Peters, Annette and Thorand, Barbara and Koenig, Wolfgang and Gaunt, Tom R and Humphries, Steve E and Clarke, Robert and Watkins, Hugh and Farrall, Martin and Wilson, James G and Rich, Stephen S and de Bakker, Paul I W and Lange, Leslie A and Davey Smith, George and Reiner, Alex P and Talmud, Philippa J and Kivimaki, Mika and Lawlor, Debbie A and Dudbridge, Frank and Samani, Nilesh J and Keating, Brendan J and Hingorani, Aroon D and Casas, Juan P} } @article {6812, title = {Meta-Analysis of Genome-Wide Association Studies Identifies Genetic Risk Factors for Stroke in African Americans.}, journal = {Stroke}, volume = {46}, year = {2015}, month = {2015 Aug}, pages = {2063-8}, abstract = {

BACKGROUND AND PURPOSE: The majority of genome-wide association studies (GWAS) of stroke have focused on European-ancestry populations; however, none has been conducted in African Americans, despite the disproportionately high burden of stroke in this population. The Consortium of Minority Population Genome-Wide Association Studies of Stroke (COMPASS) was established to identify stroke susceptibility loci in minority populations.

METHODS: Using METAL, we conducted meta-analyses of GWAS in 14 746 African Americans (1365 ischemic and 1592 total stroke cases) from COMPASS, and tested genetic variants with P<10(-6) for validation in METASTROKE, a consortium of ischemic stroke genetic studies in European-ancestry populations. We also evaluated stroke loci previously identified in European-ancestry populations.

RESULTS: The 15q21.3 locus linked with lipid levels and hypertension was associated with total stroke (rs4471613; P=3.9{\texttimes}10(-8)) in African Americans. Nominal associations (P<10(-6)) for total or ischemic stroke were observed for 18 variants in or near genes implicated in cell cycle/mRNA presplicing (PTPRG, CDC5L), platelet function (HPS4), blood-brain barrier permeability (CLDN17), immune response (ELTD1, WDFY4, and IL1F10-IL1RN), and histone modification (HDAC9). Two of these loci achieved nominal significance in METASTROKE: 5q35.2 (P=0.03), and 1p31.1 (P=0.018). Four of 7 previously reported ischemic stroke loci (PITX2, HDAC9, CDKN2A/CDKN2B, and ZFHX3) were nominally associated (P<0.05) with stroke in COMPASS.

CONCLUSIONS: We identified a novel genetic variant associated with total stroke in African Americans and found that ischemic stroke loci identified in European-ancestry populations may also be relevant for African Americans. Our findings support investigation of diverse populations to identify and characterize genetic risk factors, and the importance of shared genetic risk across populations.

}, keywords = {African Americans, Case-Control Studies, Cohort Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Risk Factors, Stroke}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.115.009044}, author = {Carty, Cara L and Keene, Keith L and Cheng, Yu-Ching and Meschia, James F and Chen, Wei-Min and Nalls, Mike and Bis, Joshua C and Kittner, Steven J and Rich, Stephen S and Tajuddin, Salman and Zonderman, Alan B and Evans, Michele K and Langefeld, Carl D and Gottesman, Rebecca and Mosley, Thomas H and Shahar, Eyal and Woo, Daniel and Yaffe, Kristine and Liu, Yongmei and Sale, Mich{\`e}le M and Dichgans, Martin and Malik, Rainer and Longstreth, W T and Mitchell, Braxton D and Psaty, Bruce M and Kooperberg, Charles and Reiner, Alexander and Worrall, Bradford B and Fornage, Myriam} } @article {6849, title = {Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project.}, journal = {JAMA Neurol}, volume = {72}, year = {2015}, month = {2015 Jul}, pages = {781-8}, abstract = {

IMPORTANCE: Stroke is the second leading cause of death and the third leading cause of years of life lost. Genetic factors contribute to stroke prevalence, and candidate gene and genome-wide association studies (GWAS) have identified variants associated with ischemic stroke risk. These variants often have small effects without obvious biological significance. Exome sequencing may discover predicted protein-altering variants with a potentially large effect on ischemic stroke risk.

OBJECTIVE: To investigate the contribution of rare and common genetic variants to ischemic stroke risk by targeting the protein-coding regions of the human genome.

DESIGN, SETTING, AND PARTICIPANTS: The National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) analyzed approximately 6000 participants from numerous cohorts of European and African ancestry. For discovery, 365 cases of ischemic stroke (small-vessel and large-vessel subtypes) and 809 European ancestry controls were sequenced; for replication, 47 affected sibpairs concordant for stroke subtype and an African American case-control series were sequenced, with 1672 cases and 4509 European ancestry controls genotyped. The ESP{\textquoteright}s exome sequencing and genotyping started on January 1, 2010, and continued through June 30, 2012. Analyses were conducted on the full data set between July 12, 2012, and July 13, 2013.

MAIN OUTCOMES AND MEASURES: Discovery of new variants or genes contributing to ischemic stroke risk and subtype (primary analysis) and determination of support for protein-coding variants contributing to risk in previously published candidate genes (secondary analysis).

RESULTS: We identified 2 novel genes associated with an increased risk of ischemic stroke: a protein-coding variant in PDE4DIP (rs1778155; odds ratio, 2.15; P = 2.63 {\texttimes} 10(-8)) with an intracellular signal transduction mechanism and in ACOT4 (rs35724886; odds ratio, 2.04; P = 1.24 {\texttimes} 10(-7)) with a fatty acid metabolism; confirmation of PDE4DIP was observed in affected sibpair families with large-vessel stroke subtype and in African Americans. Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke).

CONCLUSIONS AND RELEVANCE: Exome sequencing discovered 2 novel genes and mechanisms, PDE4DIP and ACOT4, associated with increased risk for ischemic stroke. In addition, ZFHX3 and ABCA1 were discovered to have protein-coding variants associated with ischemic stroke. These results suggest that genetic variation in novel pathways contributes to ischemic stroke risk and serves as a target for prediction, prevention, and therapy.

}, keywords = {Aged, Brain Ischemia, Exome, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Male, Middle Aged, Muscle Proteins, National Heart, Lung, and Blood Institute (U.S.), Nuclear Proteins, Open Reading Frames, Palmitoyl-CoA Hydrolase, Stroke, United States}, issn = {2168-6157}, doi = {10.1001/jamaneurol.2015.0582}, author = {Auer, Paul L and Nalls, Mike and Meschia, James F and Worrall, Bradford B and Longstreth, W T and Seshadri, Sudha and Kooperberg, Charles and Burger, Kathleen M and Carlson, Christopher S and Carty, Cara L and Chen, Wei-Min and Cupples, L Adrienne and DeStefano, Anita L and Fornage, Myriam and Hardy, John and Hsu, Li and Jackson, Rebecca D and Jarvik, Gail P and Kim, Daniel S and Lakshminarayan, Kamakshi and Lange, Leslie A and Manichaikul, Ani and Quinlan, Aaron R and Singleton, Andrew B and Thornton, Timothy A and Nickerson, Deborah A and Peters, Ulrike and Rich, Stephen S} } @article {6951, title = {Interaction of methylation-related genetic variants with circulating fatty acids on plasma lipids: a meta-analysis of 7 studies and methylation analysis of 3 studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.}, journal = {Am J Clin Nutr}, volume = {103}, year = {2016}, month = {2016 Feb}, pages = {567-78}, abstract = {

BACKGROUND: DNA methylation is influenced by diet and single nucleotide polymorphisms (SNPs), and methylation modulates gene expression.

OBJECTIVE: We aimed to explore whether the gene-by-diet interactions on blood lipids act through DNA methylation.

DESIGN: We selected 7 SNPs on the basis of predicted relations in fatty acids, methylation, and lipids. We conducted a meta-analysis and a methylation and mediation analysis with the use of data from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium and the ENCODE (Encyclopedia of DNA Elements) consortium.

RESULTS: On the basis of the meta-analysis of 7 cohorts in the CHARGE consortium, higher plasma HDL cholesterol was associated with fewer C alleles at ATP-binding cassette subfamily A member 1 (ABCA1) rs2246293 (β = -0.6 mg/dL, P = 0.015) and higher circulating eicosapentaenoic acid (EPA) (β = 3.87 mg/dL, P = 5.62 {\texttimes} 10(21)). The difference in HDL cholesterol associated with higher circulating EPA was dependent on genotypes at rs2246293, and it was greater for each additional C allele (β = 1.69 mg/dL, P = 0.006). In the GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study, higher ABCA1 promoter cg14019050 methylation was associated with more C alleles at rs2246293 (β = 8.84\%, P = 3.51 {\texttimes} 10(18)) and lower circulating EPA (β = -1.46\%, P = 0.009), and the mean difference in methylation of cg14019050 that was associated with higher EPA was smaller with each additional C allele of rs2246293 (β = -2.83\%, P = 0.007). Higher ABCA1 cg14019050 methylation was correlated with lower ABCA1 expression (r = -0.61, P = 0.009) in the ENCODE consortium and lower plasma HDL cholesterol in the GOLDN study (r = -0.12, P = 0.0002). An additional mediation analysis was meta-analyzed across the GOLDN study, Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. Compared with the model without the adjustment of cg14019050 methylation, the model with such adjustment provided smaller estimates of the mean plasma HDL cholesterol concentration in association with both the rs2246293 C allele and EPA and a smaller difference by rs2246293 genotypes in the EPA-associated HDL cholesterol. However, the differences between 2 nested models were NS (P > 0.05).

CONCLUSION: We obtained little evidence that the gene-by-fatty acid interactions on blood lipids act through DNA methylation.

}, keywords = {Apolipoproteins E, ATP Binding Cassette Transporter 1, Cholesterol, HDL, Cohort Studies, Diet, DNA Methylation, Eicosapentaenoic Acid, Epigenesis, Genetic, Fatty Acids, Gene Expression Regulation, Humans, Lipids, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Triglycerides}, issn = {1938-3207}, doi = {10.3945/ajcn.115.112987}, author = {Ma, Yiyi and Follis, Jack L and Smith, Caren E and Tanaka, Toshiko and Manichaikul, Ani W and Chu, Audrey Y and Samieri, Cecilia and Zhou, Xia and Guan, Weihua and Wang, Lu and Biggs, Mary L and Chen, Yii-der I and Hernandez, Dena G and Borecki, Ingrid and Chasman, Daniel I and Rich, Stephen S and Ferrucci, Luigi and Irvin, Marguerite Ryan and Aslibekyan, Stella and Zhi, Degui and Tiwari, Hemant K and Claas, Steven A and Sha, Jin and Kabagambe, Edmond K and Lai, Chao-Qiang and Parnell, Laurence D and Lee, Yu-Chi and Amouyel, Philippe and Lambert, Jean-Charles and Psaty, Bruce M and King, Irena B and Mozaffarian, Dariush and McKnight, Barbara and Bandinelli, Stefania and Tsai, Michael Y and Ridker, Paul M and Ding, Jingzhong and Mstat, Kurt Lohmant and Liu, Yongmei and Sotoodehnia, Nona and Barberger-Gateau, Pascale and Steffen, Lyn M and Siscovick, David S and Absher, Devin and Arnett, Donna K and Ordovas, Jose M and Lemaitre, Rozenn N} } @article {7146, title = {Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Jul 7}, pages = {22-39}, abstract = {

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of~\~{}157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3{\textquoteright} UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.05.003}, author = {Tajuddin, Salman M and Schick, Ursula M and Eicher, John D and Chami, Nathalie and Giri, Ayush and Brody, Jennifer A and Hill, W David and Kacprowski, Tim and Li, Jin and Lyytik{\"a}inen, Leo-Pekka and Manichaikul, Ani and Mihailov, Evelin and O{\textquoteright}Donoghue, Michelle L and Pankratz, Nathan and Pazoki, Raha and Polfus, Linda M and Smith, Albert Vernon and Schurmann, Claudia and Vacchi-Suzzi, Caterina and Waterworth, Dawn M and Evangelou, Evangelos and Yanek, Lisa R and Burt, Amber and Chen, Ming-Huei and van Rooij, Frank J A and Floyd, James S and Greinacher, Andreas and Harris, Tamara B and Highland, Heather M and Lange, Leslie A and Liu, Yongmei and M{\"a}gi, Reedik and Nalls, Mike A and Mathias, Rasika A and Nickerson, Deborah A and Nikus, Kjell and Starr, John M and Tardif, Jean-Claude and Tzoulaki, Ioanna and Velez Edwards, Digna R and Wallentin, Lars and Bartz, Traci M and Becker, Lewis C and Denny, Joshua C and Raffield, Laura M and Rioux, John D and Friedrich, Nele and Fornage, Myriam and Gao, He and Hirschhorn, Joel N and Liewald, David C M and Rich, Stephen S and Uitterlinden, Andre and Bastarache, Lisa and Becker, Diane M and Boerwinkle, Eric and de Denus, Simon and Bottinger, Erwin P and Hayward, Caroline and Hofman, Albert and Homuth, Georg and Lange, Ethan and Launer, Lenore J and Lehtim{\"a}ki, Terho and Lu, Yingchang and Metspalu, Andres and O{\textquoteright}Donnell, Chris J and Quarells, Rakale C and Richard, Melissa and Torstenson, Eric S and Taylor, Kent D and Vergnaud, Anne-Claire and Zonderman, Alan B and Crosslin, David R and Deary, Ian J and D{\"o}rr, Marcus and Elliott, Paul and Evans, Michele K and Gudnason, Vilmundur and K{\"a}h{\"o}nen, Mika and Psaty, Bruce M and Rotter, Jerome I and Slater, Andrew J and Dehghan, Abbas and White, Harvey D and Ganesh, Santhi K and Loos, Ruth J F and Esko, T{\~o}nu and Faraday, Nauder and Wilson, James G and Cushman, Mary and Johnson, Andrew D and Edwards, Todd L and Zakai, Neil A and Lettre, Guillaume and Reiner, Alex P and Auer, Paul L} } @article {7011, title = {Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels.}, journal = {J Med Genet}, volume = {53}, year = {2016}, month = {2016 Jul}, pages = {441-9}, abstract = {

BACKGROUND: So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.

METHODS: We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from \~{}60 000 individuals in the discovery stage and \~{}90 000 samples in the replication stage.

RESULTS: Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.

CONCLUSIONS: This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.

}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2015-103439}, author = {van Leeuwen, Elisabeth M and Sabo, Aniko and Bis, Joshua C and Huffman, Jennifer E and Manichaikul, Ani and Smith, Albert V and Feitosa, Mary F and Demissie, Serkalem and Joshi, Peter K and Duan, Qing and Marten, Jonathan and van Klinken, Jan B and Surakka, Ida and Nolte, Ilja M and Zhang, Weihua and Mbarek, Hamdi and Li-Gao, Ruifang and Trompet, Stella and Verweij, Niek and Evangelou, Evangelos and Lyytik{\"a}inen, Leo-Pekka and Tayo, Bamidele O and Deelen, Joris and van der Most, Peter J and van der Laan, Sander W and Arking, Dan E and Morrison, Alanna and Dehghan, Abbas and Franco, Oscar H and Hofman, Albert and Rivadeneira, Fernando and Sijbrands, Eric J and Uitterlinden, Andr{\'e} G and Mychaleckyj, Josyf C and Campbell, Archie and Hocking, Lynne J and Padmanabhan, Sandosh and Brody, Jennifer A and Rice, Kenneth M and White, Charles C and Harris, Tamara and Isaacs, Aaron and Campbell, Harry and Lange, Leslie A and Rudan, Igor and Kolcic, Ivana and Navarro, Pau and Zemunik, Tatijana and Salomaa, Veikko and Kooner, Angad S and Kooner, Jaspal S and Lehne, Benjamin and Scott, William R and Tan, Sian-Tsung and de Geus, Eco J and Milaneschi, Yuri and Penninx, Brenda W J H and Willemsen, Gonneke and de Mutsert, Ren{\'e}e and Ford, Ian and Gansevoort, Ron T and Segura-Lepe, Marcelo P and Raitakari, Olli T and Viikari, Jorma S and Nikus, Kjell and Forrester, Terrence and McKenzie, Colin A and de Craen, Anton J M and de Ruijter, Hester M and Pasterkamp, Gerard and Snieder, Harold and Oldehinkel, Albertine J and Slagboom, P Eline and Cooper, Richard S and K{\"a}h{\"o}nen, Mika and Lehtim{\"a}ki, Terho and Elliott, Paul and van der Harst, Pim and Jukema, J Wouter and Mook-Kanamori, Dennis O and Boomsma, Dorret I and Chambers, John C and Swertz, Morris and Ripatti, Samuli and Willems van Dijk, Ko and Vitart, Veronique and Polasek, Ozren and Hayward, Caroline and Wilson, James G and Wilson, James F and Gudnason, Vilmundur and Rich, Stephen S and Psaty, Bruce M and Borecki, Ingrid B and Boerwinkle, Eric and Rotter, Jerome I and Cupples, L Adrienne and van Duijn, Cornelia M} } @article {7358, title = {Meta-analysis of genome-wide association studies of HDL cholesterol response to statins.}, journal = {J Med Genet}, volume = {53}, year = {2016}, month = {2016 Dec}, pages = {835-845}, abstract = {

BACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.

METHODS AND RESULTS: We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1{\texttimes}10(-4) from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5{\texttimes}10(-8)) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment.

CONCLUSIONS: Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.

}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2016-103966}, author = {Postmus, Iris and Warren, Helen R and Trompet, Stella and Arsenault, Benoit J and Avery, Christy L and Bis, Joshua C and Chasman, Daniel I and de Keyser, Catherine E and Deshmukh, Harshal A and Evans, Daniel S and Feng, QiPing and Li, Xiaohui and Smit, Roelof A J and Smith, Albert V and Sun, Fangui and Taylor, Kent D and Arnold, Alice M and Barnes, Michael R and Barratt, Bryan J and Betteridge, John and Boekholdt, S Matthijs and Boerwinkle, Eric and Buckley, Brendan M and Chen, Y-D Ida and de Craen, Anton J M and Cummings, Steven R and Denny, Joshua C and Dub{\'e}, Marie Pierre and Durrington, Paul N and Eiriksdottir, Gudny and Ford, Ian and Guo, Xiuqing and Harris, Tamara B and Heckbert, Susan R and Hofman, Albert and Hovingh, G Kees and Kastelein, John J P and Launer, Leonore J and Liu, Ching-Ti and Liu, Yongmei and Lumley, Thomas and McKeigue, Paul M and Munroe, Patricia B and Neil, Andrew and Nickerson, Deborah A and Nyberg, Fredrik and O{\textquoteright}Brien, Eoin and O{\textquoteright}Donnell, Christopher J and Post, Wendy and Poulter, Neil and Vasan, Ramachandran S and Rice, Kenneth and Rich, Stephen S and Rivadeneira, Fernando and Sattar, Naveed and Sever, Peter and Shaw-Hawkins, Sue and Shields, Denis C and Slagboom, P Eline and Smith, Nicholas L and Smith, Joshua D and Sotoodehnia, Nona and Stanton, Alice and Stott, David J and Stricker, Bruno H and St{\"u}rmer, Til and Uitterlinden, Andr{\'e} G and Wei, Wei-Qi and Westendorp, Rudi G J and Whitsel, Eric A and Wiggins, Kerri L and Wilke, Russell A and Ballantyne, Christie M and Colhoun, Helen M and Cupples, L Adrienne and Franco, Oscar H and Gudnason, Vilmundur and Hitman, Graham and Palmer, Colin N A and Psaty, Bruce M and Ridker, Paul M and Stafford, Jeanette M and Stein, Charles M and Tardif, Jean-Claude and Caulfield, Mark J and Jukema, J Wouter and Rotter, Jerome I and Krauss, Ronald M} } @article {7139, title = {Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Jul 7}, pages = {40-55}, abstract = {

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets{\textquoteright} important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.05.005}, author = {Eicher, John D and Chami, Nathalie and Kacprowski, Tim and Nomura, Akihiro and Chen, Ming-Huei and Yanek, Lisa R and Tajuddin, Salman M and Schick, Ursula M and Slater, Andrew J and Pankratz, Nathan and Polfus, Linda and Schurmann, Claudia and Giri, Ayush and Brody, Jennifer A and Lange, Leslie A and Manichaikul, Ani and Hill, W David and Pazoki, Raha and Elliot, Paul and Evangelou, Evangelos and Tzoulaki, Ioanna and Gao, He and Vergnaud, Anne-Claire and Mathias, Rasika A and Becker, Diane M and Becker, Lewis C and Burt, Amber and Crosslin, David R and Lyytik{\"a}inen, Leo-Pekka and Nikus, Kjell and Hernesniemi, Jussi and K{\"a}h{\"o}nen, Mika and Raitoharju, Emma and Mononen, Nina and Raitakari, Olli T and Lehtim{\"a}ki, Terho and Cushman, Mary and Zakai, Neil A and Nickerson, Deborah A and Raffield, Laura M and Quarells, Rakale and Willer, Cristen J and Peloso, Gina M and Abecasis, Goncalo R and Liu, Dajiang J and Deloukas, Panos and Samani, Nilesh J and Schunkert, Heribert and Erdmann, Jeanette and Fornage, Myriam and Richard, Melissa and Tardif, Jean-Claude and Rioux, John D and Dub{\'e}, Marie-Pierre and de Denus, Simon and Lu, Yingchang and Bottinger, Erwin P and Loos, Ruth J F and Smith, Albert Vernon and Harris, Tamara B and Launer, Lenore J and Gudnason, Vilmundur and Velez Edwards, Digna R and Torstenson, Eric S and Liu, Yongmei and Tracy, Russell P and Rotter, Jerome I and Rich, Stephen S and Highland, Heather M and Boerwinkle, Eric and Li, Jin and Lange, Ethan and Wilson, James G and Mihailov, Evelin and M{\"a}gi, Reedik and Hirschhorn, Joel and Metspalu, Andres and Esko, T{\~o}nu and Vacchi-Suzzi, Caterina and Nalls, Mike A and Zonderman, Alan B and Evans, Michele K and Engstr{\"o}m, Gunnar and Orho-Melander, Marju and Melander, Olle and O{\textquoteright}Donoghue, Michelle L and Waterworth, Dawn M and Wallentin, Lars and White, Harvey D and Floyd, James S and Bartz, Traci M and Rice, Kenneth M and Psaty, Bruce M and Starr, J M and Liewald, David C M and Hayward, Caroline and Deary, Ian J and Greinacher, Andreas and V{\"o}lker, Uwe and Thiele, Thomas and V{\"o}lzke, Henry and van Rooij, Frank J A and Uitterlinden, Andr{\'e} G and Franco, Oscar H and Dehghan, Abbas and Edwards, Todd L and Ganesh, Santhi K and Kathiresan, Sekar and Faraday, Nauder and Auer, Paul L and Reiner, Alex P and Lettre, Guillaume and Johnson, Andrew D} } @article {7141, title = {Trans-ethnic Meta-analysis and Functional Annotation Illuminates the~Genetic Architecture of Fasting Glucose and Insulin.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Jul 7}, pages = {56-75}, abstract = {

Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.05.006}, author = {Liu, Ching-Ti and Raghavan, Sridharan and Maruthur, Nisa and Kabagambe, Edmond Kato and Hong, Jaeyoung and Ng, Maggie C Y and Hivert, Marie-France and Lu, Yingchang and An, Ping and Bentley, Amy R and Drolet, Anne M and Gaulton, Kyle J and Guo, Xiuqing and Armstrong, Loren L and Irvin, Marguerite R and Li, Man and Lipovich, Leonard and Rybin, Denis V and Taylor, Kent D and Agyemang, Charles and Palmer, Nicholette D and Cade, Brian E and Chen, Wei-Min and Dauriz, Marco and Delaney, Joseph A C and Edwards, Todd L and Evans, Daniel S and Evans, Michele K and Lange, Leslie A and Leong, Aaron and Liu, Jingmin and Liu, Yongmei and Nayak, Uma and Patel, Sanjay R and Porneala, Bianca C and Rasmussen-Torvik, Laura J and Snijder, Marieke B and Stallings, Sarah C and Tanaka, Toshiko and Yanek, Lisa R and Zhao, Wei and Becker, Diane M and Bielak, Lawrence F and Biggs, Mary L and Bottinger, Erwin P and Bowden, Donald W and Chen, Guanjie and Correa, Adolfo and Couper, David J and Crawford, Dana C and Cushman, Mary and Eicher, John D and Fornage, Myriam and Franceschini, Nora and Fu, Yi-Ping and Goodarzi, Mark O and Gottesman, Omri and Hara, Kazuo and Harris, Tamara B and Jensen, Richard A and Johnson, Andrew D and Jhun, Min A and Karter, Andrew J and Keller, Margaux F and Kho, Abel N and Kizer, Jorge R and Krauss, Ronald M and Langefeld, Carl D and Li, Xiaohui and Liang, Jingling and Liu, Simin and Lowe, William L and Mosley, Thomas H and North, Kari E and Pacheco, Jennifer A and Peyser, Patricia A and Patrick, Alan L and Rice, Kenneth M and Selvin, Elizabeth and Sims, Mario and Smith, Jennifer A and Tajuddin, Salman M and Vaidya, Dhananjay and Wren, Mary P and Yao, Jie and Zhu, Xiaofeng and Ziegler, Julie T and Zmuda, Joseph M and Zonderman, Alan B and Zwinderman, Aeilko H and Adeyemo, Adebowale and Boerwinkle, Eric and Ferrucci, Luigi and Hayes, M Geoffrey and Kardia, Sharon L R and Miljkovic, Iva and Pankow, James S and Rotimi, Charles N and Sale, Mich{\`e}le M and Wagenknecht, Lynne E and Arnett, Donna K and Chen, Yii-Der Ida and Nalls, Michael A and Province, Michael A and Kao, W H Linda and Siscovick, David S and Psaty, Bruce M and Wilson, James G and Loos, Ruth J F and Dupuis, Jos{\'e}e and Rich, Stephen S and Florez, Jose C and Rotter, Jerome I and Morris, Andrew P and Meigs, James B} } @article {7263, title = {Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Sep 01}, pages = {785}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.08.002}, author = {Polfus, Linda M and Khajuria, Rajiv K and Schick, Ursula M and Pankratz, Nathan and Pazoki, Raha and Brody, Jennifer A and Chen, Ming-Huei and Auer, Paul L and Floyd, James S and Huang, Jie and Lange, Leslie and van Rooij, Frank J A and Gibbs, Richard A and Metcalf, Ginger and Muzny, Donna and Veeraraghavan, Narayanan and Walter, Klaudia and Chen, Lu and Yanek, Lisa and Becker, Lewis C and Peloso, Gina M and Wakabayashi, Aoi and Kals, Mart and Metspalu, Andres and Esko, T{\~o}nu and Fox, Keolu and Wallace, Robert and Franceschini, Nora and Matijevic, Nena and Rice, Kenneth M and Bartz, Traci M and Lyytik{\"a}inen, Leo-Pekka and K{\"a}h{\"o}nen, Mika and Lehtim{\"a}ki, Terho and Raitakari, Olli T and Li-Gao, Ruifang and Mook-Kanamori, Dennis O and Lettre, Guillaume and van Duijn, Cornelia M and Franco, Oscar H and Rich, Stephen S and Rivadeneira, Fernando and Hofman, Albert and Uitterlinden, Andr{\'e} G and Wilson, James G and Psaty, Bruce M and Soranzo, Nicole and Dehghan, Abbas and Boerwinkle, Eric and Zhang, Xiaoling and Johnson, Andrew D and O{\textquoteright}Donnell, Christopher J and Johnsen, Jill M and Reiner, Alexander P and Ganesh, Santhi K and Sankaran, Vijay G} } @article {7553, title = {Analysis commons, a team approach to discovery in a big-data environment for genetic epidemiology.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Oct 27}, pages = {1560-1563}, issn = {1546-1718}, doi = {10.1038/ng.3968}, author = {Brody, Jennifer A and Morrison, Alanna C and Bis, Joshua C and O{\textquoteright}Connell, Jeffrey R and Brown, Michael R and Huffman, Jennifer E and Ames, Darren C and Carroll, Andrew and Conomos, Matthew P and Gabriel, Stacey and Gibbs, Richard A and Gogarten, Stephanie M and Gupta, Namrata and Jaquish, Cashell E and Johnson, Andrew D and Lewis, Joshua P and Liu, Xiaoming and Manning, Alisa K and Papanicolaou, George J and Pitsillides, Achilleas N and Rice, Kenneth M and Salerno, William and Sitlani, Colleen M and Smith, Nicholas L and Heckbert, Susan R and Laurie, Cathy C and Mitchell, Braxton D and Vasan, Ramachandran S and Rich, Stephen S and Rotter, Jerome I and Wilson, James G and Boerwinkle, Eric and Psaty, Bruce M and Cupples, L Adrienne} } @article {7346, title = {Discovery and fine-mapping of loci associated with monounsaturated fatty acids through trans-ethnic meta-analysis in Chinese and European populations.}, journal = {J Lipid Res}, year = {2017}, month = {2017 Mar 15}, abstract = {

Monounsaturated fatty acids (MUFAs) are unsaturated fatty acids with one double bond and are derived from endogenous synthesis and dietary intake. Accumulating evidence has suggested that plasma and erythrocyte MUFA levels were associated with cardiometabolic disorders including cardiovascular disease (CVD), type 2 diabetes (T2D) and metabolic syndrome (MS). Previous genome-wide association studies (GWAS) have identified seven loci for plasma and erythrocyte palmitoleic acid and oleic acid levels in populations of European origin. To identify additional MUFA-associated loci and the potential causal variant at each locus, we performed ethnic-specific GWAS meta-analyses and trans-ethnic meta-analyses in over 15,000 participants of Chinese- and European-ancestry. We identified novel genome-wide significant associations for vaccenic acid at FADS1/2 and PKD2L1 [log10(Bayes factor)>=8.07] and for gondoic acid at FADS1/2 and GCKR [log10(Bayes factor)>=61619;6.22], and also observed improved fine-mapping resolutions at FADS1/2 and GCKR loci. The greatest improvement was observed at GCKR, where the number of variants in the 99\% credible set was reduced from 16 (covering ~95kb) to five (covering ~20kb, including a missense variant rs1260326) after trans-ethnic meta-analysis. We also confirmed the previously reported associations of PKD2L1, FADS1/2, GCKR and HIF1AN with palmitoleic acid and of FADS1/2 and LPCAT3 with oleic acid in the Chinese-specific GWAS and trans-ethnic meta-analyses. Pathway-based analyses suggested that the identified loci were enriched in unsaturated fatty acids metabolism and signaling pathways. Our findings provided novel insight into the genetic basis relevant to MUFA metabolism and biology.

}, issn = {1539-7262}, doi = {10.1194/jlr.P071860}, author = {Hu, Yao and Tanaka, Toshiko and Zhu, Jingwen and Guan, Weihua and Wu, Jason H Y and Psaty, Bruce M and McKnight, Barbara and King, Irena B and Sun, Qi and Richard, Melissa and Manichaikul, Ani and Frazier-Wood, Alexis C and Kabagambe, Edmond K and Hopkins, Paul N and Ordovas, Jose M and Ferrucci, Luigi and Bandinelli, Stefania and Arnett, Donna K and Chen, Yii-der I and Liang, Shuang and Siscovick, David S and Tsai, Michael Y and Rich, Stephen S and Fornage, Myriam and Hu, Frank B and Rimm, Eric B and Jensen, Majken K and Lemaitre, Rozenn N and Mozaffarian, Dariush and Steffen, Lyn M and Morris, Andrew P and Li, Huaixing and Lin, Xu} } @article {7573, title = {Exome-wide association study of plasma lipids in >300,000 individuals.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Dec}, pages = {1758-1766}, abstract = {

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

}, keywords = {Coronary Artery Disease, Diabetes Mellitus, Type 2, Exome, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Genotype, Humans, Lipids, Macular Degeneration, Phenotype, Risk Factors}, issn = {1546-1718}, doi = {10.1038/ng.3977}, author = {Liu, Dajiang J and Peloso, Gina M and Yu, Haojie and Butterworth, Adam S and Wang, Xiao and Mahajan, Anubha and Saleheen, Danish and Emdin, Connor and Alam, Dewan and Alves, Alexessander Couto and Amouyel, Philippe and Di Angelantonio, Emanuele and Arveiler, Dominique and Assimes, Themistocles L and Auer, Paul L and Baber, Usman and Ballantyne, Christie M and Bang, Lia E and Benn, Marianne and Bis, Joshua C and Boehnke, Michael and Boerwinkle, Eric and Bork-Jensen, Jette and Bottinger, Erwin P and Brandslund, Ivan and Brown, Morris and Busonero, Fabio and Caulfield, Mark J and Chambers, John C and Chasman, Daniel I and Chen, Y Eugene and Chen, Yii-Der Ida and Chowdhury, Rajiv and Christensen, Cramer and Chu, Audrey Y and Connell, John M and Cucca, Francesco and Cupples, L Adrienne and Damrauer, Scott M and Davies, Gail and Deary, Ian J and Dedoussis, George and Denny, Joshua C and Dominiczak, Anna and Dub{\'e}, Marie-Pierre and Ebeling, Tapani and Eiriksdottir, Gudny and Esko, T{\~o}nu and Farmaki, Aliki-Eleni and Feitosa, Mary F and Ferrario, Marco and Ferrieres, Jean and Ford, Ian and Fornage, Myriam and Franks, Paul W and Frayling, Timothy M and Frikke-Schmidt, Ruth and Fritsche, Lars G and Frossard, Philippe and Fuster, Valentin and Ganesh, Santhi K and Gao, Wei and Garcia, Melissa E and Gieger, Christian and Giulianini, Franco and Goodarzi, Mark O and Grallert, Harald and Grarup, Niels and Groop, Leif and Grove, Megan L and Gudnason, Vilmundur and Hansen, Torben and Harris, Tamara B and Hayward, Caroline and Hirschhorn, Joel N and Holmen, Oddgeir L and Huffman, Jennifer and Huo, Yong and Hveem, Kristian and Jabeen, Sehrish and Jackson, Anne U and Jakobsdottir, Johanna and Jarvelin, Marjo-Riitta and Jensen, Gorm B and J{\o}rgensen, Marit E and Jukema, J Wouter and Justesen, Johanne M and Kamstrup, Pia R and Kanoni, Stavroula and Karpe, Fredrik and Kee, Frank and Khera, Amit V and Klarin, Derek and Koistinen, Heikki A and Kooner, Jaspal S and Kooperberg, Charles and Kuulasmaa, Kari and Kuusisto, Johanna and Laakso, Markku and Lakka, Timo and Langenberg, Claudia and Langsted, Anne and Launer, Lenore J and Lauritzen, Torsten and Liewald, David C M and Lin, Li An and Linneberg, Allan and Loos, Ruth J F and Lu, Yingchang and Lu, Xiangfeng and M{\"a}gi, Reedik and M{\"a}larstig, Anders and Manichaikul, Ani and Manning, Alisa K and M{\"a}ntyselk{\"a}, Pekka and Marouli, Eirini and Masca, Nicholas G D and Maschio, Andrea and Meigs, James B and Melander, Olle and Metspalu, Andres and Morris, Andrew P and Morrison, Alanna C and Mulas, Antonella and M{\"u}ller-Nurasyid, Martina and Munroe, Patricia B and Neville, Matt J and Nielsen, Jonas B and Nielsen, Sune F and Nordestgaard, B{\o}rge G and Ordovas, Jose M and Mehran, Roxana and O{\textquoteright}Donnell, Christoper J and Orho-Melander, Marju and Molony, Cliona M and Muntendam, Pieter and Padmanabhan, Sandosh and Palmer, Colin N A and Pasko, Dorota and Patel, Aniruddh P and Pedersen, Oluf and Perola, Markus and Peters, Annette and Pisinger, Charlotta and Pistis, Giorgio and Polasek, Ozren and Poulter, Neil and Psaty, Bruce M and Rader, Daniel J and Rasheed, Asif and Rauramaa, Rainer and Reilly, Dermot F and Reiner, Alex P and Renstrom, Frida and Rich, Stephen S and Ridker, Paul M and Rioux, John D and Robertson, Neil R and Roden, Dan M and Rotter, Jerome I and Rudan, Igor and Salomaa, Veikko and Samani, Nilesh J and Sanna, Serena and Sattar, Naveed and Schmidt, Ellen M and Scott, Robert A and Sever, Peter and Sevilla, Raquel S and Shaffer, Christian M and Sim, Xueling and Sivapalaratnam, Suthesh and Small, Kerrin S and Smith, Albert V and Smith, Blair H and Somayajula, Sangeetha and Southam, Lorraine and Spector, Timothy D and Speliotes, Elizabeth K and Starr, John M and Stirrups, Kathleen E and Stitziel, Nathan and Strauch, Konstantin and Stringham, Heather M and Surendran, Praveen and Tada, Hayato and Tall, Alan R and Tang, Hua and Tardif, Jean-Claude and Taylor, Kent D and Trompet, Stella and Tsao, Philip S and Tuomilehto, Jaakko and Tybjaerg-Hansen, Anne and van Zuydam, Natalie R and Varbo, Anette and Varga, Tibor V and Virtamo, Jarmo and Waldenberger, Melanie and Wang, Nan and Wareham, Nick J and Warren, Helen R and Weeke, Peter E and Weinstock, Joshua and Wessel, Jennifer and Wilson, James G and Wilson, Peter W F and Xu, Ming and Yaghootkar, Hanieh and Young, Robin and Zeggini, Eleftheria and Zhang, He and Zheng, Neil S and Zhang, Weihua and Zhang, Yan and Zhou, Wei and Zhou, Yanhua and Zoledziewska, Magdalena and Howson, Joanna M M and Danesh, John and McCarthy, Mark I and Cowan, Chad A and Abecasis, Goncalo and Deloukas, Panos and Musunuru, Kiran and Willer, Cristen J and Kathiresan, Sekar} } @article {7463, title = {Fine mapping of QT interval regions in global populations refines previously identified QT interval loci and identifies signals unique to African and Hispanic descent populations.}, journal = {Heart Rhythm}, volume = {14}, year = {2017}, month = {2017 Apr}, pages = {572-580}, abstract = {

BACKGROUND: The electrocardiographically measured QT interval (QT) is heritable and its prolongation is an established risk factor for several cardiovascular diseases. Yet, most QT genetic studies have been performed in European ancestral populations, possibly reducing their global relevance.

OBJECTIVE: To leverage diversity and improve biological insight, we fine mapped 16 of the 35 previously identified QT loci (46\%) in populations of African American (n = 12,410) and Hispanic/Latino (n = 14,837) ancestry.

METHODS: Racial/ethnic-specific multiple linear regression analyses adjusted for heart rate and clinical covariates were examined separately and in combination after inverse-variance weighted trans-ethnic meta-analysis.

RESULTS: The 16 fine-mapped QT loci included on the Illumina Metabochip represented 21 independent signals, of which 16 (76\%) were significantly (P-value<=9.1{\texttimes}10(-5)) associated with QT. Through sequential conditional analysis we also identified three trans-ethnic novel SNPs at ATP1B1, SCN5A-SCN10A, and KCNQ1 and three Hispanic/Latino-specific novel SNPs at NOS1AP and SCN5A-SCN10A (two novel SNPs) with evidence of associations with QT independent of previous identified GWAS lead SNPs. Linkage disequilibrium patterns helped to narrow the region likely to contain the functional variants at several loci, including NOS1AP, USP50-TRPM7, and PRKCA, although intervals surrounding SLC35F1-PLN and CNOT1 remained broad in size (>100 kb). Finally, bioinformatics-based functional characterization suggested a regulatory function in cardiac tissues for the majority of independent signals that generalized and the novel SNPs.

CONCLUSION: Our findings suggest that a majority of identified SNPs implicate gene regulatory dysfunction in QT prolongation, that the same loci influence variation in QT across global populations, and that additional, novel, population-specific QT signals exist.

}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2016.12.021}, author = {Avery, Christy L and Wassel, Christina L and Richard, Melissa A and Highland, Heather M and Bien, Stephanie and Zubair, Niha and Soliman, Elsayed Z and Fornage, Myriam and Bielinski, Suzette J and Tao, Ran and Seyerle, Amanda A and Shah, Sanjiv J and Lloyd-Jones, Donald M and Buyske, Steven and Rotter, Jerome I and Post, Wendy S and Rich, Stephen S and Hindorff, Lucia A and Jeff, Janina M and Shohet, Ralph V and Sotoodehnia, Nona and Lin, Dan Yu and Whitsel, Eric A and Peters, Ulrike and Haiman, Christopher A and Crawford, Dana C and Kooperberg, Charles and North, Kari E} } @article {7345, title = {Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Mar}, pages = {426-432}, abstract = {

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 {\texttimes} 10(-6)) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.

}, issn = {1546-1718}, doi = {10.1038/ng.3752}, author = {Hobbs, Brian D and de Jong, Kim and Lamontagne, Maxime and Boss{\'e}, Yohan and Shrine, Nick and Artigas, Maria Soler and Wain, Louise V and Hall, Ian P and Jackson, Victoria E and Wyss, Annah B and London, Stephanie J and North, Kari E and Franceschini, Nora and Strachan, David P and Beaty, Terri H and Hokanson, John E and Crapo, James D and Castaldi, Peter J and Chase, Robert P and Bartz, Traci M and Heckbert, Susan R and Psaty, Bruce M and Gharib, Sina A and Zanen, Pieter and Lammers, Jan W and Oudkerk, Matthijs and Groen, H J and Locantore, Nicholas and Tal-Singer, Ruth and Rennard, Stephen I and Vestbo, J{\o}rgen and Timens, Wim and Par{\'e}, Peter D and Latourelle, Jeanne C and Dupuis, Jos{\'e}e and O{\textquoteright}Connor, George T and Wilk, Jemma B and Kim, Woo Jin and Lee, Mi Kyeong and Oh, Yeon-Mok and Vonk, Judith M and de Koning, Harry J and Leng, Shuguang and Belinsky, Steven A and Tesfaigzi, Yohannes and Manichaikul, Ani and Wang, Xin-Qun and Rich, Stephen S and Barr, R Graham and Sparrow, David and Litonjua, Augusto A and Bakke, Per and Gulsvik, Amund and Lahousse, Lies and Brusselle, Guy G and Stricker, Bruno H and Uitterlinden, Andr{\'e} G and Ampleford, Elizabeth J and Bleecker, Eugene R and Woodruff, Prescott G and Meyers, Deborah A and Qiao, Dandi and Lomas, David A and Yim, Jae-Joon and Kim, Deog Kyeom and Hawrylkiewicz, Iwona and Sliwinski, Pawel and Hardin, Megan and Fingerlin, Tasha E and Schwartz, David A and Postma, Dirkje S and MacNee, William and Tobin, Martin D and Silverman, Edwin K and Boezen, H Marike and Cho, Michael H} } @article {7588, title = {Genome-Wide Interactions with Dairy Intake for Body Mass Index in Adults of European Descent.}, journal = {Mol Nutr Food Res}, year = {2017}, month = {2017 Sep 21}, abstract = {

SCOPE: Body weight responds variably to the intake of dairy foods. Genetic variation may contribute to inter-individual variability in associations between body weight and dairy consumption.

METHODS AND RESULTS: A genome-wide interaction study to discover genetic variants that account for variation in BMI in the context of low-fat, high-fat and total dairy intake in cross-sectional analysis was conducted. Data from nine discovery studies (up to 25 513 European descent individuals) were meta-analyzed. Twenty-six genetic variants reached the selected significance threshold (p-interaction <10-7) , and six independent variants (LINC01512-rs7751666, PALM2/AKAP2-rs914359, ACTA2-rs1388, PPP1R12A-rs7961195, LINC00333-rs9635058, AC098847.1-rs1791355) were evaluated meta-analytically for replication of interaction in up to 17 675 individuals. Variant rs9635058 (128 kb 3{\textquoteright} of LINC00333) was replicated (p-interaction = 0.004). In the discovery cohorts, rs9635058 interacted with dairy (p-interaction = 7.36 {\texttimes} 10-8) such that each serving of low-fat dairy was associated with 0.225 kg m-2 lower BMI per each additional copy of the effect allele (A). A second genetic variant (ACTA2-rs1388) approached interaction replication significance for low-fat dairy exposure.

CONCLUSION: Body weight responses to dairy intake may be modified by genotype, in that greater dairy intake may protect a genetic subgroup from higher body weight.

}, issn = {1613-4133}, doi = {10.1002/mnfr.201700347}, author = {Smith, Caren E and Follis, Jack L and Dashti, Hassan S and Tanaka, Toshiko and Graff, Mariaelisa and Fretts, Amanda M and Kilpel{\"a}inen, Tuomas O and Wojczynski, Mary K and Richardson, Kris and Nalls, Mike A and Schulz, Christina-Alexandra and Liu, Yongmei and Frazier-Wood, Alexis C and van Eekelen, Esther and Wang, Carol and de Vries, Paul S and Mikkil{\"a}, Vera and Rohde, Rebecca and Psaty, Bruce M and Hansen, Torben and Feitosa, Mary F and Lai, Chao-Qiang and Houston, Denise K and Ferruci, Luigi and Ericson, Ulrika and Wang, Zhe and de Mutsert, Ren{\'e}e and Oddy, Wendy H and de Jonge, Ester A L and Sepp{\"a}l{\"a}, Ilkka and Justice, Anne E and Lemaitre, Rozenn N and S{\o}rensen, Thorkild I A and Province, Michael A and Parnell, Laurence D and Garcia, Melissa E and Bandinelli, Stefania and Orho-Melander, Marju and Rich, Stephen S and Rosendaal, Frits R and Pennell, Craig E and Kiefte-de Jong, Jessica C and K{\"a}h{\"o}nen, Mika and Young, Kristin L and Pedersen, Oluf and Aslibekyan, Stella and Rotter, Jerome I and Mook-Kanamori, Dennis O and Zillikens, M Carola and Raitakari, Olli T and North, Kari E and Overvad, Kim and Arnett, Donna K and Hofman, Albert and Lehtim{\"a}ki, Terho and Tj{\o}nneland, Anne and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Franco, Oscar H and German, J Bruce and Siscovick, David S and Cupples, L Adrienne and Ordovas, Jose M} } @article {7596, title = {Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.}, journal = {PLoS Med}, volume = {14}, year = {2017}, month = {2017 Sep}, pages = {e1002383}, abstract = {

BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.

METHODS \& FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95\% CI 1.04-1.06, per HbA1c-raising allele, p = 3 {\texttimes} 10-29); whereas GS-E was not (OR = 1.00, 95\% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11\%) was associated with an absolute decrease in HbA1c of 0.81\%-units (95\% CI 0.66-0.96) per allele in hemizygous men, and 0.68\%-units (95\% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2\% (N = 0.65 million, 95\% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.

CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

}, keywords = {Diabetes Mellitus, Type 2, Genetic Variation, Genome-Wide Association Study, Glycated Hemoglobin A, Humans, Phenotype, Risk}, issn = {1549-1676}, doi = {10.1371/journal.pmed.1002383}, author = {Wheeler, Eleanor and Leong, Aaron and Liu, Ching-Ti and Hivert, Marie-France and Strawbridge, Rona J and Podmore, Clara and Li, Man and Yao, Jie and Sim, Xueling and Hong, Jaeyoung and Chu, Audrey Y and Zhang, Weihua and Wang, Xu and Chen, Peng and Maruthur, Nisa M and Porneala, Bianca C and Sharp, Stephen J and Jia, Yucheng and Kabagambe, Edmond K and Chang, Li-Ching and Chen, Wei-Min and Elks, Cathy E and Evans, Daniel S and Fan, Qiao and Giulianini, Franco and Go, Min Jin and Hottenga, Jouke-Jan and Hu, Yao and Jackson, Anne U and Kanoni, Stavroula and Kim, Young Jin and Kleber, Marcus E and Ladenvall, Claes and Lecoeur, C{\'e}cile and Lim, Sing-Hui and Lu, Yingchang and Mahajan, Anubha and Marzi, Carola and Nalls, Mike A and Navarro, Pau and Nolte, Ilja M and Rose, Lynda M and Rybin, Denis V and Sanna, Serena and Shi, Yuan and Stram, Daniel O and Takeuchi, Fumihiko and Tan, Shu Pei and van der Most, Peter J and van Vliet-Ostaptchouk, Jana V and Wong, Andrew and Yengo, Loic and Zhao, Wanting and Goel, Anuj and Martinez Larrad, Maria Teresa and Radke, D{\"o}rte and Salo, Perttu and Tanaka, Toshiko and van Iperen, Erik P A and Abecasis, Goncalo and Afaq, Saima and Alizadeh, Behrooz Z and Bertoni, Alain G and Bonnefond, Am{\'e}lie and B{\"o}ttcher, Yvonne and Bottinger, Erwin P and Campbell, Harry and Carlson, Olga D and Chen, Chien-Hsiun and Cho, Yoon Shin and Garvey, W Timothy and Gieger, Christian and Goodarzi, Mark O and Grallert, Harald and Hamsten, Anders and Hartman, Catharina A and Herder, Christian and Hsiung, Chao Agnes and Huang, Jie and Igase, Michiya and Isono, Masato and Katsuya, Tomohiro and Khor, Chiea-Chuen and Kiess, Wieland and Kohara, Katsuhiko and Kovacs, Peter and Lee, Juyoung and Lee, Wen-Jane and Lehne, Benjamin and Li, Huaixing and Liu, Jianjun and Lobbens, Stephane and Luan, Jian{\textquoteright}an and Lyssenko, Valeriya and Meitinger, Thomas and Miki, Tetsuro and Miljkovic, Iva and Moon, Sanghoon and Mulas, Antonella and M{\"u}ller, Gabriele and M{\"u}ller-Nurasyid, Martina and Nagaraja, Ramaiah and Nauck, Matthias and Pankow, James S and Polasek, Ozren and Prokopenko, Inga and Ramos, Paula S and Rasmussen-Torvik, Laura and Rathmann, Wolfgang and Rich, Stephen S and Robertson, Neil R and Roden, Michael and Roussel, Ronan and Rudan, Igor and Scott, Robert A and Scott, William R and Sennblad, Bengt and Siscovick, David S and Strauch, Konstantin and Sun, Liang and Swertz, Morris and Tajuddin, Salman M and Taylor, Kent D and Teo, Yik-Ying and Tham, Yih Chung and T{\"o}njes, Anke and Wareham, Nicholas J and Willemsen, Gonneke and Wilsgaard, Tom and Hingorani, Aroon D and Egan, Josephine and Ferrucci, Luigi and Hovingh, G Kees and Jula, Antti and Kivimaki, Mika and Kumari, Meena and Nj{\o}lstad, Inger and Palmer, Colin N A and Serrano R{\'\i}os, Manuel and Stumvoll, Michael and Watkins, Hugh and Aung, Tin and Bl{\"u}her, Matthias and Boehnke, Michael and Boomsma, Dorret I and Bornstein, Stefan R and Chambers, John C and Chasman, Daniel I and Chen, Yii-Der Ida and Chen, Yduan-Tsong and Cheng, Ching-Yu and Cucca, Francesco and de Geus, Eco J C and Deloukas, Panos and Evans, Michele K and Fornage, Myriam and Friedlander, Yechiel and Froguel, Philippe and Groop, Leif and Gross, Myron D and Harris, Tamara B and Hayward, Caroline and Heng, Chew-Kiat and Ingelsson, Erik and Kato, Norihiro and Kim, Bong-Jo and Koh, Woon-Puay and Kooner, Jaspal S and K{\"o}rner, Antje and Kuh, Diana and Kuusisto, Johanna and Laakso, Markku and Lin, Xu and Liu, Yongmei and Loos, Ruth J F and Magnusson, Patrik K E and M{\"a}rz, Winfried and McCarthy, Mark I and Oldehinkel, Albertine J and Ong, Ken K and Pedersen, Nancy L and Pereira, Mark A and Peters, Annette and Ridker, Paul M and Sabanayagam, Charumathi and Sale, Michele and Saleheen, Danish and Saltevo, Juha and Schwarz, Peter Eh and Sheu, Wayne H H and Snieder, Harold and Spector, Timothy D and Tabara, Yasuharu and Tuomilehto, Jaakko and van Dam, Rob M and Wilson, James G and Wilson, James F and Wolffenbuttel, Bruce H R and Wong, Tien Yin and Wu, Jer-Yuarn and Yuan, Jian-Min and Zonderman, Alan B and Soranzo, Nicole and Guo, Xiuqing and Roberts, David J and Florez, Jose C and Sladek, Robert and Dupuis, Jos{\'e}e and Morris, Andrew P and Tai, E-Shyong and Selvin, Elizabeth and Rotter, Jerome I and Langenberg, Claudia and Barroso, In{\^e}s and Meigs, James B} } @article {7802, title = {Common Coding Variants in Are Associated With the Nav1.8 Late Current and Cardiac Conduction.}, journal = {Circ Genom Precis Med}, volume = {11}, year = {2018}, month = {2018 May}, pages = {e001663}, abstract = {

BACKGROUND: Genetic variants at the / locus are strongly associated with electrocardiographic PR and QRS intervals. While is the canonical cardiac sodium channel gene, the role of in cardiac conduction is less well characterized.

METHODS: We sequenced the locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue. We explored the biophysical effect of variation on channel function using cellular electrophysiology.

RESULTS: We identified 2 intronic single nucleotide polymorphisms in high linkage disequilibrium ( =0.86) with each other to be the strongest signals for PR (rs10428132, β=-4.74, =1.52{\texttimes}10) and QRS intervals (rs6599251, QRS β=-0.73; =1.2{\texttimes}10), respectively. Although these variants were not associated with or expression in human atrial tissue (n=490), they were in high linkage disequilibrium ( >=0.72) with a common missense variant, rs6795970 (V1073A). In total, we identified 7 missense variants, 4 of which (I962V, P1045T, V1073A, and L1092P) were associated with cardiac conduction. These 4 missense variants cluster in the cytoplasmic linker of the second and third domains of the SCN10A protein and together form 6 common haplotypes. Using cellular electrophysiology, we found that haplotypes associated with shorter PR intervals had a significantly larger percentage of late current compared with wild-type (I962V+V1073A+L1092P, 20.2{\textpm}3.3\%, =0.03, and I962V+V1073A, 22.4{\textpm}0.8\%, =0.0004 versus wild-type 11.7{\textpm}1.6\%), and the haplotype associated with the longest PR interval had a significantly smaller late current percentage (P1045T, 6.4{\textpm}1.2\%, =0.03).

CONCLUSIONS: Our findings suggest an association between genetic variation in , the late sodium current, and alterations in cardiac conduction.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.116.001663}, author = {Macri, Vincenzo and Brody, Jennifer A and Arking, Dan E and Hucker, William J and Yin, Xiaoyan and Lin, Honghuang and Mills, Robert W and Sinner, Moritz F and Lubitz, Steven A and Liu, Ching-Ti and Morrison, Alanna C and Alonso, Alvaro and Li, Ning and Fedorov, Vadim V and Janssen, Paul M and Bis, Joshua C and Heckbert, Susan R and Dolmatova, Elena V and Lumley, Thomas and Sitlani, Colleen M and Cupples, L Adrienne and Pulit, Sara L and Newton-Cheh, Christopher and Barnard, John and Smith, Jonathan D and Van Wagoner, David R and Chung, Mina K and Vlahakes, Gus J and O{\textquoteright}Donnell, Christopher J and Rotter, Jerome I and Margulies, Kenneth B and Morley, Michael P and Cappola, Thomas P and Benjamin, Emelia J and Muzny, Donna and Gibbs, Richard A and Jackson, Rebecca D and Magnani, Jared W and Herndon, Caroline N and Rich, Stephen S and Psaty, Bruce M and Milan, David J and Boerwinkle, Eric and Mohler, Peter J and Sotoodehnia, Nona and Ellinor, Patrick T} } @article {7791, title = {Genome-wide association meta-analysis of circulating odd-numbered chain saturated fatty acids: Results from the CHARGE Consortium.}, journal = {PLoS One}, volume = {13}, year = {2018}, month = {2018}, pages = {e0196951}, abstract = {

BACKGROUND: Odd-numbered chain saturated fatty acids (OCSFA) have been associated with potential health benefits. Although some OCSFA (e.g., C15:0 and C17:0) are found in meats and dairy products, sources and metabolism of C19:0 and C23:0 are relatively unknown, and the influence of non-dietary determinants, including genetic factors, on circulating levels of OCSFA is not established.

OBJECTIVE: To elucidate the biological processes that influence circulating levels of OCSFA by investigating associations between genetic variation and OCSFA.

DESIGN: We performed a meta-analysis of genome-wide association studies (GWAS) of plasma phospholipid/erythrocyte levels of C15:0, C17:0, C19:0, and C23:0 among 11,494 individuals of European descent. We also investigated relationships between specific single nucleotide polymorphisms (SNPs) in the lactase (LCT) gene, associated with adult-onset lactase intolerance, with circulating levels of dairy-derived OCSFA, and evaluated associations of candidate sphingolipid genes with C23:0 levels.

RESULTS: We found no genome-wide significant evidence that common genetic variation is associated with circulating levels of C15:0 or C23:0. In two cohorts with available data, we identified one intronic SNP (rs13361131) in myosin X gene (MYO10) associated with C17:0 level (P = 1.37{\texttimes}10-8), and two intronic SNP (rs12874278 and rs17363566) in deleted in lymphocytic leukemia 1 (DLEU1) region associated with C19:0 level (P = 7.07{\texttimes}10-9). In contrast, when using a candidate-gene approach, we found evidence that three SNPs in LCT (rs11884924, rs16832067, and rs3816088) are associated with circulating C17:0 level (adjusted P = 4{\texttimes}10-2). In addition, nine SNPs in the ceramide synthase 4 (CERS4) region were associated with circulating C23:0 levels (adjusted P<5{\texttimes}10-2).

CONCLUSIONS: Our findings suggest that circulating levels of OCSFA may be predominantly influenced by non-genetic factors. SNPs associated with C17:0 level in the LCT gene may reflect genetic influence in dairy consumption or in metabolism of dairy foods. SNPs associated with C23:0 may reflect a role of genetic factors in the synthesis of sphingomyelin.

}, keywords = {Fatty Acids, Genome-Wide Association Study, Humans, Introns, Lactase, Myosins, Polymorphism, Single Nucleotide, Sphingomyelins, Sphingosine N-Acyltransferase, Tumor Suppressor Proteins}, issn = {1932-6203}, doi = {10.1371/journal.pone.0196951}, author = {de Oliveira Otto, Marcia C and Lemaitre, Rozenn N and Sun, Qi and King, Irena B and Wu, Jason H Y and Manichaikul, Ani and Rich, Stephen S and Tsai, Michael Y and Chen, Y D and Fornage, Myriam and Weihua, Guan and Aslibekyan, Stella and Irvin, Marguerite R and Kabagambe, Edmond K and Arnett, Donna K and Jensen, Majken K and McKnight, Barbara and Psaty, Bruce M and Steffen, Lyn M and Smith, Caren E and Riserus, Ulf and Lind, Lars and Hu, Frank B and Rimm, Eric B and Siscovick, David S and Mozaffarian, Dariush} } @article {7667, title = {Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 Jan 17}, pages = {260}, abstract = {

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7{\texttimes}10 at rs8018720 in SEC23A, and P = 1.9{\texttimes}10 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5\%, with statistically significant loci explaining 38\% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

}, issn = {2041-1723}, doi = {10.1038/s41467-017-02662-2}, author = {Jiang, Xia and O{\textquoteright}Reilly, Paul F and Aschard, Hugues and Hsu, Yi-Hsiang and Richards, J Brent and Dupuis, Jos{\'e}e and Ingelsson, Erik and Karasik, David and Pilz, Stefan and Berry, Diane and Kestenbaum, Bryan and Zheng, Jusheng and Luan, Jianan and Sofianopoulou, Eleni and Streeten, Elizabeth A and Albanes, Demetrius and Lutsey, Pamela L and Yao, Lu and Tang, Weihong and Econs, Michael J and Wallaschofski, Henri and V{\"o}lzke, Henry and Zhou, Ang and Power, Chris and McCarthy, Mark I and Michos, Erin D and Boerwinkle, Eric and Weinstein, Stephanie J and Freedman, Neal D and Huang, Wen-Yi and van Schoor, Natasja M and van der Velde, Nathalie and Groot, Lisette C P G M de and Enneman, Anke and Cupples, L Adrienne and Booth, Sarah L and Vasan, Ramachandran S and Liu, Ching-Ti and Zhou, Yanhua and Ripatti, Samuli and Ohlsson, Claes and Vandenput, Liesbeth and Lorentzon, Mattias and Eriksson, Johan G and Shea, M Kyla and Houston, Denise K and Kritchevsky, Stephen B and Liu, Yongmei and Lohman, Kurt K and Ferrucci, Luigi and Peacock, Munro and Gieger, Christian and Beekman, Marian and Slagboom, Eline and Deelen, Joris and Heemst, Diana van and Kleber, Marcus E and M{\"a}rz, Winfried and de Boer, Ian H and Wood, Alexis C and Rotter, Jerome I and Rich, Stephen S and Robinson-Cohen, Cassianne and den Heijer, Martin and Jarvelin, Marjo-Riitta and Cavadino, Alana and Joshi, Peter K and Wilson, James F and Hayward, Caroline and Lind, Lars and Micha{\"e}lsson, Karl and Trompet, Stella and Zillikens, M Carola and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Broer, Linda and Zgaga, Lina and Campbell, Harry and Theodoratou, Evropi and Farrington, Susan M and Timofeeva, Maria and Dunlop, Malcolm G and Valdes, Ana M and Tikkanen, Emmi and Lehtim{\"a}ki, Terho and Lyytik{\"a}inen, Leo-Pekka and K{\"a}h{\"o}nen, Mika and Raitakari, Olli T and Mikkil{\"a}, Vera and Ikram, M Arfan and Sattar, Naveed and Jukema, J Wouter and Wareham, Nicholas J and Langenberg, Claudia and Forouhi, Nita G and Gundersen, Thomas E and Khaw, Kay-Tee and Butterworth, Adam S and Danesh, John and Spector, Timothy and Wang, Thomas J and Hypp{\"o}nen, Elina and Kraft, Peter and Kiel, Douglas P} } @article {7775, title = {Meta-analysis across Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium provides evidence for an association of serum vitamin D with pulmonary function.}, journal = {Br J Nutr}, year = {2018}, month = {2018 Sep 12}, pages = {1-12}, abstract = {

The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)-pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D-pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1{\textperiodcentered}1 ml in EA (95 \% CI 0{\textperiodcentered}9, 1{\textperiodcentered}3; P<0{\textperiodcentered}0001) and 1{\textperiodcentered}8 ml (95 \% CI 1{\textperiodcentered}1, 2{\textperiodcentered}5; P<0{\textperiodcentered}0001) in AA (P race difference=0{\textperiodcentered}06), and forced vital capacity (FVC) was higher by 1{\textperiodcentered}3 ml in EA (95 \% CI 1{\textperiodcentered}0, 1{\textperiodcentered}6; P<0{\textperiodcentered}0001) and 1{\textperiodcentered}5 ml (95 \% CI 0{\textperiodcentered}8, 2{\textperiodcentered}3; P=0{\textperiodcentered}0001) in AA (P race difference=0{\textperiodcentered}56). Among EA, the 25(OH)D-FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1{\textperiodcentered}7 ml (95 \% CI 1{\textperiodcentered}1, 2{\textperiodcentered}3) for current smokers and 1{\textperiodcentered}7 ml (95 \% CI 1{\textperiodcentered}2, 2{\textperiodcentered}1) for former smokers, compared with 0{\textperiodcentered}8 ml (95 \% CI 0{\textperiodcentered}4, 1{\textperiodcentered}2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations.

}, issn = {1475-2662}, doi = {10.1017/S0007114518002180}, author = {Xu, Jiayi and Bartz, Traci M and Chittoor, Geetha and Eiriksdottir, Gudny and Manichaikul, Ani W and Sun, Fangui and Terzikhan, Natalie and Zhou, Xia and Booth, Sarah L and Brusselle, Guy G and de Boer, Ian H and Fornage, Myriam and Frazier-Wood, Alexis C and Graff, Mariaelisa and Gudnason, Vilmundur and Harris, Tamara B and Hofman, Albert and Hou, Ruixue and Houston, Denise K and Jacobs, David R and Kritchevsky, Stephen B and Latourelle, Jeanne and Lemaitre, Rozenn N and Lutsey, Pamela L and O{\textquoteright}Connor, George and Oelsner, Elizabeth C and Pankow, James S and Psaty, Bruce M and Rohde, Rebecca R and Rich, Stephen S and Rotter, Jerome I and Smith, Lewis J and Stricker, Bruno H and Voruganti, V Saroja and Wang, Thomas J and Zillikens, M Carola and Barr, R Graham and Dupuis, Jos{\'e}e and Gharib, Sina A and Lahousse, Lies and London, Stephanie J and North, Kari E and Smith, Albert V and Steffen, Lyn M and Hancock, Dana B and Cassano, Patricia A} } @article {7795, title = {Meta-analysis of exome array data identifies six novel genetic loci for lung function.}, journal = {Wellcome Open Res}, volume = {3}, year = {2018}, month = {2018}, pages = {4}, abstract = {

Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV ), forced vital capacity (FVC) and the ratio of FEV to FVC (FEV /FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. We identified significant (P<2{\textperiodcentered}8x10 ) associations with six SNPs: a nonsynonymous variant in , which is predicted to be damaging, three intronic SNPs ( and ) and two intergenic SNPs near to and Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including and . Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

}, issn = {2398-502X}, doi = {10.12688/wellcomeopenres.12583.3}, author = {Jackson, Victoria E and Latourelle, Jeanne C and Wain, Louise V and Smith, Albert V and Grove, Megan L and Bartz, Traci M and Obeidat, Ma{\textquoteright}en and Province, Michael A and Gao, Wei and Qaiser, Beenish and Porteous, David J and Cassano, Patricia A and Ahluwalia, Tarunveer S and Grarup, Niels and Li, Jin and Altmaier, Elisabeth and Marten, Jonathan and Harris, Sarah E and Manichaikul, Ani and Pottinger, Tess D and Li-Gao, Ruifang and Lind-Thomsen, Allan and Mahajan, Anubha and Lahousse, Lies and Imboden, Medea and Teumer, Alexander and Prins, Bram and Lyytik{\"a}inen, Leo-Pekka and Eiriksdottir, Gudny and Franceschini, Nora and Sitlani, Colleen M and Brody, Jennifer A and Boss{\'e}, Yohan and Timens, Wim and Kraja, Aldi and Loukola, Anu and Tang, Wenbo and Liu, Yongmei and Bork-Jensen, Jette and Justesen, Johanne M and Linneberg, Allan and Lange, Leslie A and Rawal, Rajesh and Karrasch, Stefan and Huffman, Jennifer E and Smith, Blair H and Davies, Gail and Burkart, Kristin M and Mychaleckyj, Josyf C and Bonten, Tobias N and Enroth, Stefan and Lind, Lars and Brusselle, Guy G and Kumar, Ashish and Stubbe, Beate and K{\"a}h{\"o}nen, Mika and Wyss, Annah B and Psaty, Bruce M and Heckbert, Susan R and Hao, Ke and Rantanen, Taina and Kritchevsky, Stephen B and Lohman, Kurt and Skaaby, Tea and Pisinger, Charlotta and Hansen, Torben and Schulz, Holger and Polasek, Ozren and Campbell, Archie and Starr, John M and Rich, Stephen S and Mook-Kanamori, Dennis O and Johansson, Asa and Ingelsson, Erik and Uitterlinden, Andr{\'e} G and Weiss, Stefan and Raitakari, Olli T and Gudnason, Vilmundur and North, Kari E and Gharib, Sina A and Sin, Don D and Taylor, Kent D and O{\textquoteright}Connor, George T and Kaprio, Jaakko and Harris, Tamara B and Pederson, Oluf and Vestergaard, Henrik and Wilson, James G and Strauch, Konstantin and Hayward, Caroline and Kerr, Shona and Deary, Ian J and Barr, R Graham and de Mutsert, Ren{\'e}e and Gyllensten, Ulf and Morris, Andrew P and Ikram, M Arfan and Probst-Hensch, Nicole and Gl{\"a}ser, Sven and Zeggini, Eleftheria and Lehtim{\"a}ki, Terho and Strachan, David P and Dupuis, Jos{\'e}e and Morrison, Alanna C and Hall, Ian P and Tobin, Martin D and London, Stephanie J} } @article {7558, title = {Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Jan}, pages = {42-53}, abstract = {

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

}, issn = {1546-1718}, doi = {10.1038/s41588-017-0014-7}, author = {Demenais, Florence and Margaritte-Jeannin, Patricia and Barnes, Kathleen C and Cookson, William O C and Altm{\"u}ller, Janine and Ang, Wei and Barr, R Graham and Beaty, Terri H and Becker, Allan B and Beilby, John and Bisgaard, Hans and Bjornsdottir, Unnur Steina and Bleecker, Eugene and B{\o}nnelykke, Klaus and Boomsma, Dorret I and Bouzigon, Emmanuelle and Brightling, Christopher E and Brossard, Myriam and Brusselle, Guy G and Burchard, Esteban and Burkart, Kristin M and Bush, Andrew and Chan-Yeung, Moira and Chung, Kian Fan and Couto Alves, Alexessander and Curtin, John A and Custovic, Adnan and Daley, Denise and de Jongste, Johan C and Del-Rio-Navarro, Blanca E and Donohue, Kathleen M and Duijts, Liesbeth and Eng, Celeste and Eriksson, Johan G and Farrall, Martin and Fedorova, Yuliya and Feenstra, Bjarke and Ferreira, Manuel A and Freidin, Maxim B and Gajdos, Zofia and Gauderman, Jim and Gehring, Ulrike and Geller, Frank and Genuneit, Jon and Gharib, Sina A and Gilliland, Frank and Granell, Raquel and Graves, Penelope E and Gudbjartsson, Daniel F and Haahtela, Tari and Heckbert, Susan R and Heederik, Dick and Heinrich, Joachim and Heli{\"o}vaara, Markku and Henderson, John and Himes, Blanca E and Hirose, Hiroshi and Hirschhorn, Joel N and Hofman, Albert and Holt, Patrick and Hottenga, Jouke and Hudson, Thomas J and Hui, Jennie and Imboden, Medea and Ivanov, Vladimir and Jaddoe, Vincent W V and James, Alan and Janson, Christer and Jarvelin, Marjo-Riitta and Jarvis, Deborah and Jones, Graham and Jonsdottir, Ingileif and Jousilahti, Pekka and Kabesch, Michael and K{\"a}h{\"o}nen, Mika and Kantor, David B and Karunas, Alexandra S and Khusnutdinova, Elza and Koppelman, Gerard H and Kozyrskyj, Anita L and Kreiner, Eskil and Kubo, Michiaki and Kumar, Rajesh and Kumar, Ashish and Kuokkanen, Mikko and Lahousse, Lies and Laitinen, Tarja and Laprise, Catherine and Lathrop, Mark and Lau, Susanne and Lee, Young-Ae and Lehtim{\"a}ki, Terho and Letort, S{\'e}bastien and Levin, Albert M and Li, Guo and Liang, Liming and Loehr, Laura R and London, Stephanie J and Loth, Daan W and Manichaikul, Ani and Marenholz, Ingo and Martinez, Fernando J and Matheson, Melanie C and Mathias, Rasika A and Matsumoto, Kenji and Mbarek, Hamdi and McArdle, Wendy L and Melbye, Mads and Mel{\'e}n, Erik and Meyers, Deborah and Michel, Sven and Mohamdi, Hamida and Musk, Arthur W and Myers, Rachel A and Nieuwenhuis, Maartje A E and Noguchi, Emiko and O{\textquoteright}Connor, George T and Ogorodova, Ludmila M and Palmer, Cameron D and Palotie, Aarno and Park, Julie E and Pennell, Craig E and Pershagen, G{\"o}ran and Polonikov, Alexey and Postma, Dirkje S and Probst-Hensch, Nicole and Puzyrev, Valery P and Raby, Benjamin A and Raitakari, Olli T and Ramasamy, Adaikalavan and Rich, Stephen S and Robertson, Colin F and Romieu, Isabelle and Salam, Muhammad T and Salomaa, Veikko and Schl{\"u}nssen, Vivi and Scott, Robert and Selivanova, Polina A and Sigsgaard, Torben and Simpson, Angela and Siroux, Val{\'e}rie and Smith, Lewis J and Solodilova, Maria and Standl, Marie and Stefansson, Kari and Strachan, David P and Stricker, Bruno H and Takahashi, Atsushi and Thompson, Philip J and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tiesler, Carla M T and Torgerson, Dara G and Tsunoda, Tatsuhiko and Uitterlinden, Andr{\'e} G and van der Valk, Ralf J P and Vaysse, Amaury and Vedantam, Sailaja and von Berg, Andrea and von Mutius, Erika and Vonk, Judith M and Waage, Johannes and Wareham, Nick J and Weiss, Scott T and White, Wendy B and Wickman, Magnus and Widen, Elisabeth and Willemsen, Gonneke and Williams, L Keoki and Wouters, Inge M and Yang, James J and Zhao, Jing Hua and Moffatt, Miriam F and Ober, Carole and Nicolae, Dan L} } @article {7683, title = {Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Apr}, pages = {524-537}, abstract = {

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and~using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0058-3}, author = {Malik, Rainer and Chauhan, Ganesh and Traylor, Matthew and Sargurupremraj, Muralidharan and Okada, Yukinori and Mishra, Aniket and Rutten-Jacobs, Loes and Giese, Anne-Katrin and van der Laan, Sander W and Gretarsdottir, Solveig and Anderson, Christopher D and Chong, Michael and Adams, Hieab H H and Ago, Tetsuro and Almgren, Peter and Amouyel, Philippe and Ay, Hakan and Bartz, Traci M and Benavente, Oscar R and Bevan, Steve and Boncoraglio, Giorgio B and Brown, Robert D and Butterworth, Adam S and Carrera, Caty and Carty, Cara L and Chasman, Daniel I and Chen, Wei-Min and Cole, John W and Correa, Adolfo and Cotlarciuc, Ioana and Cruchaga, Carlos and Danesh, John and de Bakker, Paul I W and DeStefano, Anita L and den Hoed, Marcel and Duan, Qing and Engelter, Stefan T and Falcone, Guido J and Gottesman, Rebecca F and Grewal, Raji P and Gudnason, Vilmundur and Gustafsson, Stefan and Haessler, Jeffrey and Harris, Tamara B and Hassan, Ahamad and Havulinna, Aki S and Heckbert, Susan R and Holliday, Elizabeth G and Howard, George and Hsu, Fang-Chi and Hyacinth, Hyacinth I and Ikram, M Arfan and Ingelsson, Erik and Irvin, Marguerite R and Jian, Xueqiu and Jimenez-Conde, Jordi and Johnson, Julie A and Jukema, J Wouter and Kanai, Masahiro and Keene, Keith L and Kissela, Brett M and Kleindorfer, Dawn O and Kooperberg, Charles and Kubo, Michiaki and Lange, Leslie A and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Lee, Jin-Moo and Lemmens, Robin and Leys, Didier and Lewis, Cathryn M and Lin, Wei-Yu and Lindgren, Arne G and Lorentzen, Erik and Magnusson, Patrik K and Maguire, Jane and Manichaikul, Ani and McArdle, Patrick F and Meschia, James F and Mitchell, Braxton D and Mosley, Thomas H and Nalls, Michael A and Ninomiya, Toshiharu and O{\textquoteright}Donnell, Martin J and Psaty, Bruce M and Pulit, Sara L and Rannikmae, Kristiina and Reiner, Alexander P and Rexrode, Kathryn M and Rice, Kenneth and Rich, Stephen S and Ridker, Paul M and Rost, Natalia S and Rothwell, Peter M and Rotter, Jerome I and Rundek, Tatjana and Sacco, Ralph L and Sakaue, Saori and Sale, Mich{\`e}le M and Salomaa, Veikko and Sapkota, Bishwa R and Schmidt, Reinhold and Schmidt, Carsten O and Schminke, Ulf and Sharma, Pankaj and Slowik, Agnieszka and Sudlow, Cathie L M and Tanislav, Christian and Tatlisumak, Turgut and Taylor, Kent D and Thijs, Vincent N S and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tiedt, Steffen and Trompet, Stella and Tzourio, Christophe and van Duijn, Cornelia M and Walters, Matthew and Wareham, Nicholas J and Wassertheil-Smoller, Sylvia and Wilson, James G and Wiggins, Kerri L and Yang, Qiong and Yusuf, Salim and Bis, Joshua C and Pastinen, Tomi and Ruusalepp, Arno and Schadt, Eric E and Koplev, Simon and Bj{\"o}rkegren, Johan L M and Codoni, Veronica and Civelek, Mete and Smith, Nicholas L and Tr{\'e}gou{\"e}t, David A and Christophersen, Ingrid E and Roselli, Carolina and Lubitz, Steven A and Ellinor, Patrick T and Tai, E Shyong and Kooner, Jaspal S and Kato, Norihiro and He, Jiang and van der Harst, Pim and Elliott, Paul and Chambers, John C and Takeuchi, Fumihiko and Johnson, Andrew D and Sanghera, Dharambir K and Melander, Olle and Jern, Christina and Strbian, Daniel and Fernandez-Cadenas, Israel and Longstreth, W T and Rolfs, Arndt and Hata, Jun and Woo, Daniel and Rosand, Jonathan and Par{\'e}, Guillaume and Hopewell, Jemma C and Saleheen, Danish and Stefansson, Kari and Worrall, Bradford B and Kittner, Steven J and Seshadri, Sudha and Fornage, Myriam and Markus, Hugh S and Howson, Joanna M M and Kamatani, Yoichiro and Debette, Stephanie and Dichgans, Martin and Malik, Rainer and Chauhan, Ganesh and Traylor, Matthew and Sargurupremraj, Muralidharan and Okada, Yukinori and Mishra, Aniket and Rutten-Jacobs, Loes and Giese, Anne-Katrin and van der Laan, Sander W and Gretarsdottir, Solveig and Anderson, Christopher D and Chong, Michael and Adams, Hieab H H and Ago, Tetsuro and Almgren, Peter and Amouyel, Philippe and Ay, Hakan and Bartz, Traci M and Benavente, Oscar R and Bevan, Steve and Boncoraglio, Giorgio B and Brown, Robert D and Butterworth, Adam S and Carrera, Caty and Carty, Cara L and Chasman, Daniel I and Chen, Wei-Min and Cole, John W and Correa, Adolfo and Cotlarciuc, Ioana and Cruchaga, Carlos and Danesh, John and de Bakker, Paul I W and DeStefano, Anita L and Hoed, Marcel den and Duan, Qing and Engelter, Stefan T and Falcone, Guido J and Gottesman, Rebecca F and Grewal, Raji P and Gudnason, Vilmundur and Gustafsson, Stefan and Haessler, Jeffrey and Harris, Tamara B and Hassan, Ahamad and Havulinna, Aki S and Heckbert, Susan R and Holliday, Elizabeth G and Howard, George and Hsu, Fang-Chi and Hyacinth, Hyacinth I and Ikram, M Arfan and Ingelsson, Erik and Irvin, Marguerite R and Jian, Xueqiu and Jimenez-Conde, Jordi and Johnson, Julie A and Jukema, J Wouter and Kanai, Masahiro and Keene, Keith L and Kissela, Brett M and Kleindorfer, Dawn O and Kooperberg, Charles and Kubo, Michiaki and Lange, Leslie A and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Lee, Jin-Moo and Lemmens, Robin and Leys, Didier and Lewis, Cathryn M and Lin, Wei-Yu and Lindgren, Arne G and Lorentzen, Erik and Magnusson, Patrik K and Maguire, Jane and Manichaikul, Ani and McArdle, Patrick F and Meschia, James F and Mitchell, Braxton D and Mosley, Thomas H and Nalls, Michael A and Ninomiya, Toshiharu and O{\textquoteright}Donnell, Martin J and Psaty, Bruce M and Pulit, Sara L and Rannikmae, Kristiina and Reiner, Alexander P and Rexrode, Kathryn M and Rice, Kenneth and Rich, Stephen S and Ridker, Paul M and Rost, Natalia S and Rothwell, Peter M and Rotter, Jerome I and Rundek, Tatjana and Sacco, Ralph L and Sakaue, Saori and Sale, Mich{\`e}le M and Salomaa, Veikko and Sapkota, Bishwa R and Schmidt, Reinhold and Schmidt, Carsten O and Schminke, Ulf and Sharma, Pankaj and Slowik, Agnieszka and Sudlow, Cathie L M and Tanislav, Christian and Tatlisumak, Turgut and Taylor, Kent D and Thijs, Vincent N S and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tiedt, Steffen and Trompet, Stella and Tzourio, Christophe and van Duijn, Cornelia M and Walters, Matthew and Wareham, Nicholas J and Wassertheil-Smoller, Sylvia and Wilson, James G and Wiggins, Kerri L and Yang, Qiong and Yusuf, Salim and Amin, Najaf and Aparicio, Hugo S and Arnett, Donna K and Attia, John and Beiser, Alexa S and Berr, Claudine and Buring, Julie E and Bustamante, Mariana and Caso, Valeria and Cheng, Yu-Ching and Choi, Seung Hoan and Chowhan, Ayesha and Cullell, Natalia and Dartigues, Jean-Fran{\c c}ois and Delavaran, Hossein and Delgado, Pilar and D{\"o}rr, Marcus and Engstr{\"o}m, Gunnar and Ford, Ian and Gurpreet, Wander S and Hamsten, Anders and Heitsch, Laura and Hozawa, Atsushi and Ibanez, Laura and Ilinca, Andreea and Ingelsson, Martin and Iwasaki, Motoki and Jackson, Rebecca D and Jood, Katarina and Jousilahti, Pekka and Kaffashian, Sara and Kalra, Lalit and Kamouchi, Masahiro and Kitazono, Takanari and Kjartansson, Olafur and Kloss, Manja and Koudstaal, Peter J and Krupinski, Jerzy and Labovitz, Daniel L and Laurie, Cathy C and Levi, Christopher R and Li, Linxin and Lind, Lars and Lindgren, Cecilia M and Lioutas, Vasileios and Liu, Yong Mei and Lopez, Oscar L and Makoto, Hirata and Martinez-Majander, Nicolas and Matsuda, Koichi and Minegishi, Naoko and Montaner, Joan and Morris, Andrew P and Mui{\~n}o, Elena and M{\"u}ller-Nurasyid, Martina and Norrving, Bo and Ogishima, Soichi and Parati, Eugenio A and Peddareddygari, Leema Reddy and Pedersen, Nancy L and Pera, Joanna and Perola, Markus and Pezzini, Alessandro and Pileggi, Silvana and Rabionet, Raquel and Riba-Llena, Iolanda and Ribas{\'e}s, Marta and Romero, Jose R and Roquer, Jaume and Rudd, Anthony G and Sarin, Antti-Pekka and Sarju, Ralhan and Sarnowski, Chloe and Sasaki, Makoto and Satizabal, Claudia L and Satoh, Mamoru and Sattar, Naveed and Sawada, Norie and Sibolt, Gerli and Sigurdsson, {\'A}sgeir and Smith, Albert and Sobue, Kenji and Soriano-T{\'a}rraga, Carolina and Stanne, Tara and Stine, O Colin and Stott, David J and Strauch, Konstantin and Takai, Takako and Tanaka, Hideo and Tanno, Kozo and Teumer, Alexander and Tomppo, Liisa and Torres-Aguila, Nuria P and Touze, Emmanuel and Tsugane, Shoichiro and Uitterlinden, Andr{\'e} G and Valdimarsson, Einar M and van der Lee, Sven J and V{\"o}lzke, Henry and Wakai, Kenji and Weir, David and Williams, Stephen R and Wolfe, Charles D A and Wong, Quenna and Xu, Huichun and Yamaji, Taiki and Sanghera, Dharambir K and Melander, Olle and Jern, Christina and Strbian, Daniel and Fernandez-Cadenas, Israel and Longstreth, W T and Rolfs, Arndt and Hata, Jun and Woo, Daniel and Rosand, Jonathan and Par{\'e}, Guillaume and Hopewell, Jemma C and Saleheen, Danish and Stefansson, Kari and Worrall, Bradford B and Kittner, Steven J and Seshadri, Sudha and Fornage, Myriam and Markus, Hugh S and Howson, Joanna M M and Kamatani, Yoichiro and Debette, Stephanie and Dichgans, Martin} } @article {7819, title = {Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 Jul 30}, pages = {2976}, abstract = {

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.

}, issn = {2041-1723}, doi = {10.1038/s41467-018-05369-0}, author = {Wyss, Annah B and Sofer, Tamar and Lee, Mi Kyeong and Terzikhan, Natalie and Nguyen, Jennifer N and Lahousse, Lies and Latourelle, Jeanne C and Smith, Albert Vernon and Bartz, Traci M and Feitosa, Mary F and Gao, Wei and Ahluwalia, Tarunveer S and Tang, Wenbo and Oldmeadow, Christopher and Duan, Qing and de Jong, Kim and Wojczynski, Mary K and Wang, Xin-Qun and Noordam, Raymond and Hartwig, Fernando Pires and Jackson, Victoria E and Wang, Tianyuan and Obeidat, Ma{\textquoteright}en and Hobbs, Brian D and Huan, Tianxiao and Gui, Hongsheng and Parker, Margaret M and Hu, Donglei and Mogil, Lauren S and Kichaev, Gleb and Jin, Jianping and Graff, Mariaelisa and Harris, Tamara B and Kalhan, Ravi and Heckbert, Susan R and Paternoster, Lavinia and Burkart, Kristin M and Liu, Yongmei and Holliday, Elizabeth G and Wilson, James G and Vonk, Judith M and Sanders, Jason L and Barr, R Graham and de Mutsert, Ren{\'e}e and Menezes, Ana Maria Baptista and Adams, Hieab H H and van den Berge, Maarten and Joehanes, Roby and Levin, Albert M and Liberto, Jennifer and Launer, Lenore J and Morrison, Alanna C and Sitlani, Colleen M and Celed{\'o}n, Juan C and Kritchevsky, Stephen B and Scott, Rodney J and Christensen, Kaare and Rotter, Jerome I and Bonten, Tobias N and Wehrmeister, Fernando C{\'e}sar and Boss{\'e}, Yohan and Xiao, Shujie and Oh, Sam and Franceschini, Nora and Brody, Jennifer A and Kaplan, Robert C and Lohman, Kurt and McEvoy, Mark and Province, Michael A and Rosendaal, Frits R and Taylor, Kent D and Nickle, David C and Williams, L Keoki and Burchard, Esteban G and Wheeler, Heather E and Sin, Don D and Gudnason, Vilmundur and North, Kari E and Fornage, Myriam and Psaty, Bruce M and Myers, Richard H and O{\textquoteright}Connor, George and Hansen, Torben and Laurie, Cathy C and Cassano, Patricia A and Sung, Joohon and Kim, Woo Jin and Attia, John R and Lange, Leslie and Boezen, H Marike and Thyagarajan, Bharat and Rich, Stephen S and Mook-Kanamori, Dennis O and Horta, Bernardo Lessa and Uitterlinden, Andr{\'e} G and Im, Hae Kyung and Cho, Michael H and Brusselle, Guy G and Gharib, Sina A and Dupuis, Jos{\'e}e and Manichaikul, Ani and London, Stephanie J} } @article {7776, title = {Omega-3 Fatty Acids and Genome-wide Interaction Analyses Reveal DPP10-Pulmonary Function Association.}, journal = {Am J Respir Crit Care Med}, year = {2018}, month = {2018 Sep 10}, abstract = {

RATIONALE: Omega-3 poly-unsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health.

OBJECTIVE: To investigate n-3 PUFA associations with spirometric measures of pulmonary function tests (PFTs) and determine underlying genetic susceptibility.

METHODS: Associations of n-3 PUFA biomarkers (alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (forced expiratory volume in the first second [FEV], forced vital capacity [FVC], and [FEV/FVC]) in meta-analyses across seven cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (N=16,134 of European or African ancestry). PFT-associated n-3 PUFAs were carried forward to genome-wide interaction analyses in the four largest cohorts (N=11,962) and replicated in one cohort (N=1,687). Cohort-specific results were combined using joint 2 degree-of-freedom (2df) meta-analyses of single nucleotide polymorphism (SNP) associations and their interactions with n-3 PUFAs.

RESULTS: DPA and DHA were positively associated with FEV1 and FVC (P<0.025), with evidence for effect modification by smoking and by sex. Genome-wide analyses identified a novel association of rs11693320-an intronic DPP10 SNP-with FVC when incorporating an interaction with DHA, and the finding was replicated (P=9.4{\texttimes}10 across discovery and replication cohorts). The rs11693320-A allele (frequency~80\%) was associated with lower FVC (P=2.1{\texttimes}10; β= -161.0mL), and the association was attenuated by higher DHA levels (P=2.1{\texttimes}10; β=36.2mL).

CONCLUSIONS: We corroborated beneficial effects of n-3 PUFAs on pulmonary function. By modeling genome-wide n-3 PUFA interactions, we identified a novel DPP10 SNP association with FVC that was not detectable in much larger studies ignoring this interaction.

}, issn = {1535-4970}, doi = {10.1164/rccm.201802-0304OC}, author = {Xu, Jiayi and Gaddis, Nathan C and Bartz, Traci M and Hou, Ruixue and Manichaikul, Ani W and Pankratz, Nathan and Smith, Albert V and Sun, Fangui and Terzikhan, Natalie and Markunas, Christina A and Patchen, Bonnie K and Schu, Matthew and Beydoun, May A and Brusselle, Guy G and Eiriksdottir, Gudny and Zhou, Xia and Wood, Alexis C and Graff, Mariaelisa and Harris, Tamara B and Ikram, M Arfan and Jacobs, David R and Launer, Lenore J and Lemaitre, Rozenn N and O{\textquoteright}Connor, George and Oelsner, Elizabeth C and Psaty, Bruce M and Ramachandran, Vasan S and Rohde, Rebecca R and Rich, Stephen S and Rotter, Jerome I and Seshadri, Sudha and Smith, Lewis J and Tiemeier, Henning and Tsai, Michael Y and Uitterlinden, Andr{\'e} G and Voruganti, V Saroja and Xu, Hanfei and Zilh{\~a}o, Nuno R and Fornage, Myriam and Zillikens, M Carola and London, Stephanie J and Barr, R Graham and Dupuis, Jos{\'e}e and Gharib, Sina A and Gudnason, Vilmundur and Lahousse, Lies and North, Kari E and Steffen, Lyn M and Cassano, Patricia A and Hancock, Dana B} } @article {7668, title = {Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Apr}, pages = {559-571}, abstract = {

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 {\texttimes} 10); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio <=1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent {\textquoteright}false leads{\textquoteright} with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0084-1}, author = {Mahajan, Anubha and Wessel, Jennifer and Willems, Sara M and Zhao, Wei and Robertson, Neil R and Chu, Audrey Y and Gan, Wei and Kitajima, Hidetoshi and Taliun, Daniel and Rayner, N William and Guo, Xiuqing and Lu, Yingchang and Li, Man and Jensen, Richard A and Hu, Yao and Huo, Shaofeng and Lohman, Kurt K and Zhang, Weihua and Cook, James P and Prins, Bram Peter and Flannick, Jason and Grarup, Niels and Trubetskoy, Vassily Vladimirovich and Kravic, Jasmina and Kim, Young Jin and Rybin, Denis V and Yaghootkar, Hanieh and M{\"u}ller-Nurasyid, Martina and Meidtner, Karina and Li-Gao, Ruifang and Varga, Tibor V and Marten, Jonathan and Li, Jin and Smith, Albert Vernon and An, Ping and Ligthart, Symen and Gustafsson, Stefan and Malerba, Giovanni and Demirkan, Ayse and Tajes, Juan Fernandez and Steinthorsdottir, Valgerdur and Wuttke, Matthias and Lecoeur, C{\'e}cile and Preuss, Michael and Bielak, Lawrence F and Graff, Marielisa and Highland, Heather M and Justice, Anne E and Liu, Dajiang J and Marouli, Eirini and Peloso, Gina Marie and Warren, Helen R and Afaq, Saima and Afzal, Shoaib and Ahlqvist, Emma and Almgren, Peter and Amin, Najaf and Bang, Lia B and Bertoni, Alain G and Bombieri, Cristina and Bork-Jensen, Jette and Brandslund, Ivan and Brody, Jennifer A and Burtt, Noel P and Canouil, Micka{\"e}l and Chen, Yii-Der Ida and Cho, Yoon Shin and Christensen, Cramer and Eastwood, Sophie V and Eckardt, Kai-Uwe and Fischer, Krista and Gambaro, Giovanni and Giedraitis, Vilmantas and Grove, Megan L and de Haan, Hugoline G and Hackinger, Sophie and Hai, Yang and Han, Sohee and Tybj{\ae}rg-Hansen, Anne and Hivert, Marie-France and Isomaa, Bo and J{\"a}ger, Susanne and J{\o}rgensen, Marit E and J{\o}rgensen, Torben and K{\"a}r{\"a}j{\"a}m{\"a}ki, AnneMari and Kim, Bong-Jo and Kim, Sung Soo and Koistinen, Heikki A and Kovacs, Peter and Kriebel, Jennifer and Kronenberg, Florian and L{\"a}ll, Kristi and Lange, Leslie A and Lee, Jung-Jin and Lehne, Benjamin and Li, Huaixing and Lin, Keng-Hung and Linneberg, Allan and Liu, Ching-Ti and Liu, Jun and Loh, Marie and M{\"a}gi, Reedik and Mamakou, Vasiliki and McKean-Cowdin, Roberta and Nadkarni, Girish and Neville, Matt and Nielsen, Sune F and Ntalla, Ioanna and Peyser, Patricia A and Rathmann, Wolfgang and Rice, Kenneth and Rich, Stephen S and Rode, Line and Rolandsson, Olov and Sch{\"o}nherr, Sebastian and Selvin, Elizabeth and Small, Kerrin S and Stan{\v c}{\'a}kov{\'a}, Alena and Surendran, Praveen and Taylor, Kent D and Teslovich, Tanya M and Thorand, Barbara and Thorleifsson, Gudmar and Tin, Adrienne and T{\"o}njes, Anke and Varbo, Anette and Witte, Daniel R and Wood, Andrew R and Yajnik, Pranav and Yao, Jie and Yengo, Loic and Young, Robin and Amouyel, Philippe and Boeing, Heiner and Boerwinkle, Eric and Bottinger, Erwin P and Chowdhury, Rajiv and Collins, Francis S and Dedoussis, George and Dehghan, Abbas and Deloukas, Panos and Ferrario, Marco M and Ferrieres, Jean and Florez, Jose C and Frossard, Philippe and Gudnason, Vilmundur and Harris, Tamara B and Heckbert, Susan R and Howson, Joanna M M and Ingelsson, Martin and Kathiresan, Sekar and Kee, Frank and Kuusisto, Johanna and Langenberg, Claudia and Launer, Lenore J and Lindgren, Cecilia M and M{\"a}nnist{\"o}, Satu and Meitinger, Thomas and Melander, Olle and Mohlke, Karen L and Moitry, Marie and Morris, Andrew D and Murray, Alison D and de Mutsert, Ren{\'e}e and Orho-Melander, Marju and Owen, Katharine R and Perola, Markus and Peters, Annette and Province, Michael A and Rasheed, Asif and Ridker, Paul M and Rivadineira, Fernando and Rosendaal, Frits R and Rosengren, Anders H and Salomaa, Veikko and Sheu, Wayne H-H and Sladek, Rob and Smith, Blair H and Strauch, Konstantin and Uitterlinden, Andr{\'e} G and Varma, Rohit and Willer, Cristen J and Bl{\"u}her, Matthias and Butterworth, Adam S and Chambers, John Campbell and Chasman, Daniel I and Danesh, John and van Duijn, Cornelia and Dupuis, Jos{\'e}e and Franco, Oscar H and Franks, Paul W and Froguel, Philippe and Grallert, Harald and Groop, Leif and Han, Bok-Ghee and Hansen, Torben and Hattersley, Andrew T and Hayward, Caroline and Ingelsson, Erik and Kardia, Sharon L R and Karpe, Fredrik and Kooner, Jaspal Singh and K{\"o}ttgen, Anna and Kuulasmaa, Kari and Laakso, Markku and Lin, Xu and Lind, Lars and Liu, Yongmei and Loos, Ruth J F and Marchini, Jonathan and Metspalu, Andres and Mook-Kanamori, Dennis and Nordestgaard, B{\o}rge G and Palmer, Colin N A and Pankow, James S and Pedersen, Oluf and Psaty, Bruce M and Rauramaa, Rainer and Sattar, Naveed and Schulze, Matthias B and Soranzo, Nicole and Spector, Timothy D and Stefansson, Kari and Stumvoll, Michael and Thorsteinsdottir, Unnur and Tuomi, Tiinamaija and Tuomilehto, Jaakko and Wareham, Nicholas J and Wilson, James G and Zeggini, Eleftheria and Scott, Robert A and Barroso, In{\^e}s and Frayling, Timothy M and Goodarzi, Mark O and Meigs, James B and Boehnke, Michael and Saleheen, Danish and Morris, Andrew P and Rotter, Jerome I and McCarthy, Mark I} } @article {7576, title = {Sugar-sweetened beverage intake associations with fasting glucose and insulin concentrations are not modified by selected genetic variants in a ChREBP-FGF21 pathway: a meta-analysis.}, journal = {Diabetologia}, volume = {61}, year = {2018}, month = {2018 Feb}, pages = {317-330}, abstract = {

AIMS/HYPOTHESIS: Sugar-sweetened beverages (SSBs) are a major dietary contributor to fructose intake. A molecular pathway involving the carbohydrate responsive element-binding protein (ChREBP) and the metabolic hormone fibroblast growth factor 21 (FGF21) may influence sugar metabolism and, thereby, contribute to fructose-induced metabolic disease. We hypothesise that common variants in 11 genes involved in fructose metabolism and the ChREBP-FGF21 pathway may interact with SSB intake to exacerbate positive associations between higher SSB intake and glycaemic traits.

METHODS: Data from 11 cohorts (six discovery and five replication) in the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided association and interaction results from 34,748 adults of European descent. SSB intake (soft drinks, fruit punches, lemonades or other fruit drinks) was derived from food-frequency questionnaires and food diaries. In fixed-effects meta-analyses, we quantified: (1) the associations between SSBs and glycaemic traits (fasting glucose and fasting insulin); and (2) the interactions between SSBs and 18 independent SNPs related to the ChREBP-FGF21 pathway.

RESULTS: In our combined meta-analyses of discovery and replication cohorts, after adjustment for age, sex, energy intake, BMI and other dietary covariates, each additional serving of SSB intake was associated with higher fasting glucose (β~{\textpm}~SE 0.014~{\textpm}~0.004 [mmol/l], p~=~1.5~{\texttimes}~10-3) and higher fasting insulin (0.030~{\textpm}~0.005 [log e pmol/l], p~=~2.0~{\texttimes}~10-10). No significant interactions on glycaemic traits were observed between SSB intake and selected SNPs. While a suggestive interaction was observed in the discovery cohorts with a SNP (rs1542423) in the β-Klotho (KLB) locus on fasting insulin (0.030~{\textpm}~0.011 log e pmol/l, uncorrected p~=~0.006), results in the replication cohorts and combined meta-analyses were non-significant.

CONCLUSIONS/INTERPRETATION: In this large meta-analysis, we observed that SSB intake was associated with higher fasting glucose and insulin. Although a suggestive interaction with a genetic variant in the ChREBP-FGF21 pathway was observed in the discovery cohorts, this observation was not confirmed in the replication analysis.

TRIAL REGISTRATION: Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005121 (Framingham Offspring Study), NCT00005487 (Multi-Ethnic Study of Atherosclerosis) and NCT00005152 (Nurses{\textquoteright} Health Study).

}, issn = {1432-0428}, doi = {10.1007/s00125-017-4475-0}, author = {McKeown, Nicola M and Dashti, Hassan S and Ma, Jiantao and Haslam, Danielle E and Kiefte-de Jong, Jessica C and Smith, Caren E and Tanaka, Toshiko and Graff, Mariaelisa and Lemaitre, Rozenn N and Rybin, Denis and Sonestedt, Emily and Frazier-Wood, Alexis C and Mook-Kanamori, Dennis O and Li, Yanping and Wang, Carol A and Leermakers, Elisabeth T M and Mikkil{\"a}, Vera and Young, Kristin L and Mukamal, Kenneth J and Cupples, L Adrienne and Schulz, Christina-Alexandra and Chen, Tzu-An and Li-Gao, Ruifang and Huang, Tao and Oddy, Wendy H and Raitakari, Olli and Rice, Kenneth and Meigs, James B and Ericson, Ulrika and Steffen, Lyn M and Rosendaal, Frits R and Hofman, Albert and K{\"a}h{\"o}nen, Mika and Psaty, Bruce M and Brunkwall, Louise and Uitterlinden, Andr{\'e} G and Viikari, Jorma and Siscovick, David S and Sepp{\"a}l{\"a}, Ilkka and North, Kari E and Mozaffarian, Dariush and Dupuis, Jos{\'e}e and Orho-Melander, Marju and Rich, Stephen S and de Mutsert, Ren{\'e}e and Qi, Lu and Pennell, Craig E and Franco, Oscar H and Lehtim{\"a}ki, Terho and Herman, Mark A} } @article {8198, title = {Associations of autozygosity with a broad range of human phenotypes.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 Oct 31}, pages = {4957}, abstract = {

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55\% decrease [95\% CI 44-66\%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.

}, issn = {2041-1723}, doi = {10.1038/s41467-019-12283-6}, author = {Clark, David W and Okada, Yukinori and Moore, Kristjan H S and Mason, Dan and Pirastu, Nicola and Gandin, Ilaria and Mattsson, Hannele and Barnes, Catriona L K and Lin, Kuang and Zhao, Jing Hua and Deelen, Patrick and Rohde, Rebecca and Schurmann, Claudia and Guo, Xiuqing and Giulianini, Franco and Zhang, Weihua and Medina-G{\'o}mez, Carolina and Karlsson, Robert and Bao, Yanchun and Bartz, Traci M and Baumbach, Clemens and Biino, Ginevra and Bixley, Matthew J and Brumat, Marco and Chai, Jin-Fang and Corre, Tanguy and Cousminer, Diana L and Dekker, Annelot M and Eccles, David A and van Eijk, Kristel R and Fuchsberger, Christian and Gao, He and Germain, Marine and Gordon, Scott D and de Haan, Hugoline G and Harris, Sarah E and Hofer, Edith and Huerta-Chagoya, Alicia and Igartua, Catherine and Jansen, Iris E and Jia, Yucheng and Kacprowski, Tim and Karlsson, Torgny and Kleber, Marcus E and Li, Shengchao Alfred and Li-Gao, Ruifang and Mahajan, Anubha and Matsuda, Koichi and Meidtner, Karina and Meng, Weihua and Montasser, May E and van der Most, Peter J and Munz, Matthias and Nutile, Teresa and Palviainen, Teemu and Prasad, Gauri and Prasad, Rashmi B and Priyanka, Tallapragada Divya Sri and Rizzi, Federica and Salvi, Erika and Sapkota, Bishwa R and Shriner, Daniel and Skotte, Line and Smart, Melissa C and Smith, Albert Vernon and van der Spek, Ashley and Spracklen, Cassandra N and Strawbridge, Rona J and Tajuddin, Salman M and Trompet, Stella and Turman, Constance and Verweij, Niek and Viberti, Clara and Wang, Lihua and Warren, Helen R and Wootton, Robyn E and Yanek, Lisa R and Yao, Jie and Yousri, Noha A and Zhao, Wei and Adeyemo, Adebowale A and Afaq, Saima and Aguilar-Salinas, Carlos Alberto and Akiyama, Masato and Albert, Matthew L and Allison, Matthew A and Alver, Maris and Aung, Tin and Azizi, Fereidoun and Bentley, Amy R and Boeing, Heiner and Boerwinkle, Eric and Borja, Judith B and de Borst, Gert J and Bottinger, Erwin P and Broer, Linda and Campbell, Harry and Chanock, Stephen and Chee, Miao-Li and Chen, Guanjie and Chen, Yii-der I and Chen, Zhengming and Chiu, Yen-Feng and Cocca, Massimiliano and Collins, Francis S and Concas, Maria Pina and Corley, Janie and Cugliari, Giovanni and van Dam, Rob M and Damulina, Anna and Daneshpour, Maryam S and Day, Felix R and Delgado, Graciela E and Dhana, Klodian and Doney, Alexander S F and D{\"o}rr, Marcus and Doumatey, Ayo P and Dzimiri, Nduna and Ebenesersd{\'o}ttir, S Sunna and Elliott, Joshua and Elliott, Paul and Ewert, Ralf and Felix, Janine F and Fischer, Krista and Freedman, Barry I and Girotto, Giorgia and Goel, Anuj and G{\"o}gele, Martin and Goodarzi, Mark O and Graff, Mariaelisa and Granot-Hershkovitz, Einat and Grodstein, Francine and Guarrera, Simonetta and Gudbjartsson, Daniel F and Guity, Kamran and Gunnarsson, Bjarni and Guo, Yu and Hagenaars, Saskia P and Haiman, Christopher A and Halevy, Avner and Harris, Tamara B and Hedayati, Mehdi and van Heel, David A and Hirata, Makoto and H{\"o}fer, Imo and Hsiung, Chao Agnes and Huang, Jinyan and Hung, Yi-Jen and Ikram, M Arfan and Jagadeesan, Anuradha and Jousilahti, Pekka and Kamatani, Yoichiro and Kanai, Masahiro and Kerrison, Nicola D and Kessler, Thorsten and Khaw, Kay-Tee and Khor, Chiea Chuen and de Kleijn, Dominique P V and Koh, Woon-Puay and Kolcic, Ivana and Kraft, Peter and Kr{\"a}mer, Bernhard K and Kutalik, Zolt{\'a}n and Kuusisto, Johanna and Langenberg, Claudia and Launer, Lenore J and Lawlor, Deborah A and Lee, I-Te and Lee, Wen-Jane and Lerch, Markus M and Li, Liming and Liu, Jianjun and Loh, Marie and London, Stephanie J and Loomis, Stephanie and Lu, Yingchang and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Manichaikul, Ani W and Manunta, Paolo and M{\'a}sson, G{\'\i}sli and Matoba, Nana and Mei, Xue W and Meisinger, Christa and Meitinger, Thomas and Mezzavilla, Massimo and Milani, Lili and Millwood, Iona Y and Momozawa, Yukihide and Moore, Amy and Morange, Pierre-Emmanuel and Moreno-Macias, Hortensia and Mori, Trevor A and Morrison, Alanna C and Muka, Taulant and Murakami, Yoshinori and Murray, Alison D and de Mutsert, Ren{\'e}e and Mychaleckyj, Josyf C and Nalls, Mike A and Nauck, Matthias and Neville, Matt J and Nolte, Ilja M and Ong, Ken K and Orozco, Lorena and Padmanabhan, Sandosh and P{\'a}lsson, Gunnar and Pankow, James S and Pattaro, Cristian and Pattie, Alison and Polasek, Ozren and Poulter, Neil and Pramstaller, Peter P and Quintana-Murci, Lluis and R{\"a}ikk{\"o}nen, Katri and Ralhan, Sarju and Rao, Dabeeru C and van Rheenen, Wouter and Rich, Stephen S and Ridker, Paul M and Rietveld, Cornelius A and Robino, Antonietta and van Rooij, Frank J A and Ruggiero, Daniela and Saba, Yasaman and Sabanayagam, Charumathi and Sabater-Lleal, Maria and Sala, Cinzia Felicita and Salomaa, Veikko and Sandow, Kevin and Schmidt, Helena and Scott, Laura J and Scott, William R and Sedaghati-Khayat, Bahareh and Sennblad, Bengt and van Setten, Jessica and Sever, Peter J and Sheu, Wayne H-H and Shi, Yuan and Shrestha, Smeeta and Shukla, Sharvari Rahul and Sigurdsson, Jon K and Sikka, Timo Tonis and Singh, Jai Rup and Smith, Blair H and Stan{\v c}{\'a}kov{\'a}, Alena and Stanton, Alice and Starr, John M and Stefansdottir, Lilja and Straker, Leon and Sulem, Patrick and Sveinbjornsson, Gardar and Swertz, Morris A and Taylor, Adele M and Taylor, Kent D and Terzikhan, Natalie and Tham, Yih-Chung and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tillander, Annika and Tracy, Russell P and Tusi{\'e}-Luna, Teresa and Tzoulaki, Ioanna and Vaccargiu, Simona and Vangipurapu, Jagadish and Veldink, Jan H and Vitart, Veronique and V{\"o}lker, Uwe and Vuoksimaa, Eero and Wakil, Salma M and Waldenberger, Melanie and Wander, Gurpreet S and Wang, Ya Xing and Wareham, Nicholas J and Wild, Sarah and Yajnik, Chittaranjan S and Yuan, Jian-Min and Zeng, Lingyao and Zhang, Liang and Zhou, Jie and Amin, Najaf and Asselbergs, Folkert W and Bakker, Stephan J L and Becker, Diane M and Lehne, Benjamin and Bennett, David A and van den Berg, Leonard H and Berndt, Sonja I and Bharadwaj, Dwaipayan and Bielak, Lawrence F and Bochud, Murielle and Boehnke, Mike and Bouchard, Claude and Bradfield, Jonathan P and Brody, Jennifer A and Campbell, Archie and Carmi, Shai and Caulfield, Mark J and Cesarini, David and Chambers, John C and Chandak, Giriraj Ratan and Cheng, Ching-Yu and Ciullo, Marina and Cornelis, Marilyn and Cusi, Daniele and Smith, George Davey and Deary, Ian J and Dorajoo, Rajkumar and van Duijn, Cornelia M and Ellinghaus, David and Erdmann, Jeanette and Eriksson, Johan G and Evangelou, Evangelos and Evans, Michele K and Faul, Jessica D and Feenstra, Bjarke and Feitosa, Mary and Foisy, Sylvain and Franke, Andre and Friedlander, Yechiel and Gasparini, Paolo and Gieger, Christian and Gonzalez, Clicerio and Goyette, Philippe and Grant, Struan F A and Griffiths, Lyn R and Groop, Leif and Gudnason, Vilmundur and Gyllensten, Ulf and Hakonarson, Hakon and Hamsten, Anders and van der Harst, Pim and Heng, Chew-Kiat and Hicks, Andrew A and Hochner, Hagit and Huikuri, Heikki and Hunt, Steven C and Jaddoe, Vincent W V and De Jager, Philip L and Johannesson, Magnus and Johansson, Asa and Jonas, Jost B and Jukema, J Wouter and Junttila, Juhani and Kaprio, Jaakko and Kardia, Sharon L R and Karpe, Fredrik and Kumari, Meena and Laakso, Markku and van der Laan, Sander W and Lahti, Jari and Laudes, Matthias and Lea, Rodney A and Lieb, Wolfgang and Lumley, Thomas and Martin, Nicholas G and M{\"a}rz, Winfried and Matullo, Giuseppe and McCarthy, Mark I and Medland, Sarah E and Merriman, Tony R and Metspalu, Andres and Meyer, Brian F and Mohlke, Karen L and Montgomery, Grant W and Mook-Kanamori, Dennis and Munroe, Patricia B and North, Kari E and Nyholt, Dale R and O{\textquoteright}Connell, Jeffery R and Ober, Carole and Oldehinkel, Albertine J and Palmas, Walter and Palmer, Colin and Pasterkamp, Gerard G and Patin, Etienne and Pennell, Craig E and Perusse, Louis and Peyser, Patricia A and Pirastu, Mario and Polderman, Tinca J C and Porteous, David J and Posthuma, Danielle and Psaty, Bruce M and Rioux, John D and Rivadeneira, Fernando and Rotimi, Charles and Rotter, Jerome I and Rudan, Igor and den Ruijter, Hester M and Sanghera, Dharambir K and Sattar, Naveed and Schmidt, Reinhold and Schulze, Matthias B and Schunkert, Heribert and Scott, Robert A and Shuldiner, Alan R and Sim, Xueling and Small, Neil and Smith, Jennifer A and Sotoodehnia, Nona and Tai, E-Shyong and Teumer, Alexander and Timpson, Nicholas J and Toniolo, Daniela and Tr{\'e}gou{\"e}t, David-Alexandre and Tuomi, Tiinamaija and Vollenweider, Peter and Wang, Carol A and Weir, David R and Whitfield, John B and Wijmenga, Cisca and Wong, Tien-Yin and Wright, John and Yang, Jingyun and Yu, Lei and Zemel, Babette S and Zonderman, Alan B and Perola, Markus and Magnusson, Patrik K E and Uitterlinden, Andr{\'e} G and Kooner, Jaspal S and Chasman, Daniel I and Loos, Ruth J F and Franceschini, Nora and Franke, Lude and Haley, Chris S and Hayward, Caroline and Walters, Robin G and Perry, John R B and Esko, T{\~o}nu and Helgason, Agnar and Stefansson, Kari and Joshi, Peter K and Kubo, Michiaki and Wilson, James F} } @article {8205, title = {Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Oct 03}, pages = {706-718}, abstract = {

Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12\% in African-Americans, MAF = 2\% in Hispanics) lowered HbA1c (-0.88\% in hemizygous males, -0.34\% in heterozygous females) and explained 23\% of HbA1c variance in African-Americans and 4\% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5\%; -0.98\% in hemizygous males, -0.46\% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.08.010}, author = {Sarnowski, Chloe and Leong, Aaron and Raffield, Laura M and Wu, Peitao and de Vries, Paul S and DiCorpo, Daniel and Guo, Xiuqing and Xu, Huichun and Liu, Yongmei and Zheng, Xiuwen and Hu, Yao and Brody, Jennifer A and Goodarzi, Mark O and Hidalgo, Bertha A and Highland, Heather M and Jain, Deepti and Liu, Ching-Ti and Naik, Rakhi P and O{\textquoteright}Connell, Jeffrey R and Perry, James A and Porneala, Bianca C and Selvin, Elizabeth and Wessel, Jennifer and Psaty, Bruce M and Curran, Joanne E and Peralta, Juan M and Blangero, John and Kooperberg, Charles and Mathias, Rasika and Johnson, Andrew D and Reiner, Alexander P and Mitchell, Braxton D and Cupples, L Adrienne and Vasan, Ramachandran S and Correa, Adolfo and Morrison, Alanna C and Boerwinkle, Eric and Rotter, Jerome I and Rich, Stephen S and Manning, Alisa K and Dupuis, Jos{\'e}e and Meigs, James B} } @article {7970, title = {Multi-Ancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions.}, journal = {Am J Epidemiol}, year = {2019}, month = {2019 Jan 29}, abstract = {

An individual{\textquoteright}s lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multi-ancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in Stage 1 (genome-wide discovery) and 66 studies in Stage 2 (focused follow-up), for a total of 394,584 individuals from five ancestry groups. Genetic main and interaction effects were jointly assessed by a 2 degrees of freedom (DF) test, and a 1 DF test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P~<~1~{\texttimes}~10-6) with lipid levels in Stage 1 and were evaluated in Stage 2, followed by combined analyses of Stage 1 and Stage 2. In the combined analysis of Stage 1 and Stage 2, 147 independent loci were associated with lipid levels at P~<~5~{\texttimes}~10-8 using 2 DF tests, of which 18 were novel. No genome-wide significant associations were found testing the interaction effect alone. The novel loci included several genes (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.

}, issn = {1476-6256}, doi = {10.1093/aje/kwz005}, author = {de Vries, Paul S and Brown, Michael R and Bentley, Amy R and Sung, Yun J and Winkler, Thomas W and Ntalla, Ioanna and Schwander, Karen and Kraja, Aldi T and Guo, Xiuqing and Franceschini, Nora and Cheng, Ching-Yu and Sim, Xueling and Vojinovic, Dina and Huffman, Jennifer E and Musani, Solomon K and Li, Changwei and Feitosa, Mary F and Richard, Melissa A and Noordam, Raymond and Aschard, Hugues and Bartz, Traci M and Bielak, Lawrence F and Deng, Xuan and Dorajoo, Rajkumar and Lohman, Kurt K and Manning, Alisa K and Rankinen, Tuomo and Smith, Albert V and Tajuddin, Salman M and Evangelou, Evangelos and Graff, Mariaelisa and Alver, Maris and Boissel, Mathilde and Chai, Jin Fang and Chen, Xu and Divers, Jasmin and Gandin, Ilaria and Gao, Chuan and Goel, Anuj and Hagemeijer, Yanick and Harris, Sarah E and Hartwig, Fernando P and He, Meian and Horimoto, Andrea R V R and Hsu, Fang-Chi and Jackson, Anne U and Kasturiratne, Anuradhani and Komulainen, Pirjo and Kuhnel, Brigitte and Laguzzi, Federica and Lee, Joseph H and Luan, Jian{\textquoteright}an and Lyytik{\"a}inen, Leo-Pekka and Matoba, Nana and Nolte, Ilja M and Pietzner, Maik and Riaz, Muhammad and Said, M Abdullah and Scott, Robert A and Sofer, Tamar and Stan{\v c}{\'a}kov{\'a}, Alena and Takeuchi, Fumihiko and Tayo, Bamidele O and van der Most, Peter J and Varga, Tibor V and Wang, Yajuan and Ware, Erin B and Wen, Wanqing and Yanek, Lisa R and Zhang, Weihua and Zhao, Jing Hua and Afaq, Saima and Amin, Najaf and Amini, Marzyeh and Arking, Dan E and Aung, Tin and Ballantyne, Christie and Boerwinkle, Eric and Broeckel, Ulrich and Campbell, Archie and Canouil, Micka{\"e}l and Charumathi, Sabanayagam and Chen, Yii-Der Ida and Connell, John M and de Faire, Ulf and de Las Fuentes, Lisa and de Mutsert, Ren{\'e}e and de Silva, H Janaka and Ding, Jingzhong and Dominiczak, Anna F and Duan, Qing and Eaton, Charles B and Eppinga, Ruben N and Faul, Jessica D and Fisher, Virginia and Forrester, Terrence and Franco, Oscar H and Friedlander, Yechiel and Ghanbari, Mohsen and Giulianini, Franco and Grabe, Hans J and Grove, Megan L and Gu, C Charles and Harris, Tamara B and Heikkinen, Sami and Heng, Chew-Kiat and Hirata, Makoto and Hixson, James E and Howard, Barbara V and Ikram, M Arfan and Jacobs, David R and Johnson, Craig and Jonas, Jost Bruno and Kammerer, Candace M and Katsuya, Tomohiro and Khor, Chiea Chuen and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Koistinen, Heikki A and Kolcic, Ivana and Kooperberg, Charles and Krieger, Jose E and Kritchevsky, Steve B and Kubo, Michiaki and Kuusisto, Johanna and Lakka, Timo A and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Lehne, Benjamin and Lemaitre, Rozenn N and Li, Yize and Liang, Jingjing and Liu, Jianjun and Liu, Kiang and Loh, Marie and Louie, Tin and M{\"a}gi, Reedik and Manichaikul, Ani W and McKenzie, Colin A and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Milani, Lili and Mohlke, Karen L and Mosley, Thomas H and Mukamal, Kenneth J and Nalls, Mike A and Nauck, Matthias and Nelson, Christopher P and Sotoodehnia, Nona and O{\textquoteright}Connell, Jeff R and Palmer, Nicholette D and Pazoki, Raha and Pedersen, Nancy L and Peters, Annette and Peyser, Patricia A and Polasek, Ozren and Poulter, Neil and Raffel, Leslie J and Raitakari, Olli T and Reiner, Alex P and Rice, Treva K and Rich, Stephen S and Robino, Antonietta and Robinson, Jennifer G and Rose, Lynda M and Rudan, Igor and Schmidt, Carsten O and Schreiner, Pamela J and Scott, William R and Sever, Peter and Shi, Yuan and Sidney, Stephen and Sims, Mario and Smith, Blair H and Smith, Jennifer A and Snieder, Harold and Starr, John M and Strauch, Konstantin and Tan, Nicholas and Taylor, Kent D and Teo, Yik Ying and Tham, Yih Chung and Uitterlinden, Andr{\'e} G and van Heemst, Diana and Vuckovic, Dragana and Waldenberger, Melanie and Wang, Lihua and Wang, Yujie and Wang, Zhe and Wei, Wen Bin and Williams, Christine and Wilson, Gregory and Wojczynski, Mary K and Yao, Jie and Yu, Bing and Yu, Caizheng and Yuan, Jian-Min and Zhao, Wei and Zonderman, Alan B and Becker, Diane M and Boehnke, Michael and Bowden, Donald W and Chambers, John C and Deary, Ian J and Esko, T{\~o}nu and Farrall, Martin and Franks, Paul W and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Horta, Bernardo L and Kamatani, Yoichiro and Kato, Norihiro and Kooner, Jaspal S and Laakso, Markku and Leander, Karin and Lehtim{\"a}ki, Terho and Magnusson, Patrik K E and Penninx, Brenda and Pereira, Alexandre C and Rauramaa, Rainer and Samani, Nilesh J and Scott, James and Shu, Xiao-Ou and van der Harst, Pim and Wagenknecht, Lynne E and Wang, Ya Xing and Wareham, Nicholas J and Watkins, Hugh and Weir, David R and Wickremasinghe, Ananda R and Zheng, Wei and Elliott, Paul and North, Kari E and Bouchard, Claude and Evans, Michele K and Gudnason, Vilmundur and Liu, Ching-Ti and Liu, Yongmei and Psaty, Bruce M and Ridker, Paul M and van Dam, Rob M and Kardia, Sharon L R and Zhu, Xiaofeng and Rotimi, Charles N and Mook-Kanamori, Dennis O and Fornage, Myriam and Kelly, Tanika N and Fox, Ervin R and Hayward, Caroline and van Duijn, Cornelia M and Tai, E Shyong and Wong, Tien Yin and Liu, Jingmin and Rotter, Jerome I and Gauderman, W James and Province, Michael A and Munroe, Patricia B and Rice, Kenneth and Chasman, Daniel I and Cupples, L Adrienne and Rao, Dabeeru C and Morrison, Alanna C} } @article {8005, title = {Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 Apr}, pages = {636-648}, abstract = {

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.

}, issn = {1546-1718}, doi = {10.1038/s41588-019-0378-y}, author = {Bentley, Amy R and Sung, Yun J and Brown, Michael R and Winkler, Thomas W and Kraja, Aldi T and Ntalla, Ioanna and Schwander, Karen and Chasman, Daniel I and Lim, Elise and Deng, Xuan and Guo, Xiuqing and Liu, Jingmin and Lu, Yingchang and Cheng, Ching-Yu and Sim, Xueling and Vojinovic, Dina and Huffman, Jennifer E and Musani, Solomon K and Li, Changwei and Feitosa, Mary F and Richard, Melissa A and Noordam, Raymond and Baker, Jenna and Chen, Guanjie and Aschard, Hugues and Bartz, Traci M and Ding, Jingzhong and Dorajoo, Rajkumar and Manning, Alisa K and Rankinen, Tuomo and Smith, Albert V and Tajuddin, Salman M and Zhao, Wei and Graff, Mariaelisa and Alver, Maris and Boissel, Mathilde and Chai, Jin Fang and Chen, Xu and Divers, Jasmin and Evangelou, Evangelos and Gao, Chuan and Goel, Anuj and Hagemeijer, Yanick and Harris, Sarah E and Hartwig, Fernando P and He, Meian and Horimoto, Andrea R V R and Hsu, Fang-Chi and Hung, Yi-Jen and Jackson, Anne U and Kasturiratne, Anuradhani and Komulainen, Pirjo and Kuhnel, Brigitte and Leander, Karin and Lin, Keng-Hung and Luan, Jian{\textquoteright}an and Lyytik{\"a}inen, Leo-Pekka and Matoba, Nana and Nolte, Ilja M and Pietzner, Maik and Prins, Bram and Riaz, Muhammad and Robino, Antonietta and Said, M Abdullah and Schupf, Nicole and Scott, Robert A and Sofer, Tamar and Stan{\v c}{\'a}kov{\'a}, Alena and Takeuchi, Fumihiko and Tayo, Bamidele O and van der Most, Peter J and Varga, Tibor V and Wang, Tzung-Dau and Wang, Yajuan and Ware, Erin B and Wen, Wanqing and Xiang, Yong-Bing and Yanek, Lisa R and Zhang, Weihua and Zhao, Jing Hua and Adeyemo, Adebowale and Afaq, Saima and Amin, Najaf and Amini, Marzyeh and Arking, Dan E and Arzumanyan, Zorayr and Aung, Tin and Ballantyne, Christie and Barr, R Graham and Bielak, Lawrence F and Boerwinkle, Eric and Bottinger, Erwin P and Broeckel, Ulrich and Brown, Morris and Cade, Brian E and Campbell, Archie and Canouil, Micka{\"e}l and Charumathi, Sabanayagam and Chen, Yii-Der Ida and Christensen, Kaare and Concas, Maria Pina and Connell, John M and de Las Fuentes, Lisa and de Silva, H Janaka and de Vries, Paul S and Doumatey, Ayo and Duan, Qing and Eaton, Charles B and Eppinga, Ruben N and Faul, Jessica D and Floyd, James S and Forouhi, Nita G and Forrester, Terrence and Friedlander, Yechiel and Gandin, Ilaria and Gao, He and Ghanbari, Mohsen and Gharib, Sina A and Gigante, Bruna and Giulianini, Franco and Grabe, Hans J and Gu, C Charles and Harris, Tamara B and Heikkinen, Sami and Heng, Chew-Kiat and Hirata, Makoto and Hixson, James E and Ikram, M Arfan and Jia, Yucheng and Joehanes, Roby and Johnson, Craig and Jonas, Jost Bruno and Justice, Anne E and Katsuya, Tomohiro and Khor, Chiea Chuen and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Kolcic, Ivana and Kooperberg, Charles and Krieger, Jose E and Kritchevsky, Stephen B and Kubo, Michiaki and Kuusisto, Johanna and Lakka, Timo A and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Lehne, Benjamin and Lewis, Cora E and Li, Yize and Liang, Jingjing and Lin, Shiow and Liu, Ching-Ti and Liu, Jianjun and Liu, Kiang and Loh, Marie and Lohman, Kurt K and Louie, Tin and Luzzi, Anna and M{\"a}gi, Reedik and Mahajan, Anubha and Manichaikul, Ani W and McKenzie, Colin A and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Milani, Lili and Mohlke, Karen L and Momozawa, Yukihide and Morris, Andrew P and Murray, Alison D and Nalls, Mike A and Nauck, Matthias and Nelson, Christopher P and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Papanicolau, George J and Pedersen, Nancy L and Peters, Annette and Peyser, Patricia A and Polasek, Ozren and Poulter, Neil and Raitakari, Olli T and Reiner, Alex P and Renstrom, Frida and Rice, Treva K and Rich, Stephen S and Robinson, Jennifer G and Rose, Lynda M and Rosendaal, Frits R and Rudan, Igor and Schmidt, Carsten O and Schreiner, Pamela J and Scott, William R and Sever, Peter and Shi, Yuan and Sidney, Stephen and Sims, Mario and Smith, Jennifer A and Snieder, Harold and Starr, John M and Strauch, Konstantin and Stringham, Heather M and Tan, Nicholas Y Q and Tang, Hua and Taylor, Kent D and Teo, Yik Ying and Tham, Yih Chung and Tiemeier, Henning and Turner, Stephen T and Uitterlinden, Andr{\'e} G and van Heemst, Diana and Waldenberger, Melanie and Wang, Heming and Wang, Lan and Wang, Lihua and Wei, Wen Bin and Williams, Christine A and Wilson, Gregory and Wojczynski, Mary K and Yao, Jie and Young, Kristin and Yu, Caizheng and Yuan, Jian-Min and Zhou, Jie and Zonderman, Alan B and Becker, Diane M and Boehnke, Michael and Bowden, Donald W and Chambers, John C and Cooper, Richard S and de Faire, Ulf and Deary, Ian J and Elliott, Paul and Esko, T{\~o}nu and Farrall, Martin and Franks, Paul W and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Horta, Bernardo L and Juang, Jyh-Ming Jimmy and Kamatani, Yoichiro and Kammerer, Candace M and Kato, Norihiro and Kooner, Jaspal S and Laakso, Markku and Laurie, Cathy C and Lee, I-Te and Lehtim{\"a}ki, Terho and Magnusson, Patrik K E and Oldehinkel, Albertine J and Penninx, Brenda W J H and Pereira, Alexandre C and Rauramaa, Rainer and Redline, Susan and Samani, Nilesh J and Scott, James and Shu, Xiao-Ou and van der Harst, Pim and Wagenknecht, Lynne E and Wang, Jun-Sing and Wang, Ya Xing and Wareham, Nicholas J and Watkins, Hugh and Weir, David R and Wickremasinghe, Ananda R and Wu, Tangchun and Zeggini, Eleftheria and Zheng, Wei and Bouchard, Claude and Evans, Michele K and Gudnason, Vilmundur and Kardia, Sharon L R and Liu, Yongmei and Psaty, Bruce M and Ridker, Paul M and van Dam, Rob M and Mook-Kanamori, Dennis O and Fornage, Myriam and Province, Michael A and Kelly, Tanika N and Fox, Ervin R and Hayward, Caroline and van Duijn, Cornelia M and Tai, E Shyong and Wong, Tien Yin and Loos, Ruth J F and Franceschini, Nora and Rotter, Jerome I and Zhu, Xiaofeng and Bierut, Laura J and Gauderman, W James and Rice, Kenneth and Munroe, Patricia B and Morrison, Alanna C and Rao, Dabeeru C and Rotimi, Charles N and Cupples, L Adrienne} } @article {8202, title = {Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 Nov 12}, pages = {5121}, abstract = {

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25\% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.

}, issn = {2041-1723}, doi = {10.1038/s41467-019-12958-0}, author = {Noordam, Raymond and Bos, Maxime M and Wang, Heming and Winkler, Thomas W and Bentley, Amy R and Kilpel{\"a}inen, Tuomas O and de Vries, Paul S and Sung, Yun Ju and Schwander, Karen and Cade, Brian E and Manning, Alisa and Aschard, Hugues and Brown, Michael R and Chen, Han and Franceschini, Nora and Musani, Solomon K and Richard, Melissa and Vojinovic, Dina and Aslibekyan, Stella and Bartz, Traci M and de Las Fuentes, Lisa and Feitosa, Mary and Horimoto, Andrea R and Ilkov, Marjan and Kho, Minjung and Kraja, Aldi and Li, Changwei and Lim, Elise and Liu, Yongmei and Mook-Kanamori, Dennis O and Rankinen, Tuomo and Tajuddin, Salman M and van der Spek, Ashley and Wang, Zhe and Marten, Jonathan and Laville, Vincent and Alver, Maris and Evangelou, Evangelos and Graff, Maria E and He, Meian and Kuhnel, Brigitte and Lyytik{\"a}inen, Leo-Pekka and Marques-Vidal, Pedro and Nolte, Ilja M and Palmer, Nicholette D and Rauramaa, Rainer and Shu, Xiao-Ou and Snieder, Harold and Weiss, Stefan and Wen, Wanqing and Yanek, Lisa R and Adolfo, Correa and Ballantyne, Christie and Bielak, Larry and Biermasz, Nienke R and Boerwinkle, Eric and Dimou, Niki and Eiriksdottir, Gudny and Gao, Chuan and Gharib, Sina A and Gottlieb, Daniel J and Haba-Rubio, Jos{\'e} and Harris, Tamara B and Heikkinen, Sami and Heinzer, Raphael and Hixson, James E and Homuth, Georg and Ikram, M Arfan and Komulainen, Pirjo and Krieger, Jose E and Lee, Jiwon and Liu, Jingmin and Lohman, Kurt K and Luik, Annemarie I and M{\"a}gi, Reedik and Martin, Lisa W and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Nalls, Mike A and O{\textquoteright}Connell, Jeff and Peters, Annette and Peyser, Patricia and Raitakari, Olli T and Reiner, Alex P and Rensen, Patrick C N and Rice, Treva K and Rich, Stephen S and Roenneberg, Till and Rotter, Jerome I and Schreiner, Pamela J and Shikany, James and Sidney, Stephen S and Sims, Mario and Sitlani, Colleen M and Sofer, Tamar and Strauch, Konstantin and Swertz, Morris A and Taylor, Kent D and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and V{\"o}lzke, Henry and Waldenberger, Melanie and Wallance, Robert B and van Dijk, Ko Willems and Yu, Caizheng and Zonderman, Alan B and Becker, Diane M and Elliott, Paul and Esko, T{\~o}nu and Gieger, Christian and Grabe, Hans J and Lakka, Timo A and Lehtim{\"a}ki, Terho and North, Kari E and Penninx, Brenda W J H and Vollenweider, Peter and Wagenknecht, Lynne E and Wu, Tangchun and Xiang, Yong-Bing and Zheng, Wei and Arnett, Donna K and Bouchard, Claude and Evans, Michele K and Gudnason, Vilmundur and Kardia, Sharon and Kelly, Tanika N and Kritchevsky, Stephen B and Loos, Ruth J F and Pereira, Alexandre C and Province, Mike and Psaty, Bruce M and Rotimi, Charles and Zhu, Xiaofeng and Amin, Najaf and Cupples, L Adrienne and Fornage, Myriam and Fox, Ervin F and Guo, Xiuqing and Gauderman, W James and Rice, Kenneth and Kooperberg, Charles and Munroe, Patricia B and Liu, Ching-Ti and Morrison, Alanna C and Rao, Dabeeru C and van Heemst, Diana and Redline, Susan} } @article {7976, title = {Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 01 22}, pages = {376}, abstract = {

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

}, keywords = {Adolescent, Adult, African Continental Ancestry Group, Aged, Aged, 80 and over, Asian Continental Ancestry Group, Brazil, Calcium-Binding Proteins, Cholesterol, Cholesterol, HDL, Cholesterol, LDL, European Continental Ancestry Group, Exercise, Female, Genetic Loci, Genome-Wide Association Study, Genotype, Hispanic Americans, Humans, LIM-Homeodomain Proteins, Lipid Metabolism, Lipids, Male, Membrane Proteins, Microtubule-Associated Proteins, Middle Aged, Muscle Proteins, Nerve Tissue Proteins, Transcription Factors, Triglycerides, Young Adult}, issn = {2041-1723}, doi = {10.1038/s41467-018-08008-w}, author = {Kilpel{\"a}inen, Tuomas O and Bentley, Amy R and Noordam, Raymond and Sung, Yun Ju and Schwander, Karen and Winkler, Thomas W and Jakupovi{\'c}, Hermina and Chasman, Daniel I and Manning, Alisa and Ntalla, Ioanna and Aschard, Hugues and Brown, Michael R and de Las Fuentes, Lisa and Franceschini, Nora and Guo, Xiuqing and Vojinovic, Dina and Aslibekyan, Stella and Feitosa, Mary F and Kho, Minjung and Musani, Solomon K and Richard, Melissa and Wang, Heming and Wang, Zhe and Bartz, Traci M and Bielak, Lawrence F and Campbell, Archie and Dorajoo, Rajkumar and Fisher, Virginia and Hartwig, Fernando P and Horimoto, Andrea R V R and Li, Changwei and Lohman, Kurt K and Marten, Jonathan and Sim, Xueling and Smith, Albert V and Tajuddin, Salman M and Alver, Maris and Amini, Marzyeh and Boissel, Mathilde and Chai, Jin Fang and Chen, Xu and Divers, Jasmin and Evangelou, Evangelos and Gao, Chuan and Graff, Mariaelisa and Harris, Sarah E and He, Meian and Hsu, Fang-Chi and Jackson, Anne U and Zhao, Jing Hua and Kraja, Aldi T and Kuhnel, Brigitte and Laguzzi, Federica and Lyytik{\"a}inen, Leo-Pekka and Nolte, Ilja M and Rauramaa, Rainer and Riaz, Muhammad and Robino, Antonietta and Rueedi, Rico and Stringham, Heather M and Takeuchi, Fumihiko and van der Most, Peter J and Varga, Tibor V and Verweij, Niek and Ware, Erin B and Wen, Wanqing and Li, Xiaoyin and Yanek, Lisa R and Amin, Najaf and Arnett, Donna K and Boerwinkle, Eric and Brumat, Marco and Cade, Brian and Canouil, Micka{\"e}l and Chen, Yii-Der Ida and Concas, Maria Pina and Connell, John and de Mutsert, Ren{\'e}e and de Silva, H Janaka and de Vries, Paul S and Demirkan, Ayse and Ding, Jingzhong and Eaton, Charles B and Faul, Jessica D and Friedlander, Yechiel and Gabriel, Kelley P and Ghanbari, Mohsen and Giulianini, Franco and Gu, Chi Charles and Gu, Dongfeng and Harris, Tamara B and He, Jiang and Heikkinen, Sami and Heng, Chew-Kiat and Hunt, Steven C and Ikram, M Arfan and Jonas, Jost B and Koh, Woon-Puay and Komulainen, Pirjo and Krieger, Jose E and Kritchevsky, Stephen B and Kutalik, Zolt{\'a}n and Kuusisto, Johanna and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Leander, Karin and Lemaitre, Rozenn N and Lewis, Cora E and Liang, Jingjing and Liu, Jianjun and M{\"a}gi, Reedik and Manichaikul, Ani and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Mohlke, Karen L and Mosley, Thomas H and Murray, Alison D and Nalls, Mike A and Nang, Ei-Ei Khaing and Nelson, Christopher P and Nona, Sotoodehnia and Norris, Jill M and Nwuba, Chiamaka Vivian and O{\textquoteright}Connell, Jeff and Palmer, Nicholette D and Papanicolau, George J and Pazoki, Raha and Pedersen, Nancy L and Peters, Annette and Peyser, Patricia A and Polasek, Ozren and Porteous, David J and Poveda, Alaitz and Raitakari, Olli T and Rich, Stephen S and Risch, Neil and Robinson, Jennifer G and Rose, Lynda M and Rudan, Igor and Schreiner, Pamela J and Scott, Robert A and Sidney, Stephen S and Sims, Mario and Smith, Jennifer A and Snieder, Harold and Sofer, Tamar and Starr, John M and Sternfeld, Barbara and Strauch, Konstantin and Tang, Hua and Taylor, Kent D and Tsai, Michael Y and Tuomilehto, Jaakko and Uitterlinden, Andr{\'e} G and van der Ende, M Yldau and van Heemst, Diana and Voortman, Trudy and Waldenberger, Melanie and Wennberg, Patrik and Wilson, Gregory and Xiang, Yong-Bing and Yao, Jie and Yu, Caizheng and Yuan, Jian-Min and Zhao, Wei and Zonderman, Alan B and Becker, Diane M and Boehnke, Michael and Bowden, Donald W and de Faire, Ulf and Deary, Ian J and Elliott, Paul and Esko, T{\~o}nu and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Kato, Norihiro and Laakso, Markku and Lakka, Timo A and Lehtim{\"a}ki, Terho and Magnusson, Patrik K E and Oldehinkel, Albertine J and Penninx, Brenda W J H and Samani, Nilesh J and Shu, Xiao-Ou and van der Harst, Pim and van Vliet-Ostaptchouk, Jana V and Vollenweider, Peter and Wagenknecht, Lynne E and Wang, Ya X and Wareham, Nicholas J and Weir, David R and Wu, Tangchun and Zheng, Wei and Zhu, Xiaofeng and Evans, Michele K and Franks, Paul W and Gudnason, Vilmundur and Hayward, Caroline and Horta, Bernardo L and Kelly, Tanika N and Liu, Yongmei and North, Kari E and Pereira, Alexandre C and Ridker, Paul M and Tai, E Shyong and van Dam, Rob M and Fox, Ervin R and Kardia, Sharon L R and Liu, Ching-Ti and Mook-Kanamori, Dennis O and Province, Michael A and Redline, Susan and van Duijn, Cornelia M and Rotter, Jerome I and Kooperberg, Charles B and Gauderman, W James and Psaty, Bruce M and Rice, Kenneth and Munroe, Patricia B and Fornage, Myriam and Cupples, L Adrienne and Rotimi, Charles N and Morrison, Alanna C and Rao, Dabeeru C and Loos, Ruth J F} } @article {8199, title = {Sequencing Analysis at 8p23 Identifies Multiple Rare Variants in DLC1 Associated with Sleep-Related Oxyhemoglobin Saturation Level.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Nov 07}, pages = {1057-1068}, abstract = {

Average arterial oxyhemoglobin saturation during sleep (AvSpOS) is a clinically relevant measure of physiological stress associated with sleep-disordered breathing, and this measure predicts incident cardiovascular disease and mortality. Using high-depth whole-genome sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) project and focusing on genes with linkage evidence on chromosome 8p23, we observed that six coding and 51 noncoding variants in a gene that encodes the GTPase-activating protein (DLC1) are significantly associated with AvSpOS and replicated in independent subjects. The combined DLC1 association evidence of discovery and replication cohorts reaches genome-wide significance in European Americans (p = 7.9~{\texttimes} 10). A risk score for these variants, built on an independent dataset, explains 0.97\% of the AvSpOS variation and contributes to the linkage evidence. The 51 noncoding variants are enriched in regulatory features in a human lung fibroblast cell line and contribute to DLC1 expression variation. Mendelian randomization analysis using these variants indicates a significant causal effect of DLC1 expression in fibroblasts on AvSpOS. Multiple sources of information, including genetic variants, gene expression, and methylation, consistently suggest that DLC1 is a gene associated with AvSpOS.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.10.002}, author = {Liang, Jingjing and Cade, Brian E and He, Karen Y and Wang, Heming and Lee, Jiwon and Sofer, Tamar and Williams, Stephanie and Li, Ruitong and Chen, Han and Gottlieb, Daniel J and Evans, Daniel S and Guo, Xiuqing and Gharib, Sina A and Hale, Lauren and Hillman, David R and Lutsey, Pamela L and Mukherjee, Sutapa and Ochs-Balcom, Heather M and Palmer, Lyle J and Rhodes, Jessica and Purcell, Shaun and Patel, Sanjay R and Saxena, Richa and Stone, Katie L and Tang, Weihong and Tranah, Gregory J and Boerwinkle, Eric and Lin, Xihong and Liu, Yongmei and Psaty, Bruce M and Vasan, Ramachandran S and Cho, Michael H and Manichaikul, Ani and Silverman, Edwin K and Barr, R Graham and Rich, Stephen S and Rotter, Jerome I and Wilson, James G and Redline, Susan and Zhu, Xiaofeng} } @article {8400, title = {Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts.}, journal = {Lancet Respir Med}, volume = {8}, year = {2020}, month = {2020 07}, pages = {696-708}, abstract = {

BACKGROUND: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes.

METHODS: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV and FEV/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV/FVC <0{\textperiodcentered}7 and FEV <80\% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth.

FINDINGS: The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1{\textperiodcentered}81 [95\% CI 1{\textperiodcentered}74-1{\textperiodcentered}88] and non-European (1{\textperiodcentered}42 [1{\textperiodcentered}34-1{\textperiodcentered}51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7{\textperiodcentered}99 (6{\textperiodcentered}56-9{\textperiodcentered}72) in European ancestry and 4{\textperiodcentered}83 (3{\textperiodcentered}45-6{\textperiodcentered}77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0{\textperiodcentered}80 [0{\textperiodcentered}79-0{\textperiodcentered}81] vs 0{\textperiodcentered}76 [0{\textperiodcentered}75-0{\textperiodcentered}76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern.

INTERPRETATION: A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth.

FUNDING: US National Institutes of Health, Wellcome Trust.

}, keywords = {Adult, Case-Control Studies, Cohort Studies, Female, Forced Expiratory Volume, Genome-Wide Association Study, Humans, Male, Middle Aged, Phenotype, Pulmonary Disease, Chronic Obstructive, Risk Factors, Vital Capacity}, issn = {2213-2619}, doi = {10.1016/S2213-2600(20)30101-6}, author = {Moll, Matthew and Sakornsakolpat, Phuwanat and Shrine, Nick and Hobbs, Brian D and DeMeo, Dawn L and John, Catherine and Guyatt, Anna L and McGeachie, Michael J and Gharib, Sina A and Obeidat, Ma{\textquoteright}en and Lahousse, Lies and Wijnant, Sara R A and Brusselle, Guy and Meyers, Deborah A and Bleecker, Eugene R and Li, Xingnan and Tal-Singer, Ruth and Manichaikul, Ani and Rich, Stephen S and Won, Sungho and Kim, Woo Jin and Do, Ah Ra and Washko, George R and Barr, R Graham and Psaty, Bruce M and Bartz, Traci M and Hansel, Nadia N and Barnes, Kathleen and Hokanson, John E and Crapo, James D and Lynch, David and Bakke, Per and Gulsvik, Amund and Hall, Ian P and Wain, Louise and Weiss, Scott T and Silverman, Edwin K and Dudbridge, Frank and Tobin, Martin D and Cho, Michael H} } @article {8625, title = {Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.}, journal = {PLoS One}, volume = {15}, year = {2020}, month = {2020}, pages = {e0230035}, abstract = {

BACKGROUND: Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome.

METHODS AND RESULTS: Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95\% confidence interval: 1.43, 2.27; P = 7.12 {\texttimes} 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) >= 5 and variants with minor allele frequency (MAF) < 5\%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event.

CONCLUSION: This study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.

}, keywords = {Aging, Coronary Artery Disease, Cross-Sectional Studies, Europe, European Continental Ancestry Group, Genetic Loci, Genome-Wide Association Study, Humans, Myocardial Infarction, Polymorphism, Single Nucleotide, Prospective Studies}, issn = {1932-6203}, doi = {10.1371/journal.pone.0230035}, author = {Hahn, Julie and Fu, Yi-Ping and Brown, Michael R and Bis, Joshua C and de Vries, Paul S and Feitosa, Mary F and Yanek, Lisa R and Weiss, Stefan and Giulianini, Franco and Smith, Albert Vernon and Guo, Xiuqing and Bartz, Traci M and Becker, Diane M and Becker, Lewis C and Boerwinkle, Eric and Brody, Jennifer A and Chen, Yii-Der Ida and Franco, Oscar H and Grove, Megan and Harris, Tamara B and Hofman, Albert and Hwang, Shih-Jen and Kral, Brian G and Launer, Lenore J and Markus, Marcello R P and Rice, Kenneth M and Rich, Stephen S and Ridker, Paul M and Rivadeneira, Fernando and Rotter, Jerome I and Sotoodehnia, Nona and Taylor, Kent D and Uitterlinden, Andr{\'e} G and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Yao, Jie and Chasman, Daniel I and D{\"o}rr, Marcus and Gudnason, Vilmundur and Mathias, Rasika A and Post, Wendy and Psaty, Bruce M and Dehghan, Abbas and O{\textquoteright}Donnell, Christopher J and Morrison, Alanna C} } @article {8621, title = {Inherited causes of clonal haematopoiesis in 97,691 whole genomes.}, journal = {Nature}, volume = {586}, year = {2020}, month = {2020 10}, pages = {763-768}, abstract = {

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is~termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP~driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

}, issn = {1476-4687}, doi = {10.1038/s41586-020-2819-2}, author = {Bick, Alexander G and Weinstock, Joshua S and Nandakumar, Satish K and Fulco, Charles P and Bao, Erik L and Zekavat, Seyedeh M and Szeto, Mindy D and Liao, Xiaotian and Leventhal, Matthew J and Nasser, Joseph and Chang, Kyle and Laurie, Cecelia and Burugula, Bala Bharathi and Gibson, Christopher J and Lin, Amy E and Taub, Margaret A and Aguet, Francois and Ardlie, Kristin and Mitchell, Braxton D and Barnes, Kathleen C and Moscati, Arden and Fornage, Myriam and Redline, Susan and Psaty, Bruce M and Silverman, Edwin K and Weiss, Scott T and Palmer, Nicholette D and Vasan, Ramachandran S and Burchard, Esteban G and Kardia, Sharon L R and He, Jiang and Kaplan, Robert C and Smith, Nicholas L and Arnett, Donna K and Schwartz, David A and Correa, Adolfo and de Andrade, Mariza and Guo, Xiuqing and Konkle, Barbara A and Custer, Brian and Peralta, Juan M and Gui, Hongsheng and Meyers, Deborah A and McGarvey, Stephen T and Chen, Ida Yii-Der and Shoemaker, M Benjamin and Peyser, Patricia A and Broome, Jai G and Gogarten, Stephanie M and Wang, Fei Fei and Wong, Quenna and Montasser, May E and Daya, Michelle and Kenny, Eimear E and North, Kari E and Launer, Lenore J and Cade, Brian E and Bis, Joshua C and Cho, Michael H and Lasky-Su, Jessica and Bowden, Donald W and Cupples, L Adrienne and Mak, Angel C Y and Becker, Lewis C and Smith, Jennifer A and Kelly, Tanika N and Aslibekyan, Stella and Heckbert, Susan R and Tiwari, Hemant K and Yang, Ivana V and Heit, John A and Lubitz, Steven A and Johnsen, Jill M and Curran, Joanne E and Wenzel, Sally E and Weeks, Daniel E and Rao, Dabeeru C and Darbar, Dawood and Moon, Jee-Young and Tracy, Russell P and Buth, Erin J and Rafaels, Nicholas and Loos, Ruth J F and Durda, Peter and Liu, Yongmei and Hou, Lifang and Lee, Jiwon and Kachroo, Priyadarshini and Freedman, Barry I and Levy, Daniel and Bielak, Lawrence F and Hixson, James E and Floyd, James S and Whitsel, Eric A and Ellinor, Patrick T and Irvin, Marguerite R and Fingerlin, Tasha E and Raffield, Laura M and Armasu, Sebastian M and Wheeler, Marsha M and Sabino, Ester C and Blangero, John and Williams, L Keoki and Levy, Bruce D and Sheu, Wayne Huey-Herng and Roden, Dan M and Boerwinkle, Eric and Manson, JoAnn E and Mathias, Rasika A and Desai, Pinkal and Taylor, Kent D and Johnson, Andrew D and Auer, Paul L and Kooperberg, Charles and Laurie, Cathy C and Blackwell, Thomas W and Smith, Albert V and Zhao, Hongyu and Lange, Ethan and Lange, Leslie and Rich, Stephen S and Rotter, Jerome I and Wilson, James G and Scheet, Paul and Kitzman, Jacob O and Lander, Eric S and Engreitz, Jesse M and Ebert, Benjamin L and Reiner, Alexander P and Jaiswal, Siddhartha and Abecasis, Goncalo and Sankaran, Vijay G and Kathiresan, Sekar and Natarajan, Pradeep} } @article {8490, title = {The Polygenic and Monogenic Basis of Blood Traits and Diseases.}, journal = {Cell}, volume = {182}, year = {2020}, month = {2020 Sep 03}, pages = {1214-1231.e11}, abstract = {

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

}, issn = {1097-4172}, doi = {10.1016/j.cell.2020.08.008}, author = {Vuckovic, Dragana and Bao, Erik L and Akbari, Parsa and Lareau, Caleb A and Mousas, Abdou and Jiang, Tao and Chen, Ming-Huei and Raffield, Laura M and Tardaguila, Manuel and Huffman, Jennifer E and Ritchie, Scott C and Megy, Karyn and Ponstingl, Hannes and Penkett, Christopher J and Albers, Patrick K and Wigdor, Emilie M and Sakaue, Saori and Moscati, Arden and Manansala, Regina and Lo, Ken Sin and Qian, Huijun and Akiyama, Masato and Bartz, Traci M and Ben-Shlomo, Yoav and Beswick, Andrew and Bork-Jensen, Jette and Bottinger, Erwin P and Brody, Jennifer A and van Rooij, Frank J A and Chitrala, Kumaraswamy N and Wilson, Peter W F and Choquet, Helene and Danesh, John and Di Angelantonio, Emanuele and Dimou, Niki and Ding, Jingzhong and Elliott, Paul and Esko, T{\~o}nu and Evans, Michele K and Felix, Stephan B and Floyd, James S and Broer, Linda and Grarup, Niels and Guo, Michael H and Guo, Qi and Greinacher, Andreas and Haessler, Jeff and Hansen, Torben and Howson, Joanna M M and Huang, Wei and Jorgenson, Eric and Kacprowski, Tim and K{\"a}h{\"o}nen, Mika and Kamatani, Yoichiro and Kanai, Masahiro and Karthikeyan, Savita and Koskeridis, Fotios and Lange, Leslie A and Lehtim{\"a}ki, Terho and Linneberg, Allan and Liu, Yongmei and Lyytik{\"a}inen, Leo-Pekka and Manichaikul, Ani and Matsuda, Koichi and Mohlke, Karen L and Mononen, Nina and Murakami, Yoshinori and Nadkarni, Girish N and Nikus, Kjell and Pankratz, Nathan and Pedersen, Oluf and Preuss, Michael and Psaty, Bruce M and Raitakari, Olli T and Rich, Stephen S and Rodriguez, Benjamin A T and Rosen, Jonathan D and Rotter, Jerome I and Schubert, Petra and Spracklen, Cassandra N and Surendran, Praveen and Tang, Hua and Tardif, Jean-Claude and Ghanbari, Mohsen and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Watkins, Nicholas A and Weiss, Stefan and Cai, Na and Kundu, Kousik and Watt, Stephen B and Walter, Klaudia and Zonderman, Alan B and Cho, Kelly and Li, Yun and Loos, Ruth J F and Knight, Julian C and Georges, Michel and Stegle, Oliver and Evangelou, Evangelos and Okada, Yukinori and Roberts, David J and Inouye, Michael and Johnson, Andrew D and Auer, Paul L and Astle, William J and Reiner, Alexander P and Butterworth, Adam S and Ouwehand, Willem H and Lettre, Guillaume and Sankaran, Vijay G and Soranzo, Nicole} } @article {8407, title = {Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels.}, journal = {Circ Genom Precis Med}, volume = {13}, year = {2020}, month = {2020 Aug}, pages = {e002772}, abstract = {

BACKGROUND: Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels.

METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, <=5\%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered.

RESULTS: We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (, , , , , , , and ) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered (=6.65{\texttimes}10 for the interaction test) and replicated at nominal significance level (=0.013) in .

CONCLUSIONS: In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.119.002772}, author = {Wang, Zhe and Chen, Han and Bartz, Traci M and Bielak, Lawrence F and Chasman, Daniel I and Feitosa, Mary F and Franceschini, Nora and Guo, Xiuqing and Lim, Elise and Noordam, Raymond and Richard, Melissa A and Wang, Heming and Cade, Brian and Cupples, L Adrienne and de Vries, Paul S and Giulanini, Franco and Lee, Jiwon and Lemaitre, Rozenn N and Martin, Lisa W and Reiner, Alex P and Rich, Stephen S and Schreiner, Pamela J and Sidney, Stephen and Sitlani, Colleen M and Smith, Jennifer A and Willems van Dijk, Ko and Yao, Jie and Zhao, Wei and Fornage, Myriam and Kardia, Sharon L R and Kooperberg, Charles and Liu, Ching-Ti and Mook-Kanamori, Dennis O and Province, Michael A and Psaty, Bruce M and Redline, Susan and Ridker, Paul M and Rotter, Jerome I and Boerwinkle, Eric and Morrison, Alanna C} } @article {8481, title = {Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations.}, journal = {Cell}, volume = {182}, year = {2020}, month = {2020 Sep 03}, pages = {1198-1213.e14}, abstract = {

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p~< 5~{\texttimes} 10, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in~vivo and IL-7 secretion levels in~vitro. Fine-mapping prioritized variants annotated as functional and generated 95\% credible sets that were 30\% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

}, issn = {1097-4172}, doi = {10.1016/j.cell.2020.06.045}, author = {Chen, Ming-Huei and Raffield, Laura M and Mousas, Abdou and Sakaue, Saori and Huffman, Jennifer E and Moscati, Arden and Trivedi, Bhavi and Jiang, Tao and Akbari, Parsa and Vuckovic, Dragana and Bao, Erik L and Zhong, Xue and Manansala, Regina and Laplante, V{\'e}ronique and Chen, Minhui and Lo, Ken Sin and Qian, Huijun and Lareau, Caleb A and Beaudoin, M{\'e}lissa and Hunt, Karen A and Akiyama, Masato and Bartz, Traci M and Ben-Shlomo, Yoav and Beswick, Andrew and Bork-Jensen, Jette and Bottinger, Erwin P and Brody, Jennifer A and van Rooij, Frank J A and Chitrala, Kumaraswamynaidu and Cho, Kelly and Choquet, Helene and Correa, Adolfo and Danesh, John and Di Angelantonio, Emanuele and Dimou, Niki and Ding, Jingzhong and Elliott, Paul and Esko, T{\~o}nu and Evans, Michele K and Floyd, James S and Broer, Linda and Grarup, Niels and Guo, Michael H and Greinacher, Andreas and Haessler, Jeff and Hansen, Torben and Howson, Joanna M M and Huang, Qin Qin and Huang, Wei and Jorgenson, Eric and Kacprowski, Tim and K{\"a}h{\"o}nen, Mika and Kamatani, Yoichiro and Kanai, Masahiro and Karthikeyan, Savita and Koskeridis, Fotis and Lange, Leslie A and Lehtim{\"a}ki, Terho and Lerch, Markus M and Linneberg, Allan and Liu, Yongmei and Lyytik{\"a}inen, Leo-Pekka and Manichaikul, Ani and Martin, Hilary C and Matsuda, Koichi and Mohlke, Karen L and Mononen, Nina and Murakami, Yoshinori and Nadkarni, Girish N and Nauck, Matthias and Nikus, Kjell and Ouwehand, Willem H and Pankratz, Nathan and Pedersen, Oluf and Preuss, Michael and Psaty, Bruce M and Raitakari, Olli T and Roberts, David J and Rich, Stephen S and Rodriguez, Benjamin A T and Rosen, Jonathan D and Rotter, Jerome I and Schubert, Petra and Spracklen, Cassandra N and Surendran, Praveen and Tang, Hua and Tardif, Jean-Claude and Trembath, Richard C and Ghanbari, Mohsen and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Watkins, Nicholas A and Zonderman, Alan B and Wilson, Peter W F and Li, Yun and Butterworth, Adam S and Gauchat, Jean-Fran{\c c}ois and Chiang, Charleston W K and Li, Bingshan and Loos, Ruth J F and Astle, William J and Evangelou, Evangelos and van Heel, David A and Sankaran, Vijay G and Okada, Yukinori and Soranzo, Nicole and Johnson, Andrew D and Reiner, Alexander P and Auer, Paul L and Lettre, Guillaume} } @article {8639, title = {Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 10 14}, pages = {5182}, abstract = {

Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.

}, keywords = {Adult, African Americans, Aged, Aged, 80 and over, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Calcium-Binding Proteins, Feasibility Studies, Female, Follow-Up Studies, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Intracellular Signaling Peptides and Proteins, Lung, Male, Middle Aged, Polymorphism, Single Nucleotide, Protein Inhibitors of Activated STAT, Pulmonary Disease, Chronic Obstructive, Respiratory Physiological Phenomena, Small Ubiquitin-Related Modifier Proteins, Whole Genome Sequencing}, issn = {2041-1723}, doi = {10.1038/s41467-020-18334-7}, author = {Zhao, Xutong and Qiao, Dandi and Yang, Chaojie and Kasela, Silva and Kim, Wonji and Ma, Yanlin and Shrine, Nick and Batini, Chiara and Sofer, Tamar and Taliun, Sarah A Gagliano and Sakornsakolpat, Phuwanat and Balte, Pallavi P and Prokopenko, Dmitry and Yu, Bing and Lange, Leslie A and Dupuis, Jos{\'e}e and Cade, Brian E and Lee, Jiwon and Gharib, Sina A and Daya, Michelle and Laurie, Cecelia A and Ruczinski, Ingo and Cupples, L Adrienne and Loehr, Laura R and Bartz, Traci M and Morrison, Alanna C and Psaty, Bruce M and Vasan, Ramachandran S and Wilson, James G and Taylor, Kent D and Durda, Peter and Johnson, W Craig and Cornell, Elaine and Guo, Xiuqing and Liu, Yongmei and Tracy, Russell P and Ardlie, Kristin G and Aguet, Francois and VanDenBerg, David J and Papanicolaou, George J and Rotter, Jerome I and Barnes, Kathleen C and Jain, Deepti and Nickerson, Deborah A and Muzny, Donna M and Metcalf, Ginger A and Doddapaneni, Harshavardhan and Dugan-Perez, Shannon and Gupta, Namrata and Gabriel, Stacey and Rich, Stephen S and O{\textquoteright}Connor, George T and Redline, Susan and Reed, Robert M and Laurie, Cathy C and Daviglus, Martha L and Preudhomme, Liana K and Burkart, Kristin M and Kaplan, Robert C and Wain, Louise V and Tobin, Martin D and London, Stephanie J and Lappalainen, Tuuli and Oelsner, Elizabeth C and Abecasis, Goncalo R and Silverman, Edwin K and Barr, R Graham and Cho, Michael H and Manichaikul, Ani} } @article {8997, title = {Association of mitochondrial DNA copy number with cardiometabolic diseases.}, journal = {Cell Genom}, volume = {1}, year = {2021}, month = {2021 Oct 13}, abstract = {

Mitochondrial DNA (mtDNA) is present in multiple copies in human cells. We evaluated cross-sectional associations of whole blood mtDNA copy number (CN) with several cardiometabolic disease traits in 408,361 participants of multiple ancestries in TOPMed and UK Biobank. Age showed a threshold association with mtDNA CN: among younger participants (<65 years of age), each additional 10 years of age was associated with 0.03 standard deviation (s.d.) higher level of mtDNA CN ( = 0.0014) versus a 0.14 s.d. lower level of mtDNA CN ( = 1.82 {\texttimes} 10) among older participants (>=65 years). At lower mtDNA CN levels, we found age-independent associations with increased odds of obesity ( = 5.6 {\texttimes} 10), hypertension ( = 2.8 {\texttimes} 10), diabetes ( = 3.6 {\texttimes} 10), and hyperlipidemia ( = 6.3 {\texttimes} 10). The observed decline in mtDNA CN after 65 years of age may be a key to understanding age-related diseases.

}, issn = {2666-979X}, doi = {10.1016/j.xgen.2021.100006}, author = {Liu, Xue and Longchamps, Ryan J and Wiggins, Kerri L and Raffield, Laura M and Bielak, Lawrence F and Zhao, Wei and Pitsillides, Achilleas and Blackwell, Thomas W and Yao, Jie and Guo, Xiuqing and Kurniansyah, Nuzulul and Thyagarajan, Bharat and Pankratz, Nathan and Rich, Stephen S and Taylor, Kent D and Peyser, Patricia A and Heckbert, Susan R and Seshadri, Sudha and Cupples, L Adrienne and Boerwinkle, Eric and Grove, Megan L and Larson, Nicholas B and Smith, Jennifer A and Vasan, Ramachandran S and Sofer, Tamar and Fitzpatrick, Annette L and Fornage, Myriam and Ding, Jun and Correa, Adolfo and Abecasis, Goncalo and Psaty, Bruce M and Wilson, James G and Levy, Daniel and Rotter, Jerome I and Bis, Joshua C and Satizabal, Claudia L and Arking, Dan E and Liu, Chunyu} } @article {8838, title = {BinomiRare: A robust test for association of a rare genetic variant with a binary outcome for mixed models and any case-control proportion.}, journal = {HGG Adv}, volume = {2}, year = {2021}, month = {2021 Jul 08}, abstract = {

Whole-genome sequencing (WGS) and whole-exome sequencing studies have become increasingly available and are being used to identify rare genetic variants associated with health and disease outcomes. Investigators routinely use mixed models to account for genetic relatedness or other clustering variables (e.g., family or household) when testing genetic associations. However, no existing tests of the association of a rare variant with a binary outcome in the presence of correlated data control the type 1 error where there are (1) few individuals harboring the rare allele, (2) a small proportion of cases relative to controls, and (3) covariates to adjust for. Here, we address all three issues in developing a framework for testing rare variant association with a binary trait in individuals harboring at least one risk allele. In this framework, we estimate outcome probabilities under the null hypothesis and then use them, within the individuals with at least one risk allele, to test variant associations. We extend the BinomiRare test, which was previously proposed for independent observations, and develop the Conway-Maxwell-Poisson (CMP) test and study their properties in simulations. We show that the BinomiRare test always controls the type 1 error, while the CMP test sometimes does not. We then use the BinomiRare test to test the association of rare genetic variants in target genes with small-vessel disease (SVD) stroke, short sleep, and venous thromboembolism (VTE), in whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program.

}, issn = {2666-2477}, doi = {10.1016/j.xhgg.2021.100040}, author = {Sofer, Tamar and Lee, Jiwon and Kurniansyah, Nuzulul and Jain, Deepti and Laurie, Cecelia A and Gogarten, Stephanie M and Conomos, Matthew P and Heavner, Ben and Hu, Yao and Kooperberg, Charles and Haessler, Jeffrey and Vasan, Ramachandran S and Cupples, L Adrienne and Coombes, Brandon J and Seyerle, Amanda and Gharib, Sina A and Chen, Han and O{\textquoteright}Connell, Jeffrey R and Zhang, Man and Gottlieb, Daniel J and Psaty, Bruce M and Longstreth, W T and Rotter, Jerome I and Taylor, Kent D and Rich, Stephen S and Guo, Xiuqing and Boerwinkle, Eric and Morrison, Alanna C and Pankow, James S and Johnson, Andrew D and Pankratz, Nathan and Reiner, Alex P and Redline, Susan and Smith, Nicholas L and Rice, Kenneth M and Schifano, Elizabeth D} } @article {8711, title = {Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 04 12}, pages = {2182}, abstract = {

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 {\texttimes} 10), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 {\texttimes} 10), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 {\texttimes} 10). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.

}, issn = {2041-1723}, doi = {10.1038/s41467-021-22339-1}, author = {Natarajan, Pradeep and Pampana, Akhil and Graham, Sarah E and Ruotsalainen, Sanni E and Perry, James A and de Vries, Paul S and Broome, Jai G and Pirruccello, James P and Honigberg, Michael C and Aragam, Krishna and Wolford, Brooke and Brody, Jennifer A and Antonacci-Fulton, Lucinda and Arden, Moscati and Aslibekyan, Stella and Assimes, Themistocles L and Ballantyne, Christie M and Bielak, Lawrence F and Bis, Joshua C and Cade, Brian E and Do, Ron and Doddapaneni, Harsha and Emery, Leslie S and Hung, Yi-Jen and Irvin, Marguerite R and Khan, Alyna T and Lange, Leslie and Lee, Jiwon and Lemaitre, Rozenn N and Martin, Lisa W and Metcalf, Ginger and Montasser, May E and Moon, Jee-Young and Muzny, Donna and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Peralta, Juan M and Peyser, Patricia A and Stilp, Adrienne M and Tsai, Michael and Wang, Fei Fei and Weeks, Daniel E and Yanek, Lisa R and Wilson, James G and Abecasis, Goncalo and Arnett, Donna K and Becker, Lewis C and Blangero, John and Boerwinkle, Eric and Bowden, Donald W and Chang, Yi-Cheng and Chen, Yii-der I and Choi, Won Jung and Correa, Adolfo and Curran, Joanne E and Daly, Mark J and Dutcher, Susan K and Ellinor, Patrick T and Fornage, Myriam and Freedman, Barry I and Gabriel, Stacey and Germer, Soren and Gibbs, Richard A and He, Jiang and Hveem, Kristian and Jarvik, Gail P and Kaplan, Robert C and Kardia, Sharon L R and Kenny, Eimear and Kim, Ryan W and Kooperberg, Charles and Laurie, Cathy C and Lee, Seonwook and Lloyd-Jones, Don M and Loos, Ruth J F and Lubitz, Steven A and Mathias, Rasika A and Martinez, Karine A Viaud and McGarvey, Stephen T and Mitchell, Braxton D and Nickerson, Deborah A and North, Kari E and Palotie, Aarno and Park, Cheol Joo and Psaty, Bruce M and Rao, D C and Redline, Susan and Reiner, Alexander P and Seo, Daekwan and Seo, Jeong-Sun and Smith, Albert V and Tracy, Russell P and Vasan, Ramachandran S and Kathiresan, Sekar and Cupples, L Adrienne and Rotter, Jerome I and Morrison, Alanna C and Rich, Stephen S and Ripatti, Samuli and Willer, Cristen and Peloso, Gina M} } @article {8774, title = {Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 06 09}, pages = {3505}, abstract = {

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1\% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60\% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.

}, keywords = {Adult, Biological Variation, Population, Biomarkers, Diabetes Mellitus, Type 2, Dyslipidemias, Exome, Genetic Predisposition to Disease, Genotype, Humans, Multifactorial Inheritance, Penetrance, Risk Assessment}, issn = {2041-1723}, doi = {10.1038/s41467-021-23556-4}, author = {Goodrich, Julia K and Singer-Berk, Moriel and Son, Rachel and Sveden, Abigail and Wood, Jordan and England, Eleina and Cole, Joanne B and Weisburd, Ben and Watts, Nick and Caulkins, Lizz and Dornbos, Peter and Koesterer, Ryan and Zappala, Zachary and Zhang, Haichen and Maloney, Kristin A and Dahl, Andy and Aguilar-Salinas, Carlos A and Atzmon, Gil and Barajas-Olmos, Francisco and Barzilai, Nir and Blangero, John and Boerwinkle, Eric and Bonnycastle, Lori L and Bottinger, Erwin and Bowden, Donald W and Centeno-Cruz, Federico and Chambers, John C and Chami, Nathalie and Chan, Edmund and Chan, Juliana and Cheng, Ching-Yu and Cho, Yoon Shin and Contreras-Cubas, Cecilia and C{\'o}rdova, Emilio and Correa, Adolfo and DeFronzo, Ralph A and Duggirala, Ravindranath and Dupuis, Jos{\'e}e and Garay-Sevilla, Ma Eugenia and Garc{\'\i}a-Ortiz, Humberto and Gieger, Christian and Glaser, Benjamin and Gonz{\'a}lez-Villalpando, Clicerio and Gonzalez, Ma Elena and Grarup, Niels and Groop, Leif and Gross, Myron and Haiman, Christopher and Han, Sohee and Hanis, Craig L and Hansen, Torben and Heard-Costa, Nancy L and Henderson, Brian E and Hernandez, Juan Manuel Malacara and Hwang, Mi Yeong and Islas-Andrade, Sergio and J{\o}rgensen, Marit E and Kang, Hyun Min and Kim, Bong-Jo and Kim, Young Jin and Koistinen, Heikki A and Kooner, Jaspal Singh and Kuusisto, Johanna and Kwak, Soo-Heon and Laakso, Markku and Lange, Leslie and Lee, Jong-Young and Lee, Juyoung and Lehman, Donna M and Linneberg, Allan and Liu, Jianjun and Loos, Ruth J F and Lyssenko, Valeriya and Ma, Ronald C W and Mart{\'\i}nez-Hern{\'a}ndez, Ang{\'e}lica and Meigs, James B and Meitinger, Thomas and Mendoza-Caamal, Elvia and Mohlke, Karen L and Morris, Andrew D and Morrison, Alanna C and Ng, Maggie C Y and Nilsson, Peter M and O{\textquoteright}Donnell, Christopher J and Orozco, Lorena and Palmer, Colin N A and Park, Kyong Soo and Post, Wendy S and Pedersen, Oluf and Preuss, Michael and Psaty, Bruce M and Reiner, Alexander P and Revilla-Monsalve, Cristina and Rich, Stephen S and Rotter, Jerome I and Saleheen, Danish and Schurmann, Claudia and Sim, Xueling and Sladek, Rob and Small, Kerrin S and So, Wing Yee and Spector, Timothy D and Strauch, Konstantin and Strom, Tim M and Tai, E Shyong and Tam, Claudia H T and Teo, Yik Ying and Thameem, Farook and Tomlinson, Brian and Tracy, Russell P and Tuomi, Tiinamaija and Tuomilehto, Jaakko and Tusi{\'e}-Luna, Teresa and van Dam, Rob M and Vasan, Ramachandran S and Wilson, James G and Witte, Daniel R and Wong, Tien-Yin and Burtt, Noel P and Zaitlen, Noah and McCarthy, Mark I and Boehnke, Michael and Pollin, Toni I and Flannick, Jason and Mercader, Josep M and O{\textquoteright}Donnell-Luria, Anne and Baxter, Samantha and Florez, Jose C and MacArthur, Daniel G and Udler, Miriam S} } @article {8714, title = {Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.}, journal = {Mol Psychiatry}, year = {2021}, month = {2021 Apr 15}, abstract = {

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 {\texttimes} 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 {\texttimes} 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 {\texttimes} 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

}, issn = {1476-5578}, doi = {10.1038/s41380-021-01087-0}, author = {Wang, Heming and Noordam, Raymond and Cade, Brian E and Schwander, Karen and Winkler, Thomas W and Lee, Jiwon and Sung, Yun Ju and Bentley, Amy R and Manning, Alisa K and Aschard, Hugues and Kilpel{\"a}inen, Tuomas O and Ilkov, Marjan and Brown, Michael R and Horimoto, Andrea R and Richard, Melissa and Bartz, Traci M and Vojinovic, Dina and Lim, Elise and Nierenberg, Jovia L and Liu, Yongmei and Chitrala, Kumaraswamynaidu and Rankinen, Tuomo and Musani, Solomon K and Franceschini, Nora and Rauramaa, Rainer and Alver, Maris and Zee, Phyllis C and Harris, Sarah E and van der Most, Peter J and Nolte, Ilja M and Munroe, Patricia B and Palmer, Nicholette D and Kuhnel, Brigitte and Weiss, Stefan and Wen, Wanqing and Hall, Kelly A and Lyytik{\"a}inen, Leo-Pekka and O{\textquoteright}Connell, Jeff and Eiriksdottir, Gudny and Launer, Lenore J and de Vries, Paul S and Arking, Dan E and Chen, Han and Boerwinkle, Eric and Krieger, Jose E and Schreiner, Pamela J and Sidney, Stephen and Shikany, James M and Rice, Kenneth and Chen, Yii-Der Ida and Gharib, Sina A and Bis, Joshua C and Luik, Annemarie I and Ikram, M Arfan and Uitterlinden, Andr{\'e} G and Amin, Najaf and Xu, Hanfei and Levy, Daniel and He, Jiang and Lohman, Kurt K and Zonderman, Alan B and Rice, Treva K and Sims, Mario and Wilson, Gregory and Sofer, Tamar and Rich, Stephen S and Palmas, Walter and Yao, Jie and Guo, Xiuqing and Rotter, Jerome I and Biermasz, Nienke R and Mook-Kanamori, Dennis O and Martin, Lisa W and Barac, Ana and Wallace, Robert B and Gottlieb, Daniel J and Komulainen, Pirjo and Heikkinen, Sami and M{\"a}gi, Reedik and Milani, Lili and Metspalu, Andres and Starr, John M and Milaneschi, Yuri and Waken, R J and Gao, Chuan and Waldenberger, Melanie and Peters, Annette and Strauch, Konstantin and Meitinger, Thomas and Roenneberg, Till and V{\"o}lker, Uwe and D{\"o}rr, Marcus and Shu, Xiao-Ou and Mukherjee, Sutapa and Hillman, David R and K{\"a}h{\"o}nen, Mika and Wagenknecht, Lynne E and Gieger, Christian and Grabe, Hans J and Zheng, Wei and Palmer, Lyle J and Lehtim{\"a}ki, Terho and Gudnason, Vilmundur and Morrison, Alanna C and Pereira, Alexandre C and Fornage, Myriam and Psaty, Bruce M and van Duijn, Cornelia M and Liu, Ching-Ti and Kelly, Tanika N and Evans, Michele K and Bouchard, Claude and Fox, Ervin R and Kooperberg, Charles and Zhu, Xiaofeng and Lakka, Timo A and Esko, T{\~o}nu and North, Kari E and Deary, Ian J and Snieder, Harold and Penninx, Brenda W J H and Gauderman, W James and Rao, Dabeeru C and Redline, Susan and van Heemst, Diana} } @article {8666, title = {Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.}, journal = {Nature}, volume = {590}, year = {2021}, month = {2021 02}, pages = {290-299}, abstract = {

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400~million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400~million detected variants, 97\% have frequencies of less than 1\% and 46\% are singletons that are present in only one individual (53\% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01\%.

}, issn = {1476-4687}, doi = {10.1038/s41586-021-03205-y}, author = {Taliun, Daniel and Harris, Daniel N and Kessler, Michael D and Carlson, Jedidiah and Szpiech, Zachary A and Torres, Raul and Taliun, Sarah A Gagliano and Corvelo, Andr{\'e} and Gogarten, Stephanie M and Kang, Hyun Min and Pitsillides, Achilleas N and LeFaive, Jonathon and Lee, Seung-Been and Tian, Xiaowen and Browning, Brian L and Das, Sayantan and Emde, Anne-Katrin and Clarke, Wayne E and Loesch, Douglas P and Shetty, Amol C and Blackwell, Thomas W and Smith, Albert V and Wong, Quenna and Liu, Xiaoming and Conomos, Matthew P and Bobo, Dean M and Aguet, Francois and Albert, Christine and Alonso, Alvaro and Ardlie, Kristin G and Arking, Dan E and Aslibekyan, Stella and Auer, Paul L and Barnard, John and Barr, R Graham and Barwick, Lucas and Becker, Lewis C and Beer, Rebecca L and Benjamin, Emelia J and Bielak, Lawrence F and Blangero, John and Boehnke, Michael and Bowden, Donald W and Brody, Jennifer A and Burchard, Esteban G and Cade, Brian E and Casella, James F and Chalazan, Brandon and Chasman, Daniel I and Chen, Yii-Der Ida and Cho, Michael H and Choi, Seung Hoan and Chung, Mina K and Clish, Clary B and Correa, Adolfo and Curran, Joanne E and Custer, Brian and Darbar, Dawood and Daya, Michelle and de Andrade, Mariza and DeMeo, Dawn L and Dutcher, Susan K and Ellinor, Patrick T and Emery, Leslie S and Eng, Celeste and Fatkin, Diane and Fingerlin, Tasha and Forer, Lukas and Fornage, Myriam and Franceschini, Nora and Fuchsberger, Christian and Fullerton, Stephanie M and Germer, Soren and Gladwin, Mark T and Gottlieb, Daniel J and Guo, Xiuqing and Hall, Michael E and He, Jiang and Heard-Costa, Nancy L and Heckbert, Susan R and Irvin, Marguerite R and Johnsen, Jill M and Johnson, Andrew D and Kaplan, Robert and Kardia, Sharon L R and Kelly, Tanika and Kelly, Shannon and Kenny, Eimear E and Kiel, Douglas P and Klemmer, Robert and Konkle, Barbara A and Kooperberg, Charles and K{\"o}ttgen, Anna and Lange, Leslie A and Lasky-Su, Jessica and Levy, Daniel and Lin, Xihong and Lin, Keng-Han and Liu, Chunyu and Loos, Ruth J F and Garman, Lori and Gerszten, Robert and Lubitz, Steven A and Lunetta, Kathryn L and Mak, Angel C Y and Manichaikul, Ani and Manning, Alisa K and Mathias, Rasika A and McManus, David D and McGarvey, Stephen T and Meigs, James B and Meyers, Deborah A and Mikulla, Julie L and Minear, Mollie A and Mitchell, Braxton D and Mohanty, Sanghamitra and Montasser, May E and Montgomery, Courtney and Morrison, Alanna C and Murabito, Joanne M and Natale, Andrea and Natarajan, Pradeep and Nelson, Sarah C and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Pankratz, Nathan and Peloso, Gina M and Peyser, Patricia A and Pleiness, Jacob and Post, Wendy S and Psaty, Bruce M and Rao, D C and Redline, Susan and Reiner, Alexander P and Roden, Dan and Rotter, Jerome I and Ruczinski, Ingo and Sarnowski, Chloe and Schoenherr, Sebastian and Schwartz, David A and Seo, Jeong-Sun and Seshadri, Sudha and Sheehan, Vivien A and Sheu, Wayne H and Shoemaker, M Benjamin and Smith, Nicholas L and Smith, Jennifer A and Sotoodehnia, Nona and Stilp, Adrienne M and Tang, Weihong and Taylor, Kent D and Telen, Marilyn and Thornton, Timothy A and Tracy, Russell P and Van Den Berg, David J and Vasan, Ramachandran S and Viaud-Martinez, Karine A and Vrieze, Scott and Weeks, Daniel E and Weir, Bruce S and Weiss, Scott T and Weng, Lu-Chen and Willer, Cristen J and Zhang, Yingze and Zhao, Xutong and Arnett, Donna K and Ashley-Koch, Allison E and Barnes, Kathleen C and Boerwinkle, Eric and Gabriel, Stacey and Gibbs, Richard and Rice, Kenneth M and Rich, Stephen S and Silverman, Edwin K and Qasba, Pankaj and Gan, Weiniu and Papanicolaou, George J and Nickerson, Deborah A and Browning, Sharon R and Zody, Michael C and Z{\"o}llner, Sebastian and Wilson, James G and Cupples, L Adrienne and Laurie, Cathy C and Jaquish, Cashell E and Hernandez, Ryan D and O{\textquoteright}Connor, Timothy D and Abecasis, Goncalo R} } @article {8713, title = {A System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program.}, journal = {Am J Epidemiol}, year = {2021}, month = {2021 Apr 16}, abstract = {

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute{\textquoteright}s Trans-Omics for Precision Medicine program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 studies per phenotype (participants recruited 1948-2012). We discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.

}, issn = {1476-6256}, doi = {10.1093/aje/kwab115}, author = {Stilp, Adrienne M and Emery, Leslie S and Broome, Jai G and Buth, Erin J and Khan, Alyna T and Laurie, Cecelia A and Wang, Fei Fei and Wong, Quenna and Chen, Dongquan and D{\textquoteright}Augustine, Catherine M and Heard-Costa, Nancy L and Hohensee, Chancellor R and Johnson, William Craig and Juarez, Lucia D and Liu, Jingmin and Mutalik, Karen M and Raffield, Laura M and Wiggins, Kerri L and de Vries, Paul S and Kelly, Tanika N and Kooperberg, Charles and Natarajan, Pradeep and Peloso, Gina M and Peyser, Patricia A and Reiner, Alex P and Arnett, Donna K and Aslibekyan, Stella and Barnes, Kathleen C and Bielak, Lawrence F and Bis, Joshua C and Cade, Brian E and Chen, Ming-Huei and Correa, Adolfo and Cupples, L Adrienne and de Andrade, Mariza and Ellinor, Patrick T and Fornage, Myriam and Franceschini, Nora and Gan, Weiniu and Ganesh, Santhi K and Graffelman, Jan and Grove, Megan L and Guo, Xiuqing and Hawley, Nicola L and Hsu, Wan-Ling and Jackson, Rebecca D and Jaquish, Cashell E and Johnson, Andrew D and Kardia, Sharon L R and Kelly, Shannon and Lee, Jiwon and Mathias, Rasika A and McGarvey, Stephen T and Mitchell, Braxton D and Montasser, May E and Morrison, Alanna C and North, Kari E and Nouraie, Seyed Mehdi and Oelsner, Elizabeth C and Pankratz, Nathan and Rich, Stephen S and Rotter, Jerome I and Smith, Jennifer A and Taylor, Kent D and Vasan, Ramachandran S and Weeks, Daniel E and Weiss, Scott T and Wilson, Carla G and Yanek, Lisa R and Psaty, Bruce M and Heckbert, Susan R and Laurie, Cathy C} } @article {8664, title = {Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium.}, journal = {EBioMedicine}, volume = {63}, year = {2021}, month = {2021 Jan}, pages = {103157}, abstract = {

BACKGROUND: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants.

METHODS: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity.

FINDINGS: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04\%, P~=~6.1~{\texttimes}~10; METTL8, rs116951054, MAF 0.09\%, P~=~4.5~{\texttimes}~10; and MATK, rs539182790, MAF 0.05\%, P~=~3.4~{\texttimes}~10). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P~=~1.2~{\texttimes}~10, nearest gene GATM, and rs71147340, MAF=0.34, P~=~3.3~{\texttimes}~10, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants.

INTERPRETATION: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.

}, issn = {2352-3964}, doi = {10.1016/j.ebiom.2020.103157}, author = {Lin, Bridget M and Grinde, Kelsey E and Brody, Jennifer A and Breeze, Charles E and Raffield, Laura M and Mychaleckyj, Josyf C and Thornton, Timothy A and Perry, James A and Baier, Leslie J and de Las Fuentes, Lisa and Guo, Xiuqing and Heavner, Benjamin D and Hanson, Robert L and Hung, Yi-Jen and Qian, Huijun and Hsiung, Chao A and Hwang, Shih-Jen and Irvin, Margaret R and Jain, Deepti and Kelly, Tanika N and Kobes, Sayuko and Lange, Leslie and Lash, James P and Li, Yun and Liu, Xiaoming and Mi, Xuenan and Musani, Solomon K and Papanicolaou, George J and Parsa, Afshin and Reiner, Alex P and Salimi, Shabnam and Sheu, Wayne H-H and Shuldiner, Alan R and Taylor, Kent D and Smith, Albert V and Smith, Jennifer A and Tin, Adrienne and Vaidya, Dhananjay and Wallace, Robert B and Yamamoto, Kenichi and Sakaue, Saori and Matsuda, Koichi and Kamatani, Yoichiro and Momozawa, Yukihide and Yanek, Lisa R and Young, Betsi A and Zhao, Wei and Okada, Yukinori and Abecasis, Gonzalo and Psaty, Bruce M and Arnett, Donna K and Boerwinkle, Eric and Cai, Jianwen and Yii-Der Chen, Ida and Correa, Adolfo and Cupples, L Adrienne and He, Jiang and Kardia, Sharon Lr and Kooperberg, Charles and Mathias, Rasika A and Mitchell, Braxton D and Nickerson, Deborah A and Turner, Steve T and Vasan, Ramachandran S and Rotter, Jerome I and Levy, Daniel and Kramer, Holly J and K{\"o}ttgen, Anna and Rich, Stephen S and Lin, Dan-Yu and Browning, Sharon R and Franceschini, Nora} } @article {8913, title = {Whole genome sequence analysis of platelet traits in the NHLBI trans-omics for precision medicine initiative.}, journal = {Hum Mol Genet}, year = {2021}, month = {2021 Sep 06}, abstract = {

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing from NHLBI{\textquoteright}s Trans-Omics for Precision Medicine Initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several GWAS identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of whole genome sequencing in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddab252}, author = {Little, Amarise and Hu, Yao and Sun, Quan and Jain, Deepti and Broome, Jai and Chen, Ming-Huei and Thibord, Florian and McHugh, Caitlin and Surendran, Praveen and Blackwell, Thomas W and Brody, Jennifer A and Bhan, Arunoday and Chami, Nathalie and Vries, Paul S and Ekunwe, Lynette and Heard-Costa, Nancy and Hobbs, Brian D and Manichaikul, Ani and Moon, Jee-Young and Preuss, Michael H and Ryan, Kathleen and Wang, Zhe and Wheeler, Marsha and Yanek, Lisa R and Abecasis, Goncalo R and Almasy, Laura and Beaty, Terri H and Becker, Lewis C and Blangero, John and Boerwinkle, Eric and Butterworth, Adam S and Choquet, Helene and Correa, Adolfo and Curran, Joanne E and Faraday, Nauder and Fornage, Myriam and Glahn, David C and Hou, Lifang and Jorgenson, Eric and Kooperberg, Charles and Lewis, Joshua P and Lloyd-Jones, Donald M and Loos, Ruth J F and Min, Nancy and Mitchell, Braxton D and Morrison, Alanna C and Nickerson, Debbie and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Pankratz, Nathan and Psaty, Bruce M and Vasan, Ramachandran S and Rich, Stephen S and Rotter, Jerome I and Smith, Albert V and Smith, Nicholas L and Tang, Hua and Tracy, Russell P and Conomos, Matthew P and Laurie, Cecelia A and Mathias, Rasika A and Li, Yun and Auer, Paul L and Thornton, Timothy and Reiner, Alexander P and Johnson, Andrew D and Raffield, Laura M} } @article {8920, title = {Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program.}, journal = {Genome Med}, volume = {13}, year = {2021}, month = {2021 08 26}, pages = {136}, abstract = {

BACKGROUND: Sleep-disordered breathing is a common disorder associated with significant morbidity. The genetic architecture of sleep-disordered breathing remains poorly understood. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we performed the first whole-genome sequence analysis of sleep-disordered breathing.

METHODS: The study sample was comprised of 7988 individuals of diverse ancestry. Common-variant and pathway analyses included an additional 13,257 individuals. We examined five complementary traits describing different aspects of sleep-disordered breathing: the apnea-hypopnea index, average oxyhemoglobin desaturation per event, average and minimum oxyhemoglobin saturation across the sleep episode, and the percentage of sleep with oxyhemoglobin saturation < 90\%. We adjusted for age, sex, BMI, study, and family structure using MMSKAT and EMMAX mixed linear model approaches. Additional bioinformatics analyses were performed with MetaXcan, GIGSEA, and ReMap.

RESULTS: We identified a multi-ethnic set-based rare-variant association (p = 3.48 {\texttimes} 10) on chromosome X with ARMCX3. Additional rare-variant associations include ARMCX3-AS1, MRPS33, and C16orf90. Novel common-variant loci were identified in the NRG1 and SLC45A2 regions, and previously associated loci in the IL18RAP and ATP2B4 regions were associated with novel phenotypes. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Additional analyses identified significantly associated pathways.

CONCLUSIONS: We have identified the first gene-based rare-variant associations with objectively measured sleep-disordered breathing traits. Our results increase the understanding of the genetic architecture of sleep-disordered breathing and highlight associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis, and HIF1A-mediated hypoxic response.

}, issn = {1756-994X}, doi = {10.1186/s13073-021-00917-8}, author = {Cade, Brian E and Lee, Jiwon and Sofer, Tamar and Wang, Heming and Zhang, Man and Chen, Han and Gharib, Sina A and Gottlieb, Daniel J and Guo, Xiuqing and Lane, Jacqueline M and Liang, Jingjing and Lin, Xihong and Mei, Hao and Patel, Sanjay R and Purcell, Shaun M and Saxena, Richa and Shah, Neomi A and Evans, Daniel S and Hanis, Craig L and Hillman, David R and Mukherjee, Sutapa and Palmer, Lyle J and Stone, Katie L and Tranah, Gregory J and Abecasis, Goncalo R and Boerwinkle, Eric A and Correa, Adolfo and Cupples, L Adrienne and Kaplan, Robert C and Nickerson, Deborah A and North, Kari E and Psaty, Bruce M and Rotter, Jerome I and Rich, Stephen S and Tracy, Russell P and Vasan, Ramachandran S and Wilson, James G and Zhu, Xiaofeng and Redline, Susan} } @article {8779, title = {Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 05 06}, pages = {874-893}, abstract = {

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3~bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.

}, keywords = {Adult, Aged, Chromosomes, Human, Pair 16, Datasets as Topic, Erythrocytes, Female, Gene Editing, Genetic Variation, Genome-Wide Association Study, HEK293 Cells, Humans, Male, Middle Aged, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Quality Control, Reproducibility of Results, United States}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.04.003}, author = {Hu, Yao and Stilp, Adrienne M and McHugh, Caitlin P and Rao, Shuquan and Jain, Deepti and Zheng, Xiuwen and Lane, John and M{\'e}ric de Bellefon, S{\'e}bastian and Raffield, Laura M and Chen, Ming-Huei and Yanek, Lisa R and Wheeler, Marsha and Yao, Yao and Ren, Chunyan and Broome, Jai and Moon, Jee-Young and de Vries, Paul S and Hobbs, Brian D and Sun, Quan and Surendran, Praveen and Brody, Jennifer A and Blackwell, Thomas W and Choquet, Helene and Ryan, Kathleen and Duggirala, Ravindranath and Heard-Costa, Nancy and Wang, Zhe and Chami, Nathalie and Preuss, Michael H and Min, Nancy and Ekunwe, Lynette and Lange, Leslie A and Cushman, Mary and Faraday, Nauder and Curran, Joanne E and Almasy, Laura and Kundu, Kousik and Smith, Albert V and Gabriel, Stacey and Rotter, Jerome I and Fornage, Myriam and Lloyd-Jones, Donald M and Vasan, Ramachandran S and Smith, Nicholas L and North, Kari E and Boerwinkle, Eric and Becker, Lewis C and Lewis, Joshua P and Abecasis, Goncalo R and Hou, Lifang and O{\textquoteright}Connell, Jeffrey R and Morrison, Alanna C and Beaty, Terri H and Kaplan, Robert and Correa, Adolfo and Blangero, John and Jorgenson, Eric and Psaty, Bruce M and Kooperberg, Charles and Walton, Russell T and Kleinstiver, Benjamin P and Tang, Hua and Loos, Ruth J F and Soranzo, Nicole and Butterworth, Adam S and Nickerson, Debbie and Rich, Stephen S and Mitchell, Braxton D and Johnson, Andrew D and Auer, Paul L and Li, Yun and Mathias, Rasika A and Lettre, Guillaume and Pankratz, Nathan and Laurie, Cathy C and Laurie, Cecelia A and Bauer, Daniel E and Conomos, Matthew P and Reiner, Alexander P} } @article {8914, title = {Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 10 07}, pages = {1836-1851}, abstract = {

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.

}, keywords = {Asthma, Biomarkers, Dermatitis, Atopic, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Leukocytes, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Polymorphism, Single Nucleotide, Prognosis, Proteome, Pulmonary Disease, Chronic Obstructive, Quantitative Trait Loci, United Kingdom, United States, Whole Genome Sequencing}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.08.007}, author = {Mikhaylova, Anna V and McHugh, Caitlin P and Polfus, Linda M and Raffield, Laura M and Boorgula, Meher Preethi and Blackwell, Thomas W and Brody, Jennifer A and Broome, Jai and Chami, Nathalie and Chen, Ming-Huei and Conomos, Matthew P and Cox, Corey and Curran, Joanne E and Daya, Michelle and Ekunwe, Lynette and Glahn, David C and Heard-Costa, Nancy and Highland, Heather M and Hobbs, Brian D and Ilboudo, Yann and Jain, Deepti and Lange, Leslie A and Miller-Fleming, Tyne W and Min, Nancy and Moon, Jee-Young and Preuss, Michael H and Rosen, Jonathon and Ryan, Kathleen and Smith, Albert V and Sun, Quan and Surendran, Praveen and de Vries, Paul S and Walter, Klaudia and Wang, Zhe and Wheeler, Marsha and Yanek, Lisa R and Zhong, Xue and Abecasis, Goncalo R and Almasy, Laura and Barnes, Kathleen C and Beaty, Terri H and Becker, Lewis C and Blangero, John and Boerwinkle, Eric and Butterworth, Adam S and Chavan, Sameer and Cho, Michael H and Choquet, Helene and Correa, Adolfo and Cox, Nancy and DeMeo, Dawn L and Faraday, Nauder and Fornage, Myriam and Gerszten, Robert E and Hou, Lifang and Johnson, Andrew D and Jorgenson, Eric and Kaplan, Robert and Kooperberg, Charles and Kundu, Kousik and Laurie, Cecelia A and Lettre, Guillaume and Lewis, Joshua P and Li, Bingshan and Li, Yun and Lloyd-Jones, Donald M and Loos, Ruth J F and Manichaikul, Ani and Meyers, Deborah A and Mitchell, Braxton D and Morrison, Alanna C and Ngo, Debby and Nickerson, Deborah A and Nongmaithem, Suraj and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Ortega, Victor E and Pankratz, Nathan and Perry, James A and Psaty, Bruce M and Rich, Stephen S and Soranzo, Nicole and Rotter, Jerome I and Silverman, Edwin K and Smith, Nicholas L and Tang, Hua and Tracy, Russell P and Thornton, Timothy A and Vasan, Ramachandran S and Zein, Joe and Mathias, Rasika A and Reiner, Alexander P and Auer, Paul L} } @article {9042, title = {Assessing the contribution of rare variants to complex trait heritability from whole-genome sequence data.}, journal = {Nat Genet}, volume = {54}, year = {2022}, month = {2022 Mar}, pages = {263-273}, abstract = {

Analyses of data from genome-wide association studies on unrelated individuals have shown that, for human traits and diseases, approximately one-third to two-thirds of heritability is captured by common SNPs. However, it is not known whether the remaining heritability is due to the imperfect tagging of causal variants by common SNPs, in particular whether the causal variants are rare, or whether it is overestimated due to bias in inference from pedigree data. Here we estimated heritability for height and body mass index (BMI) from whole-genome sequence data on 25,465 unrelated individuals of European ancestry. The estimated heritability was 0.68 (standard error 0.10) for height and 0.30 (standard error 0.10) for body mass index. Low minor allele frequency variants in low linkage disequilibrium (LD) with neighboring variants were enriched for heritability, to a greater extent for protein-altering variants, consistent with negative selection. Our results imply that rare variants, in particular those in regions of low linkage disequilibrium, are a major source of the still missing heritability of complex traits and disease.

}, issn = {1546-1718}, doi = {10.1038/s41588-021-00997-7}, author = {Wainschtein, Pierrick and Jain, Deepti and Zheng, Zhili and Cupples, L Adrienne and Shadyab, Aladdin H and McKnight, Barbara and Shoemaker, Benjamin M and Mitchell, Braxton D and Psaty, Bruce M and Kooperberg, Charles and Liu, Ching-Ti and Albert, Christine M and Roden, Dan and Chasman, Daniel I and Darbar, Dawood and Lloyd-Jones, Donald M and Arnett, Donna K and Regan, Elizabeth A and Boerwinkle, Eric and Rotter, Jerome I and O{\textquoteright}Connell, Jeffrey R and Yanek, Lisa R and de Andrade, Mariza and Allison, Matthew A and McDonald, Merry-Lynn N and Chung, Mina K and Fornage, Myriam and Chami, Nathalie and Smith, Nicholas L and Ellinor, Patrick T and Vasan, Ramachandran S and Mathias, Rasika A and Loos, Ruth J F and Rich, Stephen S and Lubitz, Steven A and Heckbert, Susan R and Redline, Susan and Guo, Xiuqing and Chen, Y -D Ida and Laurie, Cecelia A and Hernandez, Ryan D and McGarvey, Stephen T and Goddard, Michael E and Laurie, Cathy C and North, Kari E and Lange, Leslie A and Weir, Bruce S and Yengo, Loic and Yang, Jian and Visscher, Peter M} } @article {8986, title = {Clonal Hematopoiesis Is Associated With Higher Risk of Stroke.}, journal = {Stroke}, volume = {53}, year = {2022}, month = {2022 Mar}, pages = {788-797}, abstract = {

BACKGROUND AND PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease-related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke.

METHODS: We utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association of CHIP and commonly mutated individual CHIP driver genes (, , and ) with any stroke, ischemic stroke, and hemorrhagic stroke.

RESULTS: CHIP was associated with an increased risk of total stroke (hazard ratio, 1.14 [95\% CI, 1.03-1.27]; =0.01) after adjustment for age, sex, and race. We observed associations with CHIP with risk of hemorrhagic stroke (hazard ratio, 1.24 [95\% CI, 1.01-1.51]; =0.04) and with small vessel ischemic stroke subtypes. In gene-specific association results, showed the strongest association with total stroke and ischemic stroke, whereas and were each associated with increased risk of hemorrhagic stroke.

CONCLUSIONS: CHIP is associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke. Future studies clarifying the relationship between CHIP and subtypes of stroke are needed.

}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.121.037388}, author = {Bhattacharya, Romit and Zekavat, Seyedeh M and Haessler, Jeffrey and Fornage, Myriam and Raffield, Laura and Uddin, Md Mesbah and Bick, Alexander G and Niroula, Abhishek and Yu, Bing and Gibson, Christopher and Griffin, Gabriel and Morrison, Alanna C and Psaty, Bruce M and Longstreth, William T and Bis, Joshua C and Rich, Stephen S and Rotter, Jerome I and Tracy, Russell P and Correa, Adolfo and Seshadri, Sudha and Johnson, Andrew and Collins, Jason M and Hayden, Kathleen M and Madsen, Tracy E and Ballantyne, Christie M and Jaiswal, Siddhartha and Ebert, Benjamin L and Kooperberg, Charles and Manson, JoAnn E and Whitsel, Eric A and Natarajan, Pradeep and Reiner, Alexander P} } @article {9246, title = {Correlations between complex human phenotypes vary by genetic background, gender, and environment.}, journal = {Cell Rep Med}, volume = {3}, year = {2022}, month = {2022 Dec 20}, pages = {100844}, abstract = {

We develop a closed-form Haseman-Elston estimator for genetic and environmental correlation coefficients between complex phenotypes, which we term HEc, that is as precise as GCTA yet \~{}20{\texttimes} faster. We estimate genetic and environmental correlations between over 7,000 phenotype pairs in subgroups from the Trans-Omics in Precision Medicine (TOPMed) program. We demonstrate substantial differences in both heritabilities and genetic correlations for multiple phenotypes and phenotype pairs between individuals of self-reported Black, Hispanic/Latino, and White backgrounds. We similarly observe differences in many of the genetic and environmental correlations between genders. To estimate the contribution of genetics to the observed phenotypic correlation, we introduce "fractional genetic correlation" as the fraction of phenotypic correlation explained by genetics. Finally, we quantify the enrichment of correlations between phenotypic domains, each of which is comprised of multiple phenotypes. Altogether, we demonstrate that the observed correlations between complex human phenotypes depend on the genetic background of the individuals, their gender, and their environment.

}, keywords = {Female, Genetic Background, Humans, Male, Phenotype}, issn = {2666-3791}, doi = {10.1016/j.xcrm.2022.100844}, author = {Elgart, Michael and Goodman, Matthew O and Isasi, Carmen and Chen, Han and Morrison, Alanna C and de Vries, Paul S and Xu, Huichun and Manichaikul, Ani W and Guo, Xiuqing and Franceschini, Nora and Psaty, Bruce M and Rich, Stephen S and Rotter, Jerome I and Lloyd-Jones, Donald M and Fornage, Myriam and Correa, Adolfo and Heard-Costa, Nancy L and Vasan, Ramachandran S and Hernandez, Ryan and Kaplan, Robert C and Redline, Susan and Sofer, Tamar} } @article {9194, title = {Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors.}, journal = {Circulation}, volume = {146}, year = {2022}, month = {2022 Oct 18}, pages = {1225-1242}, abstract = {

BACKGROUND: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources.

METHODS: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations.

RESULTS: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1\% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis.

CONCLUSIONS: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

}, keywords = {Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Thrombosis, Venous Thromboembolism}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.122.059675}, author = {Thibord, Florian and Klarin, Derek and Brody, Jennifer A and Chen, Ming-Huei and Levin, Michael G and Chasman, Daniel I and Goode, Ellen L and Hveem, Kristian and Teder-Laving, Maris and Martinez-Perez, Angel and A{\"\i}ssi, Dylan and Daian-Bacq, Delphine and Ito, Kaoru and Natarajan, Pradeep and Lutsey, Pamela L and Nadkarni, Girish N and de Vries, Paul S and Cuellar-Partida, Gabriel and Wolford, Brooke N and Pattee, Jack W and Kooperberg, Charles and Braekkan, Sigrid K and Li-Gao, Ruifang and Saut, No{\'e}mie and Sept, Corriene and Germain, Marine and Judy, Renae L and Wiggins, Kerri L and Ko, Darae and O{\textquoteright}Donnell, Christopher J and Taylor, Kent D and Giulianini, Franco and de Andrade, Mariza and N{\o}st, Therese H and Boland, Anne and Empana, Jean-Philippe and Koyama, Satoshi and Gilliland, Thomas and Do, Ron and Huffman, Jennifer E and Wang, Xin and Zhou, Wei and Manuel Soria, Jose and Carlos Souto, Juan and Pankratz, Nathan and Haessler, Jeffery and Hindberg, Kristian and Rosendaal, Frits R and Turman, Constance and Olaso, Robert and Kember, Rachel L and Bartz, Traci M and Lynch, Julie A and Heckbert, Susan R and Armasu, Sebastian M and Brumpton, Ben and Smadja, David M and Jouven, Xavier and Komuro, Issei and Clapham, Katharine R and Loos, Ruth J F and Willer, Cristen J and Sabater-Lleal, Maria and Pankow, James S and Reiner, Alexander P and Morelli, Vania M and Ridker, Paul M and Vlieg, Astrid van Hylckama and Deleuze, Jean-Francois and Kraft, Peter and Rader, Daniel J and Min Lee, Kyung and Psaty, Bruce M and Heidi Skogholt, Anne and Emmerich, Joseph and Suchon, Pierre and Rich, Stephen S and Vy, Ha My T and Tang, Weihong and Jackson, Rebecca D and Hansen, John-Bjarne and Morange, Pierre-Emmanuel and Kabrhel, Christopher and Tr{\'e}gou{\"e}t, David-Alexandre and Damrauer, Scott M and Johnson, Andrew D and Smith, Nicholas L} } @article {9167, title = {Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes.}, journal = {Nat Commun}, volume = {13}, year = {2022}, month = {2022 08 30}, pages = {5106}, abstract = {

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P < 0.001 for each trait) and discriminate pathogenic from non-pathogenic variants (area under the curve 0.82-0.84 across endophenotypes). An effect size threshold of >= 0.5 times the endophenotype standard deviation nominates up to 35\% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes with pathogenic potential. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity.

}, keywords = {Disease Susceptibility, Endophenotypes, Humans, Long QT Syndrome, Virulence}, issn = {2041-1723}, doi = {10.1038/s41467-022-32009-5}, author = {Halford, Jennifer L and Morrill, Valerie N and Choi, Seung Hoan and Jurgens, Sean J and Melloni, Giorgio and Marston, Nicholas A and Weng, Lu-Chen and Nauffal, Victor and Hall, Amelia W and Gunn, Sophia and Austin-Tse, Christina A and Pirruccello, James P and Khurshid, Shaan and Rehm, Heidi L and Benjamin, Emelia J and Boerwinkle, Eric and Brody, Jennifer A and Correa, Adolfo and Fornwalt, Brandon K and Gupta, Namrata and Haggerty, Christopher M and Harris, Stephanie and Heckbert, Susan R and Hong, Charles C and Kooperberg, Charles and Lin, Henry J and Loos, Ruth J F and Mitchell, Braxton D and Morrison, Alanna C and Post, Wendy and Psaty, Bruce M and Redline, Susan and Rice, Kenneth M and Rich, Stephen S and Rotter, Jerome I and Schnatz, Peter F and Soliman, Elsayed Z and Sotoodehnia, Nona and Wong, Eugene K and Sabatine, Marc S and Ruff, Christian T and Lunetta, Kathryn L and Ellinor, Patrick T and Lubitz, Steven A} } @article {9253, title = {A framework for detecting noncoding rare-variant associations of large-scale whole-genome sequencing studies.}, journal = {Nat Methods}, volume = {19}, year = {2022}, month = {2022 Dec}, pages = {1599-1611}, abstract = {

Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate multiple functional annotations. In non-gene-centric analysis, STAARpipeline uses SCANG-STAAR to incorporate dynamic window sizes and multiple functional annotations. We apply STAARpipeline to identify noncoding RV sets associated with four lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several of them in an additional 9,123 TOPMed samples. We also analyze five non-lipid TOPMed traits.

}, keywords = {Genetic Variation, Genome, Genome-Wide Association Study, Humans, Phenotype, Whole Genome Sequencing}, issn = {1548-7105}, doi = {10.1038/s41592-022-01640-x}, author = {Li, Zilin and Li, Xihao and Zhou, Hufeng and Gaynor, Sheila M and Selvaraj, Margaret Sunitha and Arapoglou, Theodore and Quick, Corbin and Liu, Yaowu and Chen, Han and Sun, Ryan and Dey, Rounak and Arnett, Donna K and Auer, Paul L and Bielak, Lawrence F and Bis, Joshua C and Blackwell, Thomas W and Blangero, John and Boerwinkle, Eric and Bowden, Donald W and Brody, Jennifer A and Cade, Brian E and Conomos, Matthew P and Correa, Adolfo and Cupples, L Adrienne and Curran, Joanne E and de Vries, Paul S and Duggirala, Ravindranath and Franceschini, Nora and Freedman, Barry I and G{\"o}ring, Harald H H and Guo, Xiuqing and Kalyani, Rita R and Kooperberg, Charles and Kral, Brian G and Lange, Leslie A and Lin, Bridget M and Manichaikul, Ani and Manning, Alisa K and Martin, Lisa W and Mathias, Rasika A and Meigs, James B and Mitchell, Braxton D and Montasser, May E and Morrison, Alanna C and Naseri, Take and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Peyser, Patricia A and Psaty, Bruce M and Raffield, Laura M and Redline, Susan and Reiner, Alexander P and Reupena, Muagututi{\textquoteright}a Sefuiva and Rice, Kenneth M and Rich, Stephen S and Smith, Jennifer A and Taylor, Kent D and Taub, Margaret A and Vasan, Ramachandran S and Weeks, Daniel E and Wilson, James G and Yanek, Lisa R and Zhao, Wei and Rotter, Jerome I and Willer, Cristen J and Natarajan, Pradeep and Peloso, Gina M and Lin, Xihong} } @article {9099, title = {Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension.}, journal = {Hypertension}, year = {2022}, month = {2022 Jun 02}, pages = {101161HYPERTENSIONAHA12219324}, abstract = {

BACKGROUND: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.

METHODS: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.

RESULTS: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (<5{\texttimes}10). Among them, a rare intergenic variant at novel locus, , was associated with lower systolic blood pressure in stage-1 (beta [SE]=-32.6 [6.0]; =4.99{\texttimes}10) but not stage-2 analysis (=0.11). Furthermore, a novel common variant at the known locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=-0.36 [0.07]; =4.18{\texttimes}10) and attained genome-wide significance in stage-2 (beta [SE]=-0.29 [0.03]; =7.28{\texttimes}10). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings (<1{\texttimes}10 and <1{\texttimes}10, respectively).

DISCUSSION: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.

}, issn = {1524-4563}, doi = {10.1161/HYPERTENSIONAHA.122.19324}, author = {Kelly, Tanika N and Sun, Xiao and He, Karen Y and Brown, Michael R and Taliun, Sarah A Gagliano and Hellwege, Jacklyn N and Irvin, Marguerite R and Mi, Xuenan and Brody, Jennifer A and Franceschini, Nora and Guo, Xiuqing and Hwang, Shih-Jen and de Vries, Paul S and Gao, Yan and Moscati, Arden and Nadkarni, Girish N and Yanek, Lisa R and Elfassy, Tali and Smith, Jennifer A and Chung, Ren-Hua and Beitelshees, Amber L and Patki, Amit and Aslibekyan, Stella and Blobner, Brandon M and Peralta, Juan M and Assimes, Themistocles L and Palmas, Walter R and Liu, Chunyu and Bress, Adam P and Huang, Zhijie and Becker, Lewis C and Hwa, Chii-Min and O{\textquoteright}Connell, Jeffrey R and Carlson, Jenna C and Warren, Helen R and Das, Sayantan and Giri, Ayush and Martin, Lisa W and Craig Johnson, W and Fox, Ervin R and Bottinger, Erwin P and Razavi, Alexander C and Vaidya, Dhananjay and Chuang, Lee-Ming and Chang, Yen-Pei C and Naseri, Take and Jain, Deepti and Kang, Hyun Min and Hung, Adriana M and Srinivasasainagendra, Vinodh and Snively, Beverly M and Gu, Dongfeng and Montasser, May E and Reupena, Muagututi{\textquoteright}a Sefuiva and Heavner, Benjamin D and LeFaive, Jonathon and Hixson, James E and Rice, Kenneth M and Wang, Fei Fei and Nielsen, Jonas B and Huang, Jianfeng and Khan, Alyna T and Zhou, Wei and Nierenberg, Jovia L and Laurie, Cathy C and Armstrong, Nicole D and Shi, Mengyao and Pan, Yang and Stilp, Adrienne M and Emery, Leslie and Wong, Quenna and Hawley, Nicola L and Minster, Ryan L and Curran, Joanne E and Munroe, Patricia B and Weeks, Daniel E and North, Kari E and Tracy, Russell P and Kenny, Eimear E and Shimbo, Daichi and Chakravarti, Aravinda and Rich, Stephen S and Reiner, Alex P and Blangero, John and Redline, Susan and Mitchell, Braxton D and Rao, Dabeeru C and Ida Chen, Yii-Der and Kardia, Sharon L R and Kaplan, Robert C and Mathias, Rasika A and He, Jiang and Psaty, Bruce M and Fornage, Myriam and Loos, Ruth J F and Correa, Adolfo and Boerwinkle, Eric and Rotter, Jerome I and Kooperberg, Charles and Edwards, Todd L and Abecasis, Goncalo R and Zhu, Xiaofeng and Levy, Daniel and Arnett, Donna K and Morrison, Alanna C} } @article {9038, title = {Monogenic and Polygenic Contributions to QTc Prolongation in the Population.}, journal = {Circulation}, year = {2022}, month = {2022 Apr 07}, abstract = {

Rare sequence variation in genes underlying cardiac repolarization and common polygenic variation influence QT interval duration. However, current clinical genetic testing of individuals with unexplained QT prolongation is restricted to examination of monogenic rare variants. The recent emergence of large-scale biorepositories with sequence data enables examination of the joint contribution of rare and common variation to the QT interval in the population. We performed a genome wide association study (GWAS) of the QTc in 84,630 United Kingdom Biobank (UKB) participants and created a polygenic risk score (PRS). Among 26,976 participants with whole genome sequencing and electrocardiogram data in the Trans-Omics for Precision Medicine (TOPMed) program, we identified 160 carriers of putative pathogenic rare variants in 10 genes known to be associated with the QT interval. We examined QTc associations with the PRS and with rare variants in TOPMed. Fifty-four independent loci were identified by GWAS in the UKB. Twenty-one loci were novel, of which 12 were replicated in TOPMed. The PRS comprising 1,110,494 common variants was significantly associated with the QTc in TOPMed (ΔQTc/ = 1.4 ms, 95\% CI 1.3 -1.5; p-value=1.1{\texttimes}10). Carriers of putative pathogenic rare variants had longer QTc than non-carriers (ΔQTc=10.9 ms [7.4-14.4]). 23.7\% of individuals with QTc>480 ms carried either a monogenic rare variant or had a PRS in the top decile (3.4\% monogenic, 21\% top decile of PRS). QTc duration in the population is influenced by both rare variants in genes underlying cardiac repolarization and polygenic risk, with a sizeable contribution from polygenic risk. Comprehensive assessment of the genetic determinants of QTc prolongation includes incorporation of both polygenic and monogenic risk.

}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.121.057261}, author = {Nauffal, Victor and Morrill, Valerie N and Jurgens, Sean J and Choi, Seung Hoan and Hall, Amelia W and Weng, Lu-Chen and Halford, Jennifer L and Austin-Tse, Christina and Haggerty, Christopher M and Harris, Stephanie L and Wong, Eugene K and Alonso, Alvaro and Arking, Dan E and Benjamin, Emelia J and Boerwinkle, Eric and Min, Yuan-I and Correa, Adolfo and Fornwalt, Brandon K and Heckbert, Susan R and Kooperberg, Charles and Lin, Henry J and Loos, Ruth J F and Rice, Kenneth M and Gupta, Namrata and Blackwell, Thomas W and Mitchell, Braxton D and Morrison, Alanna C and Psaty, Bruce M and Post, Wendy S and Redline, Susan and Rehm, Heidi L and Rich, Stephen S and Rotter, Jerome I and Soliman, Elsayed Z and Sotoodehnia, Nona and Lunetta, Kathryn L and Ellinor, Patrick T and Lubitz, Steven A} } @article {9104, title = {Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation.}, journal = {Nat Genet}, volume = {54}, year = {2022}, month = {2022 May}, pages = {560-572}, abstract = {

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9\% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 {\texttimes} 10), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4\% of T2D associations to a single variant with >50\% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.

}, keywords = {Diabetes Mellitus, Type 2, Ethnicity, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1546-1718}, doi = {10.1038/s41588-022-01058-3}, author = {Mahajan, Anubha and Spracklen, Cassandra N and Zhang, Weihua and Ng, Maggie C Y and Petty, Lauren E and Kitajima, Hidetoshi and Yu, Grace Z and R{\"u}eger, Sina and Speidel, Leo and Kim, Young Jin and Horikoshi, Momoko and Mercader, Josep M and Taliun, Daniel and Moon, Sanghoon and Kwak, Soo-Heon and Robertson, Neil R and Rayner, Nigel W and Loh, Marie and Kim, Bong-Jo and Chiou, Joshua and Miguel-Escalada, Irene and Della Briotta Parolo, Pietro and Lin, Kuang and Bragg, Fiona and Preuss, Michael H and Takeuchi, Fumihiko and Nano, Jana and Guo, Xiuqing and Lamri, Amel and Nakatochi, Masahiro and Scott, Robert A and Lee, Jung-Jin and Huerta-Chagoya, Alicia and Graff, Mariaelisa and Chai, Jin-Fang and Parra, Esteban J and Yao, Jie and Bielak, Lawrence F and Tabara, Yasuharu and Hai, Yang and Steinthorsdottir, Valgerdur and Cook, James P and Kals, Mart and Grarup, Niels and Schmidt, Ellen M and Pan, Ian and Sofer, Tamar and Wuttke, Matthias and Sarnowski, Chloe and Gieger, Christian and Nousome, Darryl and Trompet, Stella and Long, Jirong and Sun, Meng and Tong, Lin and Chen, Wei-Min and Ahmad, Meraj and Noordam, Raymond and Lim, Victor J Y and Tam, Claudia H T and Joo, Yoonjung Yoonie and Chen, Chien-Hsiun and Raffield, Laura M and Lecoeur, C{\'e}cile and Prins, Bram Peter and Nicolas, Aude and Yanek, Lisa R and Chen, Guanjie and Jensen, Richard A and Tajuddin, Salman and Kabagambe, Edmond K and An, Ping and Xiang, Anny H and Choi, Hyeok Sun and Cade, Brian E and Tan, Jingyi and Flanagan, Jack and Abaitua, Fernando and Adair, Linda S and Adeyemo, Adebowale and Aguilar-Salinas, Carlos A and Akiyama, Masato and Anand, Sonia S and Bertoni, Alain and Bian, Zheng and Bork-Jensen, Jette and Brandslund, Ivan and Brody, Jennifer A and Brummett, Chad M and Buchanan, Thomas A and Canouil, Micka{\"e}l and Chan, Juliana C N and Chang, Li-Ching and Chee, Miao-Li and Chen, Ji and Chen, Shyh-Huei and Chen, Yuan-Tsong and Chen, Zhengming and Chuang, Lee-Ming and Cushman, Mary and Das, Swapan K and de Silva, H Janaka and Dedoussis, George and Dimitrov, Latchezar and Doumatey, Ayo P and Du, Shufa and Duan, Qing and Eckardt, Kai-Uwe and Emery, Leslie S and Evans, Daniel S and Evans, Michele K and Fischer, Krista and Floyd, James S and Ford, Ian and Fornage, Myriam and Franco, Oscar H and Frayling, Timothy M and Freedman, Barry I and Fuchsberger, Christian and Genter, Pauline and Gerstein, Hertzel C and Giedraitis, Vilmantas and Gonz{\'a}lez-Villalpando, Clicerio and Gonzalez-Villalpando, Maria Elena and Goodarzi, Mark O and Gordon-Larsen, Penny and Gorkin, David and Gross, Myron and Guo, Yu and Hackinger, Sophie and Han, Sohee and Hattersley, Andrew T and Herder, Christian and Howard, Annie-Green and Hsueh, Willa and Huang, Mengna and Huang, Wei and Hung, Yi-Jen and Hwang, Mi Yeong and Hwu, Chii-Min and Ichihara, Sahoko and Ikram, Mohammad Arfan and Ingelsson, Martin and Islam, Md Tariqul and Isono, Masato and Jang, Hye-Mi and Jasmine, Farzana and Jiang, Guozhi and Jonas, Jost B and J{\o}rgensen, Marit E and J{\o}rgensen, Torben and Kamatani, Yoichiro and Kandeel, Fouad R and Kasturiratne, Anuradhani and Katsuya, Tomohiro and Kaur, Varinderpal and Kawaguchi, Takahisa and Keaton, Jacob M and Kho, Abel N and Khor, Chiea-Chuen and Kibriya, Muhammad G and Kim, Duk-Hwan and Kohara, Katsuhiko and Kriebel, Jennifer and Kronenberg, Florian and Kuusisto, Johanna and L{\"a}ll, Kristi and Lange, Leslie A and Lee, Myung-Shik and Lee, Nanette R and Leong, Aaron and Li, Liming and Li, Yun and Li-Gao, Ruifang and Ligthart, Symen and Lindgren, Cecilia M and Linneberg, Allan and Liu, Ching-Ti and Liu, Jianjun and Locke, Adam E and Louie, Tin and Luan, Jian{\textquoteright}an and Luk, Andrea O and Luo, Xi and Lv, Jun and Lyssenko, Valeriya and Mamakou, Vasiliki and Mani, K Radha and Meitinger, Thomas and Metspalu, Andres and Morris, Andrew D and Nadkarni, Girish N and Nadler, Jerry L and Nalls, Michael A and Nayak, Uma and Nongmaithem, Suraj S and Ntalla, Ioanna and Okada, Yukinori and Orozco, Lorena and Patel, Sanjay R and Pereira, Mark A and Peters, Annette and Pirie, Fraser J and Porneala, Bianca and Prasad, Gauri and Preissl, Sebastian and Rasmussen-Torvik, Laura J and Reiner, Alexander P and Roden, Michael and Rohde, Rebecca and Roll, Kathryn and Sabanayagam, Charumathi and Sander, Maike and Sandow, Kevin and Sattar, Naveed and Sch{\"o}nherr, Sebastian and Schurmann, Claudia and Shahriar, Mohammad and Shi, Jinxiu and Shin, Dong Mun and Shriner, Daniel and Smith, Jennifer A and So, Wing Yee and Stan{\v c}{\'a}kov{\'a}, Alena and Stilp, Adrienne M and Strauch, Konstantin and Suzuki, Ken and Takahashi, Atsushi and Taylor, Kent D and Thorand, Barbara and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tomlinson, Brian and Torres, Jason M and Tsai, Fuu-Jen and Tuomilehto, Jaakko and Tusi{\'e}-Luna, Teresa and Udler, Miriam S and Valladares-Salgado, Adan and van Dam, Rob M and van Klinken, Jan B and Varma, Rohit and Vujkovic, Marijana and Wacher-Rodarte, Niels and Wheeler, Eleanor and Whitsel, Eric A and Wickremasinghe, Ananda R and van Dijk, Ko Willems and Witte, Daniel R and Yajnik, Chittaranjan S and Yamamoto, Ken and Yamauchi, Toshimasa and Yengo, Loic and Yoon, Kyungheon and Yu, Canqing and Yuan, Jian-Min and Yusuf, Salim and Zhang, Liang and Zheng, Wei and Raffel, Leslie J and Igase, Michiya and Ipp, Eli and Redline, Susan and Cho, Yoon Shin and Lind, Lars and Province, Michael A and Hanis, Craig L and Peyser, Patricia A and Ingelsson, Erik and Zonderman, Alan B and Psaty, Bruce M and Wang, Ya-Xing and Rotimi, Charles N and Becker, Diane M and Matsuda, Fumihiko and Liu, Yongmei and Zeggini, Eleftheria and Yokota, Mitsuhiro and Rich, Stephen S and Kooperberg, Charles and Pankow, James S and Engert, James C and Chen, Yii-Der Ida and Froguel, Philippe and Wilson, James G and Sheu, Wayne H H and Kardia, Sharon L R and Wu, Jer-Yuarn and Hayes, M Geoffrey and Ma, Ronald C W and Wong, Tien-Yin and Groop, Leif and Mook-Kanamori, Dennis O and Chandak, Giriraj R and Collins, Francis S and Bharadwaj, Dwaipayan and Par{\'e}, Guillaume and Sale, Mich{\`e}le M and Ahsan, Habibul and Motala, Ayesha A and Shu, Xiao-Ou and Park, Kyong-Soo and Jukema, J Wouter and Cruz, Miguel and McKean-Cowdin, Roberta and Grallert, Harald and Cheng, Ching-Yu and Bottinger, Erwin P and Dehghan, Abbas and Tai, E-Shyong and Dupuis, Jos{\'e}e and Kato, Norihiro and Laakso, Markku and K{\"o}ttgen, Anna and Koh, Woon-Puay and Palmer, Colin N A and Liu, Simin and Abecasis, Goncalo and Kooner, Jaspal S and Loos, Ruth J F and North, Kari E and Haiman, Christopher A and Florez, Jose C and Saleheen, Danish and Hansen, Torben and Pedersen, Oluf and M{\"a}gi, Reedik and Langenberg, Claudia and Wareham, Nicholas J and Maeda, Shiro and Kadowaki, Takashi and Lee, Juyoung and Millwood, Iona Y and Walters, Robin G and Stefansson, Kari and Myers, Simon R and Ferrer, Jorge and Gaulton, Kyle J and Meigs, James B and Mohlke, Karen L and Gloyn, Anna L and Bowden, Donald W and Below, Jennifer E and Chambers, John C and Sim, Xueling and Boehnke, Michael and Rotter, Jerome I and McCarthy, Mark I and Morris, Andrew P} } @article {9100, title = {A multi-ethnic polygenic risk score is associated with hypertension prevalence and progression throughout adulthood.}, journal = {Nat Commun}, volume = {13}, year = {2022}, month = {2022 Jun 21}, pages = {3549}, abstract = {

In a multi-stage analysis of 52,436 individuals aged 17-90 across diverse cohorts and biobanks, we train, test, and evaluate a polygenic risk score (PRS) for hypertension risk and progression. The PRS is trained using genome-wide association studies (GWAS) for systolic, diastolic blood pressure, and hypertension, respectively. For each trait, PRS is selected by optimizing the coefficient of variation (CV) across estimated effect sizes from multiple potential PRS using the same GWAS, after which the 3 trait-specific PRSs are combined via an unweighted sum called "PRSsum", forming the HTN-PRS. The HTN-PRS is associated with both prevalent and incident hypertension at 4-6 years of follow up. This association is further confirmed in age-stratified analysis. In an independent biobank of 40,201 individuals, the HTN-PRS is confirmed to be predictive of increased risk for coronary artery disease, ischemic stroke, type 2 diabetes, and chronic kidney disease.

}, keywords = {Adult, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hypertension, Multifactorial Inheritance, Prevalence, Risk Factors}, issn = {2041-1723}, doi = {10.1038/s41467-022-31080-2}, author = {Kurniansyah, Nuzulul and Goodman, Matthew O and Kelly, Tanika N and Elfassy, Tali and Wiggins, Kerri L and Bis, Joshua C and Guo, Xiuqing and Palmas, Walter and Taylor, Kent D and Lin, Henry J and Haessler, Jeffrey and Gao, Yan and Shimbo, Daichi and Smith, Jennifer A and Yu, Bing and Feofanova, Elena V and Smit, Roelof A J and Wang, Zhe and Hwang, Shih-Jen and Liu, Simin and Wassertheil-Smoller, Sylvia and Manson, JoAnn E and Lloyd-Jones, Donald M and Rich, Stephen S and Loos, Ruth J F and Redline, Susan and Correa, Adolfo and Kooperberg, Charles and Fornage, Myriam and Kaplan, Robert C and Psaty, Bruce M and Rotter, Jerome I and Arnett, Donna K and Morrison, Alanna C and Franceschini, Nora and Levy, Daniel and Sofer, Tamar} } @article {9161, title = {Non-linear machine learning models incorporating SNPs and PRS improve polygenic prediction in diverse human populations.}, journal = {Commun Biol}, volume = {5}, year = {2022}, month = {2022 08 22}, pages = {856}, abstract = {

Polygenic risk scores (PRS) are commonly used to quantify the inherited susceptibility for a trait, yet they fail to account for non-linear and interaction effects between single nucleotide polymorphisms (SNPs). We address this via a machine learning approach, validated in nine complex phenotypes in a multi-ancestry population. We use an ensemble method of SNP selection followed by gradient boosted trees (XGBoost) to allow for non-linearities and interaction effects. We compare our results to the standard, linear PRS model developed using PRSice, LDpred2, and lassosum2. Combining a PRS as a feature in an XGBoost model results in a relative increase in the percentage variance explained compared to the standard linear PRS model by 22\% for height, 27\% for HDL cholesterol, 43\% for body mass index, 50\% for sleep duration, 58\% for systolic blood pressure, 64\% for total cholesterol, 66\% for triglycerides, 77\% for LDL cholesterol, and 100\% for diastolic blood pressure. Multi-ancestry trained models perform similarly to specific racial/ethnic group trained models and are consistently superior to the standard linear PRS models. This work demonstrates an effective method to account for non-linearities and interaction effects in genetics-based prediction models.

}, keywords = {Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Machine Learning, Multifactorial Inheritance, Polymorphism, Single Nucleotide}, issn = {2399-3642}, doi = {10.1038/s42003-022-03812-z}, author = {Elgart, Michael and Lyons, Genevieve and Romero-Brufau, Santiago and Kurniansyah, Nuzulul and Brody, Jennifer A and Guo, Xiuqing and Lin, Henry J and Raffield, Laura and Gao, Yan and Chen, Han and de Vries, Paul and Lloyd-Jones, Donald M and Lange, Leslie A and Peloso, Gina M and Fornage, Myriam and Rotter, Jerome I and Rich, Stephen S and Morrison, Alanna C and Psaty, Bruce M and Levy, Daniel and Redline, Susan and Sofer, Tamar} } @article {9037, title = {Polygenic transcriptome risk scores for COPD and lung function improve cross-ethnic portability of prediction in the NHLBI TOPMed program.}, journal = {Am J Hum Genet}, year = {2022}, month = {2022 Mar 31}, abstract = {

While polygenic risk scores (PRSs) enable early identification of genetic risk for chronic obstructive pulmonary disease (COPD), predictive performance is limited when the discovery and target populations are not well matched. Hypothesizing that the biological mechanisms of disease are shared across ancestry groups, we introduce a PrediXcan-derived polygenic transcriptome risk score (PTRS) to improve cross-ethnic portability of risk prediction. We constructed the PTRS using summary statistics from application of PrediXcan on large-scale GWASs of lung function (forced expiratory volume in 1~s [FEV] and its ratio to forced vital capacity [FEV/FVC]) in the UK Biobank. We examined prediction performance and cross-ethnic portability of PTRS through smoking-stratified analyses both on 29,381 multi-ethnic participants from TOPMed population/family-based cohorts and on 11,771 multi-ethnic participants from TOPMed COPD-enriched studies. Analyses were carried out for two dichotomous COPD traits (moderate-to-severe and severe COPD) and two quantitative lung function traits (FEV and FEV/FVC). While the proposed PTRS showed weaker associations with disease than PRS for European ancestry, the PTRS showed stronger association with COPD than PRS for African Americans (e.g., odds ratio [OR]~= 1.24 [95\% confidence interval [CI]: 1.08-1.43] for PTRS versus 1.10 [0.96-1.26] for PRS among heavy smokers with >= 40 pack-years of smoking) for moderate-to-severe COPD. Cross-ethnic portability of the PTRS was significantly higher than the PRS (paired t test p~<~2.2~{\texttimes}~10 with portability gains ranging from 5\% to 28\%) for both dichotomous COPD traits and across all smoking strata. Our study demonstrates the value of PTRS for improved cross-ethnic portability compared to PRS in predicting COPD risk.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2022.03.007}, author = {Hu, Xiaowei and Qiao, Dandi and Kim, Wonji and Moll, Matthew and Balte, Pallavi P and Lange, Leslie A and Bartz, Traci M and Kumar, Rajesh and Li, Xingnan and Yu, Bing and Cade, Brian E and Laurie, Cecelia A and Sofer, Tamar and Ruczinski, Ingo and Nickerson, Deborah A and Muzny, Donna M and Metcalf, Ginger A and Doddapaneni, Harshavardhan and Gabriel, Stacy and Gupta, Namrata and Dugan-Perez, Shannon and Cupples, L Adrienne and Loehr, Laura R and Jain, Deepti and Rotter, Jerome I and Wilson, James G and Psaty, Bruce M and Fornage, Myriam and Morrison, Alanna C and Vasan, Ramachandran S and Washko, George and Rich, Stephen S and O{\textquoteright}Connor, George T and Bleecker, Eugene and Kaplan, Robert C and Kalhan, Ravi and Redline, Susan and Gharib, Sina A and Meyers, Deborah and Ortega, Victor and Dupuis, Jos{\'e}e and London, Stephanie J and Lappalainen, Tuuli and Oelsner, Elizabeth C and Silverman, Edwin K and Barr, R Graham and Thornton, Timothy A and Wheeler, Heather E and Cho, Michael H and Im, Hae Kyung and Manichaikul, Ani} } @article {8975, title = {Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes.}, journal = {Am J Hum Genet}, volume = {109}, year = {2022}, month = {2022 01 06}, pages = {81-96}, abstract = {

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1\%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

}, keywords = {Alleles, Blood Glucose, Case-Control Studies, Computational Biology, Databases, Genetic, Diabetes Mellitus, Type 2, Exome, Genetic Predisposition to Disease, Genetic Variation, Genetics, Population, Genome-Wide Association Study, Humans, Lipid Metabolism, Lipids, Liver, Molecular Sequence Annotation, Multifactorial Inheritance, Open Reading Frames, Phenotype, Polymorphism, Single Nucleotide}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.11.021}, author = {Hindy, George and Dornbos, Peter and Chaffin, Mark D and Liu, Dajiang J and Wang, Minxian and Selvaraj, Margaret Sunitha and Zhang, David and Park, Joseph and Aguilar-Salinas, Carlos A and Antonacci-Fulton, Lucinda and Ardissino, Diego and Arnett, Donna K and Aslibekyan, Stella and Atzmon, Gil and Ballantyne, Christie M and Barajas-Olmos, Francisco and Barzilai, Nir and Becker, Lewis C and Bielak, Lawrence F and Bis, Joshua C and Blangero, John and Boerwinkle, Eric and Bonnycastle, Lori L and Bottinger, Erwin and Bowden, Donald W and Bown, Matthew J and Brody, Jennifer A and Broome, Jai G and Burtt, Noel P and Cade, Brian E and Centeno-Cruz, Federico and Chan, Edmund and Chang, Yi-Cheng and Chen, Yii-der I and Cheng, Ching-Yu and Choi, Won Jung and Chowdhury, Rajiv and Contreras-Cubas, Cecilia and C{\'o}rdova, Emilio J and Correa, Adolfo and Cupples, L Adrienne and Curran, Joanne E and Danesh, John and de Vries, Paul S and DeFronzo, Ralph A and Doddapaneni, Harsha and Duggirala, Ravindranath and Dutcher, Susan K and Ellinor, Patrick T and Emery, Leslie S and Florez, Jose C and Fornage, Myriam and Freedman, Barry I and Fuster, Valentin and Garay-Sevilla, Ma Eugenia and Garc{\'\i}a-Ortiz, Humberto and Germer, Soren and Gibbs, Richard A and Gieger, Christian and Glaser, Benjamin and Gonzalez, Clicerio and Gonzalez-Villalpando, Maria Elena and Graff, Mariaelisa and Graham, Sarah E and Grarup, Niels and Groop, Leif C and Guo, Xiuqing and Gupta, Namrata and Han, Sohee and Hanis, Craig L and Hansen, Torben and He, Jiang and Heard-Costa, Nancy L and Hung, Yi-Jen and Hwang, Mi Yeong and Irvin, Marguerite R and Islas-Andrade, Sergio and Jarvik, Gail P and Kang, Hyun Min and Kardia, Sharon L R and Kelly, Tanika and Kenny, Eimear E and Khan, Alyna T and Kim, Bong-Jo and Kim, Ryan W and Kim, Young Jin and Koistinen, Heikki A and Kooperberg, Charles and Kuusisto, Johanna and Kwak, Soo Heon and Laakso, Markku and Lange, Leslie A and Lee, Jiwon and Lee, Juyoung and Lee, Seonwook and Lehman, Donna M and Lemaitre, Rozenn N and Linneberg, Allan and Liu, Jianjun and Loos, Ruth J F and Lubitz, Steven A and Lyssenko, Valeriya and Ma, Ronald C W and Martin, Lisa Warsinger and Mart{\'\i}nez-Hern{\'a}ndez, Ang{\'e}lica and Mathias, Rasika A and McGarvey, Stephen T and McPherson, Ruth and Meigs, James B and Meitinger, Thomas and Melander, Olle and Mendoza-Caamal, Elvia and Metcalf, Ginger A and Mi, Xuenan and Mohlke, Karen L and Montasser, May E and Moon, Jee-Young and Moreno-Macias, Hortensia and Morrison, Alanna C and Muzny, Donna M and Nelson, Sarah C and Nilsson, Peter M and O{\textquoteright}Connell, Jeffrey R and Orho-Melander, Marju and Orozco, Lorena and Palmer, Colin N A and Palmer, Nicholette D and Park, Cheol Joo and Park, Kyong Soo and Pedersen, Oluf and Peralta, Juan M and Peyser, Patricia A and Post, Wendy S and Preuss, Michael and Psaty, Bruce M and Qi, Qibin and Rao, D C and Redline, Susan and Reiner, Alexander P and Revilla-Monsalve, Cristina and Rich, Stephen S and Samani, Nilesh and Schunkert, Heribert and Schurmann, Claudia and Seo, Daekwan and Seo, Jeong-Sun and Sim, Xueling and Sladek, Rob and Small, Kerrin S and So, Wing Yee and Stilp, Adrienne M and Tai, E Shyong and Tam, Claudia H T and Taylor, Kent D and Teo, Yik Ying and Thameem, Farook and Tomlinson, Brian and Tsai, Michael Y and Tuomi, Tiinamaija and Tuomilehto, Jaakko and Tusi{\'e}-Luna, Teresa and Udler, Miriam S and van Dam, Rob M and Vasan, Ramachandran S and Viaud Martinez, Karine A and Wang, Fei Fei and Wang, Xuzhi and Watkins, Hugh and Weeks, Daniel E and Wilson, James G and Witte, Daniel R and Wong, Tien-Yin and Yanek, Lisa R and Kathiresan, Sekar and Rader, Daniel J and Rotter, Jerome I and Boehnke, Michael and McCarthy, Mark I and Willer, Cristen J and Natarajan, Pradeep and Flannick, Jason A and Khera, Amit V and Peloso, Gina M} } @article {9168, title = {Rare genetic variants explain missing heritability in smoking.}, journal = {Nat Hum Behav}, year = {2022}, month = {2022 Aug 04}, abstract = {

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this {\textquoteright}missing heritability{\textquoteright}. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74\% of it attributable to rare variants with minor allele frequencies between 0.01\% and 1\%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60\% to 100\% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.

}, issn = {2397-3374}, doi = {10.1038/s41562-022-01408-5}, author = {Jang, Seon-Kyeong and Evans, Luke and Fialkowski, Allison and Arnett, Donna K and Ashley-Koch, Allison E and Barnes, Kathleen C and Becker, Diane M and Bis, Joshua C and Blangero, John and Bleecker, Eugene R and Boorgula, Meher Preethi and Bowden, Donald W and Brody, Jennifer A and Cade, Brian E and Jenkins, Brenda W Campbell and Carson, April P and Chavan, Sameer and Cupples, L Adrienne and Custer, Brian and Damrauer, Scott M and David, Sean P and de Andrade, Mariza and Dinardo, Carla L and Fingerlin, Tasha E and Fornage, Myriam and Freedman, Barry I and Garrett, Melanie E and Gharib, Sina A and Glahn, David C and Haessler, Jeffrey and Heckbert, Susan R and Hokanson, John E and Hou, Lifang and Hwang, Shih-Jen and Hyman, Matthew C and Judy, Renae and Justice, Anne E and Kaplan, Robert C and Kardia, Sharon L R and Kelly, Shannon and Kim, Wonji and Kooperberg, Charles and Levy, Daniel and Lloyd-Jones, Donald M and Loos, Ruth J F and Manichaikul, Ani W and Gladwin, Mark T and Martin, Lisa Warsinger and Nouraie, Mehdi and Melander, Olle and Meyers, Deborah A and Montgomery, Courtney G and North, Kari E and Oelsner, Elizabeth C and Palmer, Nicholette D and Payton, Marinelle and Peljto, Anna L and Peyser, Patricia A and Preuss, Michael and Psaty, Bruce M and Qiao, Dandi and Rader, Daniel J and Rafaels, Nicholas and Redline, Susan and Reed, Robert M and Reiner, Alexander P and Rich, Stephen S and Rotter, Jerome I and Schwartz, David A and Shadyab, Aladdin H and Silverman, Edwin K and Smith, Nicholas L and Smith, J Gustav and Smith, Albert V and Smith, Jennifer A and Tang, Weihong and Taylor, Kent D and Telen, Marilyn J and Vasan, Ramachandran S and Gordeuk, Victor R and Wang, Zhe and Wiggins, Kerri L and Yanek, Lisa R and Yang, Ivana V and Young, Kendra A and Young, Kristin L and Zhang, Yingze and Liu, Dajiang J and Keller, Matthew C and Vrieze, Scott} } @article {9172, title = {Stroke genetics informs drug discovery and risk prediction across ancestries.}, journal = {Nature}, year = {2022}, month = {2022 Sep 30}, abstract = {

Previous genome-wide association studies (GWASs) of stroke~-~the second leading cause of death worldwide~-~were conducted predominantly in populations of European ancestry. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33\% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30\% non-European) and 1,013,843 control individuals, 87\% of the primary stroke risk loci and 60\% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

}, issn = {1476-4687}, doi = {10.1038/s41586-022-05165-3}, author = {Mishra, Aniket and Malik, Rainer and Hachiya, Tsuyoshi and J{\"u}rgenson, Tuuli and Namba, Shinichi and Posner, Daniel C and Kamanu, Frederick K and Koido, Masaru and Le Grand, Quentin and Shi, Mingyang and He, Yunye and Georgakis, Marios K and Caro, Ilana and Krebs, Kristi and Liaw, Yi-Ching and Vaura, Felix C and Lin, Kuang and Winsvold, Bendik Slagsvold and Srinivasasainagendra, Vinodh and Parodi, Livia and Bae, Hee-Joon and Chauhan, Ganesh and Chong, Michael R and Tomppo, Liisa and Akinyemi, Rufus and Roshchupkin, Gennady V and Habib, Naomi and Jee, Yon Ho and Thomassen, Jesper Qvist and Abedi, Vida and C{\'a}rcel-M{\'a}rquez, Jara and Nygaard, Marianne and Leonard, Hampton L and Yang, Chaojie and Yonova-Doing, Ekaterina and Knol, Maria J and Lewis, Adam J and Judy, Renae L and Ago, Tetsuro and Amouyel, Philippe and Armstrong, Nicole D and Bakker, Mark K and Bartz, Traci M and Bennett, David A and Bis, Joshua C and Bordes, Constance and B{\o}rte, Sigrid and Cain, Anael and Ridker, Paul M and Cho, Kelly and Chen, Zhengming and Cruchaga, Carlos and Cole, John W and De Jager, Phil L and de Cid, Rafael and Endres, Matthias and Ferreira, Leslie E and Geerlings, Mirjam I and Gasca, Natalie C and Gudnason, Vilmundur and Hata, Jun and He, Jing and Heath, Alicia K and Ho, Yuk-Lam and Havulinna, Aki S and Hopewell, Jemma C and Hyacinth, Hyacinth I and Inouye, Michael and Jacob, Mina A and Jeon, Christina E and Jern, Christina and Kamouchi, Masahiro and Keene, Keith L and Kitazono, Takanari and Kittner, Steven J and Konuma, Takahiro and Kumar, Amit and Lacaze, Paul and Launer, Lenore J and Lee, Keon-Joo and Lepik, Kaido and Li, Jiang and Li, Liming and Manichaikul, Ani and Markus, Hugh S and Marston, Nicholas A and Meitinger, Thomas and Mitchell, Braxton D and Montellano, Felipe A and Morisaki, Takayuki and Mosley, Thomas H and Nalls, Mike A and Nordestgaard, B{\o}rge G and O{\textquoteright}Donnell, Martin J and Okada, Yukinori and Onland-Moret, N Charlotte and Ovbiagele, Bruce and Peters, Annette and Psaty, Bruce M and Rich, Stephen S and Rosand, Jonathan and Sabatine, Marc S and Sacco, Ralph L and Saleheen, Danish and Sandset, Else Charlotte and Salomaa, Veikko and Sargurupremraj, Muralidharan and Sasaki, Makoto and Satizabal, Claudia L and Schmidt, Carsten O and Shimizu, Atsushi and Smith, Nicholas L and Sloane, Kelly L and Sutoh, Yoichi and Sun, Yan V and Tanno, Kozo and Tiedt, Steffen and Tatlisumak, Turgut and Torres-Aguila, Nuria P and Tiwari, Hemant K and Tr{\'e}gou{\"e}t, David-Alexandre and Trompet, Stella and Tuladhar, Anil Man and Tybj{\ae}rg-Hansen, Anne and van Vugt, Marion and Vibo, Riina and Verma, Shefali S and Wiggins, Kerri L and Wennberg, Patrik and Woo, Daniel and Wilson, Peter W F and Xu, Huichun and Yang, Qiong and Yoon, Kyungheon and Millwood, Iona Y and Gieger, Christian and Ninomiya, Toshiharu and Grabe, Hans J and Jukema, J Wouter and Rissanen, Ina L and Strbian, Daniel and Kim, Young Jin and Chen, Pei-Hsin and Mayerhofer, Ernst and Howson, Joanna M M and Irvin, Marguerite R and Adams, Hieab and Wassertheil-Smoller, Sylvia and Christensen, Kaare and Ikram, Mohammad A and Rundek, Tatjana and Worrall, Bradford B and Lathrop, G Mark and Riaz, Moeen and Simonsick, Eleanor M and K{\~o}rv, Janika and Fran{\c c}a, Paulo H C and Zand, Ramin and Prasad, Kameshwar and Frikke-Schmidt, Ruth and de Leeuw, Frank-Erik and Liman, Thomas and Haeusler, Karl Georg and Ruigrok, Ynte M and Heuschmann, Peter Ulrich and Longstreth, W T and Jung, Keum Ji and Bastarache, Lisa and Par{\'e}, Guillaume and Damrauer, Scott M and Chasman, Daniel I and Rotter, Jerome I and Anderson, Christopher D and Zwart, John-Anker and Niiranen, Teemu J and Fornage, Myriam and Liaw, Yung-Po and Seshadri, Sudha and Fernandez-Cadenas, Israel and Walters, Robin G and Ruff, Christian T and Owolabi, Mayowa O and Huffman, Jennifer E and Milani, Lili and Kamatani, Yoichiro and Dichgans, Martin and Debette, Stephanie} } @article {9101, title = {Targeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea.}, journal = {Am J Respir Crit Care Med}, year = {2022}, month = {2022 Jul 13}, abstract = {

INTRODUCTION: Obstructive sleep apnea (OSA) is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. There is strong clinical and epi-demiologic evidence supporting the importance of genetic factors influencing OSA, but limited data implicating specific genes.

METHODS: Leveraging high depth genomic sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program and imputed genotype data from multiple population-based studies, we performed linkage analysis in the Cleve-land Family Study (CFS) followed by multi-stage gene-based association analyses in independent cohorts to search for rare variants contributing to OSA severity as assessed by the apnea-hypopnea index (AHI) in a total of 7,708 individuals of European ancestry.

RESULTS: Linkage analysis in CFS identified a suggestive linkage peak on chromosome 7q31 (LOD=2.31). Gene-based analysis identified 21 non-coding rare variants in Caveolin-1 (CAV1) associated with lower AHI after accounting for multiple comparisons (p=7.4{\texttimes}10-8). These non-coding variants together significantly contributed to the linkage evidence (p<10-3). Follow-up anal-ysis revealed significant associations between these variants and increased CAV1 expression, and increased CAV1 expression in peripheral monocytes was associated with lower AHI (p=0.024) and higher minimum overnight oxygen saturation (p=0.007).

CONCLUSION: Rare variants in CAV1, a membrane scaffolding protein essential in multiple cellular and metabolic functions, are associated with higher CAV1 gene expression and lower OSA severity, suggesting a novel target for modulating OSA severity.

}, issn = {1535-4970}, doi = {10.1164/rccm.202203-0618OC}, author = {Liang, Jingjing and Wang, Heming and Cade, Brian E and Kurniansyah, Nuzulul and He, Karen Y and Lee, Jiwon and Sands, Scott A and Brody, Jennifer and Chen, Han and Gottlieb, Daniel J and Evans, Daniel S and Guo, Xiuqing and Gharib, Sina A and Hale, Lauren and Hillman, David R and Lutsey, Pamela L and Mukherjee, Sutapa and Ochs-Balcom, Heather M and Palmer, Lyle J and Purcell, Shaun and Saxena, Richa and Patel, Sanjay R and Stone, Katie L and Tranah, Gregory J and Boerwinkle, Eric and Lin, Xihong and Liu, Yongmei and Psaty, Bruce M and Vasan, Ramachandran S and Manichaikul, Ani and Rich, Stephen S and Rotter, Jerome I and Sofer, Tamar and Redline, Susan and Zhu, Xiaofeng} } @article {9109, title = {The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations.}, journal = {Front Endocrinol (Lausanne)}, volume = {13}, year = {2022}, month = {2022}, pages = {863893}, abstract = {

Polygenic risk scores (PRSs) aggregate the effects of genetic variants across the genome and are used to predict risk of complex diseases, such as obesity. Current PRSs only include common variants (minor allele frequency (MAF) >=1\%), whereas the contribution of rare variants in PRSs to predict disease remains unknown. Here, we examine whether augmenting the standard common variant PRS (PRS) with a rare variant PRS (PRS) improves prediction of obesity. We used genome-wide genotyped and imputed data on 451,145 European-ancestry participants of the UK Biobank, as well as whole exome sequencing (WES) data on 184,385 participants. We performed single variant analyses (for both common and rare variants) and gene-based analyses (for rare variants) for association with BMI (kg/m), obesity (BMI >= 30 kg/m), and extreme obesity (BMI >= 40 kg/m). We built PRSs and PRSs using a range of methods (Clumping+Thresholding [C+T], PRS-CS, lassosum, gene-burden test). We selected the best-performing PRSs and assessed their performance in 36,757 European-ancestry unrelated participants with whole genome sequencing (WGS) data from the Trans-Omics for Precision Medicine (TOPMed) program. The best-performing PRS explained 10.1\% of variation in BMI, and 18.3\% and 22.5\% of the susceptibility to obesity and extreme obesity, respectively, whereas the best-performing PRS explained 1.49\%, and 2.97\% and 3.68\%, respectively. The PRS was associated with an increased risk of obesity and extreme obesity (OR = 1.37 per SD, = 1.7x10; OR = 1.55 per SD, = 3.8x10), which was attenuated, after adjusting for PRS (OR = 1.08 per SD, = 9.8x10; OR= 1.09 per SD, = 0.02). When PRS and PRS are combined, the increase in explained variance attributed to PRS was small (incremental Nagelkerke R = 0.24\% for obesity and 0.51\% for extreme obesity). Consistently, combining PRS to PRS provided little improvement to the prediction of obesity (PRS AUC = 0.591; PRS AUC = 0.708; PRS AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRS provides limited improvement over PRS in the prediction of obesity risk, based on these large populations.

}, keywords = {Gene Frequency, Genetic Variation, Genome-Wide Association Study, Humans, Obesity, Whole Genome Sequencing}, issn = {1664-2392}, doi = {10.3389/fendo.2022.863893}, author = {Wang, Zhe and Choi, Shing Wan and Chami, Nathalie and Boerwinkle, Eric and Fornage, Myriam and Redline, Susan and Bis, Joshua C and Brody, Jennifer A and Psaty, Bruce M and Kim, Wonji and McDonald, Merry-Lynn N and Regan, Elizabeth A and Silverman, Edwin K and Liu, Ching-Ti and Vasan, Ramachandran S and Kalyani, Rita R and Mathias, Rasika A and Yanek, Lisa R and Arnett, Donna K and Justice, Anne E and North, Kari E and Kaplan, Robert and Heckbert, Susan R and de Andrade, Mariza and Guo, Xiuqing and Lange, Leslie A and Rich, Stephen S and Rotter, Jerome I and Ellinor, Patrick T and Lubitz, Steven A and Blangero, John and Shoemaker, M Benjamin and Darbar, Dawood and Gladwin, Mark T and Albert, Christine M and Chasman, Daniel I and Jackson, Rebecca D and Kooperberg, Charles and Reiner, Alexander P and O{\textquoteright}Reilly, Paul F and Loos, Ruth J F} } @article {9158, title = {Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program.}, journal = {Commun Biol}, volume = {5}, year = {2022}, month = {2022 07 28}, pages = {756}, abstract = {

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI{\textquoteright}s Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.

}, keywords = {Diabetes Mellitus, Type 2, Fasting, Glucose, Humans, Insulin, National Heart, Lung, and Blood Institute (U.S.), Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Precision Medicine, Receptors, Immunologic, United States}, issn = {2399-3642}, doi = {10.1038/s42003-022-03702-4}, author = {DiCorpo, Daniel and Gaynor, Sheila M and Russell, Emily M and Westerman, Kenneth E and Raffield, Laura M and Majarian, Timothy D and Wu, Peitao and Sarnowski, Chloe and Highland, Heather M and Jackson, Anne and Hasbani, Natalie R and de Vries, Paul S and Brody, Jennifer A and Hidalgo, Bertha and Guo, Xiuqing and Perry, James A and O{\textquoteright}Connell, Jeffrey R and Lent, Samantha and Montasser, May E and Cade, Brian E and Jain, Deepti and Wang, Heming and D{\textquoteright}Oliveira Albanus, Ricardo and Varshney, Arushi and Yanek, Lisa R and Lange, Leslie and Palmer, Nicholette D and Almeida, Marcio and Peralta, Juan M and Aslibekyan, Stella and Baldridge, Abigail S and Bertoni, Alain G and Bielak, Lawrence F and Chen, Chung-Shiuan and Chen, Yii-Der Ida and Choi, Won Jung and Goodarzi, Mark O and Floyd, James S and Irvin, Marguerite R and Kalyani, Rita R and Kelly, Tanika N and Lee, Seonwook and Liu, Ching-Ti and Loesch, Douglas and Manson, JoAnn E and Minster, Ryan L and Naseri, Take and Pankow, James S and Rasmussen-Torvik, Laura J and Reiner, Alexander P and Reupena, Muagututi{\textquoteright}a Sefuiva and Selvin, Elizabeth and Smith, Jennifer A and Weeks, Daniel E and Xu, Huichun and Yao, Jie and Zhao, Wei and Parker, Stephen and Alonso, Alvaro and Arnett, Donna K and Blangero, John and Boerwinkle, Eric and Correa, Adolfo and Cupples, L Adrienne and Curran, Joanne E and Duggirala, Ravindranath and He, Jiang and Heckbert, Susan R and Kardia, Sharon L R and Kim, Ryan W and Kooperberg, Charles and Liu, Simin and Mathias, Rasika A and McGarvey, Stephen T and Mitchell, Braxton D and Morrison, Alanna C and Peyser, Patricia A and Psaty, Bruce M and Redline, Susan and Shuldiner, Alan R and Taylor, Kent D and Vasan, Ramachandran S and Viaud-Martinez, Karine A and Florez, Jose C and Wilson, James G and Sladek, Robert and Rich, Stephen S and Rotter, Jerome I and Lin, Xihong and Dupuis, Jos{\'e}e and Meigs, James B and Wessel, Jennifer and Manning, Alisa K} } @article {9261, title = {Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program.}, journal = {Nat Commun}, volume = {13}, year = {2022}, month = {2022 Dec 08}, pages = {7592}, abstract = {

Genome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) to detect structural variants associated with hematologic traits. Using single variant tests, we assessed the association of common and rare structural variants with red cell-, white cell-, and platelet-related quantitative traits and observed 21 independent signals (12 common and 9 rare) reaching genome-wide significance. The majority of these associations (N = 18) replicated in independent datasets. In genome-editing experiments, we provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.

}, keywords = {Blood Cells, Genome-Wide Association Study, Humans, Whole Genome Sequencing}, issn = {2041-1723}, doi = {10.1038/s41467-022-35354-7}, author = {Wheeler, Marsha M and Stilp, Adrienne M and Rao, Shuquan and Halldorsson, Bjarni V and Beyter, Doruk and Wen, Jia and Mihkaylova, Anna V and McHugh, Caitlin P and Lane, John and Jiang, Min-Zhi and Raffield, Laura M and Jun, Goo and Sedlazeck, Fritz J and Metcalf, Ginger and Yao, Yao and Bis, Joshua B and Chami, Nathalie and de Vries, Paul S and Desai, Pinkal and Floyd, James S and Gao, Yan and Kammers, Kai and Kim, Wonji and Moon, Jee-Young and Ratan, Aakrosh and Yanek, Lisa R and Almasy, Laura and Becker, Lewis C and Blangero, John and Cho, Michael H and Curran, Joanne E and Fornage, Myriam and Kaplan, Robert C and Lewis, Joshua P and Loos, Ruth J F and Mitchell, Braxton D and Morrison, Alanna C and Preuss, Michael and Psaty, Bruce M and Rich, Stephen S and Rotter, Jerome I and Tang, Hua and Tracy, Russell P and Boerwinkle, Eric and Abecasis, Goncalo R and Blackwell, Thomas W and Smith, Albert V and Johnson, Andrew D and Mathias, Rasika A and Nickerson, Deborah A and Conomos, Matthew P and Li, Yun and {\TH}orsteinsdottir, Unnur and Magn{\'u}sson, Magn{\'u}s K and Stefansson, Kari and Pankratz, Nathan D and Bauer, Daniel E and Auer, Paul L and Reiner, Alex P} } @article {9387, title = {Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.}, journal = {Nature}, volume = {616}, year = {2023}, month = {2023 Apr}, pages = {755-763}, abstract = {

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but~this effect was not seen in~clones with~driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental~knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.

}, keywords = {Alleles, Animals, Clonal Hematopoiesis, Genome-Wide Association Study, Hematopoiesis, Hematopoietic Stem Cells, Humans, Mice, Mutation, Promoter Regions, Genetic}, issn = {1476-4687}, doi = {10.1038/s41586-023-05806-1}, author = {Weinstock, Joshua S and Gopakumar, Jayakrishnan and Burugula, Bala Bharathi and Uddin, Md Mesbah and Jahn, Nikolaus and Belk, Julia A and Bouzid, Hind and Daniel, Bence and Miao, Zhuang and Ly, Nghi and Mack, Taralynn M and Luna, Sofia E and Prothro, Katherine P and Mitchell, Shaneice R and Laurie, Cecelia A and Broome, Jai G and Taylor, Kent D and Guo, Xiuqing and Sinner, Moritz F and von Falkenhausen, Aenne S and K{\"a}{\"a}b, Stefan and Shuldiner, Alan R and O{\textquoteright}Connell, Jeffrey R and Lewis, Joshua P and Boerwinkle, Eric and Barnes, Kathleen C and Chami, Nathalie and Kenny, Eimear E and Loos, Ruth J F and Fornage, Myriam and Hou, Lifang and Lloyd-Jones, Donald M and Redline, Susan and Cade, Brian E and Psaty, Bruce M and Bis, Joshua C and Brody, Jennifer A and Silverman, Edwin K and Yun, Jeong H and Qiao, Dandi and Palmer, Nicholette D and Freedman, Barry I and Bowden, Donald W and Cho, Michael H and DeMeo, Dawn L and Vasan, Ramachandran S and Yanek, Lisa R and Becker, Lewis C and Kardia, Sharon L R and Peyser, Patricia A and He, Jiang and Rienstra, Michiel and van der Harst, Pim and Kaplan, Robert and Heckbert, Susan R and Smith, Nicholas L and Wiggins, Kerri L and Arnett, Donna K and Irvin, Marguerite R and Tiwari, Hemant and Cutler, Michael J and Knight, Stacey and Muhlestein, J Brent and Correa, Adolfo and Raffield, Laura M and Gao, Yan and de Andrade, Mariza and Rotter, Jerome I and Rich, Stephen S and Tracy, Russell P and Konkle, Barbara A and Johnsen, Jill M and Wheeler, Marsha M and Smith, J Gustav and Melander, Olle and Nilsson, Peter M and Custer, Brian S and Duggirala, Ravindranath and Curran, Joanne E and Blangero, John and McGarvey, Stephen and Williams, L Keoki and Xiao, Shujie and Yang, Mao and Gu, C Charles and Chen, Yii-Der Ida and Lee, Wen-Jane and Marcus, Gregory M and Kane, John P and Pullinger, Clive R and Shoemaker, M Benjamin and Darbar, Dawood and Roden, Dan M and Albert, Christine and Kooperberg, Charles and Zhou, Ying and Manson, JoAnn E and Desai, Pinkal and Johnson, Andrew D and Mathias, Rasika A and Blackwell, Thomas W and Abecasis, Goncalo R and Smith, Albert V and Kang, Hyun M and Satpathy, Ansuman T and Natarajan, Pradeep and Kitzman, Jacob O and Whitsel, Eric A and Reiner, Alexander P and Bick, Alexander G and Jaiswal, Siddhartha} } @article {9502, title = {Association Between Whole Blood-Derived Mitochondrial DNA Copy Number, Low-Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk.}, journal = {J Am Heart Assoc}, year = {2023}, month = {2023 Oct 07}, pages = {e029090}, abstract = {

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). <0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1-SD unit lower level of mtDNA CN was associated with 1.08 (95\% CI, 1.04-1.12; <0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; =0.11) or in the reverse direction (β=-0.012; =0.076). Additional bidirectional Mendelian randomization analyses revealed that low-density lipoprotein cholesterol had a causal effect on mtDNA CN (β=-0.084; <0.001), but the reverse direction was not significant (=0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low-density lipoprotein cholesterol level (=0.52), whereas there was a strong direct causal effect of higher low-density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=-0.092; <0.001). Conclusions Our findings indicate that high low-density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.

}, issn = {2047-9980}, doi = {10.1161/JAHA.122.029090}, author = {Liu, Xue and Sun, Xianbang and Zhang, Yuankai and Jiang, Wenqing and Lai, Meng and Wiggins, Kerri L and Raffield, Laura M and Bielak, Lawrence F and Zhao, Wei and Pitsillides, Achilleas and Haessler, Jeffrey and Zheng, Yinan and Blackwell, Thomas W and Yao, Jie and Guo, Xiuqing and Qian, Yong and Thyagarajan, Bharat and Pankratz, Nathan and Rich, Stephen S and Taylor, Kent D and Peyser, Patricia A and Heckbert, Susan R and Seshadri, Sudha and Boerwinkle, Eric and Grove, Megan L and Larson, Nicholas B and Smith, Jennifer A and Vasan, Ramachandran S and Fitzpatrick, Annette L and Fornage, Myriam and Ding, Jun and Carson, April P and Abecasis, Goncalo and Dupuis, Jos{\'e}e and Reiner, Alexander and Kooperberg, Charles and Hou, Lifang and Psaty, Bruce M and Wilson, James G and Levy, Daniel and Rotter, Jerome I and Bis, Joshua C and Satizabal, Claudia L and Arking, Dan E and Liu, Chunyu} } @article {9323, title = {Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts.}, journal = {Neurology}, year = {2023}, month = {2023 Mar 16}, abstract = {

BACKGROUND AND OBJECTIVES: Previous studies suggest lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer{\textquoteright}s disease (AD) and AD related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults.

METHODS: We included dementia-free participants from nine diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within {\textpm}5 years (i.e., cross-sectional analyses) or 5 to 20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs. >=60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed Mendelian randomization (MR) analyses to assess causality.

RESULTS: We included up to 19,152 participants (mean age 59 years, 57\% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (Beta=0.04; 95\% CI 0.02, 0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition.

DISCUSSION: Higher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the US. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community.

}, issn = {1526-632X}, doi = {10.1212/WNL.0000000000207157}, author = {Zhang, Yuankai and Liu, Xue and Wiggins, Kerri L and Kurniansyah, Nuzulul and Guo, Xiuqing and Rodrigue, Amanda L and Zhao, Wei and Yanek, Lisa R and Ratliff, Scott M and Pitsillides, Achilleas and Aguirre Pati{\~n}o, Juan Sebastian and Sofer, Tamar and Arking, Dan E and Austin, Thomas R and Beiser, Alexa S and Blangero, John and Boerwinkle, Eric and Bressler, Jan and Curran, Joanne E and Hou, Lifang and Hughes, Timothy M and Kardia, Sharon L and Launer, Lenore and Levy, Daniel and Mosley, Tom H and Nasrallah, Ilya M and Rich, Stephen S and Rotter, Jerome I and Seshadri, Sudha and Tarraf, Wassim and Gonz{\'a}lez, Kevin A and Ramachandran, Vasan and Yaffe, Kristine and Nyquist, Paul A and Psaty, Bruce M and DeCarli, Charles S and Smith, Jennifer A and Glahn, David C and Gonz{\'a}lez, Hector M and Bis, Joshua C and Fornage, Myriam and Heckbert, Susan R and Fitzpatrick, Annette L and Liu, Chunyu and Satizabal, Claudia L} } @article {9456, title = {Association of omega 3 polyunsaturated fatty acids with incident chronic kidney disease: pooled analysis of 19 cohorts.}, journal = {BMJ}, volume = {380}, year = {2023}, month = {2023 Jan 18}, pages = {e072909}, abstract = {

OBJECTIVE: To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD).

DESIGN: Pooled analysis.

DATA SOURCES: A consortium of 19 studies from 12 countries identified up to May 2020.

STUDY SELECTION: Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate.

DATA EXTRACTION AND SYNTHESIS: Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were pooled across cohorts using inverse variance weighted meta-analysis.

MAIN OUTCOME MEASURES: Primary outcome of incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m. In a sensitivity analysis, incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m and <75\% of baseline rate.

RESULTS: 25 570 participants were included in the primary outcome analysis and 4944 (19.3\%) developed incident CKD during follow-up (weighted median 11.3 years). In multivariable adjusted models, higher levels of total seafood n-3 PUFAs were associated with a lower incident CKD risk (relative risk per interquintile range 0.92, 95\% confidence interval 0.86 to 0.98; P=0.009, I=9.9\%). In categorical analyses, participants with total seafood n-3 PUFA level in the highest fifth had 13\% lower risk of incident CKD compared with those in the lowest fifth (0.87, 0.80 to 0.96; P=0.005, I=0.0\%). Plant derived α linolenic acid levels were not associated with incident CKD (1.00, 0.94 to 1.06; P=0.94, I=5.8\%). Similar results were obtained in the sensitivity analysis. The association appeared consistent across subgroups by age (>=60 <60 years), estimated glomerular filtration rate (60-89 >=90 mL/min/1.73 m), hypertension, diabetes, and coronary heart disease at baseline.

CONCLUSIONS: Higher seafood derived n-3 PUFA levels were associated with lower risk of incident CKD, although this association was not found for plant derived n-3 PUFAs. These results support a favourable role for seafood derived n-3 PUFAs in preventing CKD.

}, keywords = {alpha-Linolenic Acid, Fatty Acids, Omega-3, Fatty Acids, Unsaturated, Humans, Middle Aged, Prospective Studies, Renal Insufficiency, Chronic, Risk Factors}, issn = {1756-1833}, doi = {10.1136/bmj-2022-072909}, author = {Ong, Kwok Leung and Marklund, Matti and Huang, Liping and Rye, Kerry-Anne and Hui, Nicholas and Pan, Xiong-Fei and Rebholz, Casey M and Kim, Hyunju and Steffen, Lyn M and van Westing, Anniek C and Geleijnse, Johanna M and Hoogeveen, Ellen K and Chen, Yun-Yu and Chien, Kuo-Liong and Fretts, Amanda M and Lemaitre, Rozenn N and Imamura, Fumiaki and Forouhi, Nita G and Wareham, Nicholas J and Birukov, Anna and J{\"a}ger, Susanne and Kuxhaus, Olga and Schulze, Matthias B and de Mello, Vanessa Derenji and Tuomilehto, Jaakko and Uusitupa, Matti and Lindstr{\"o}m, Jaana and Tintle, Nathan and Harris, William S and Yamasaki, Keisuke and Hirakawa, Yoichiro and Ninomiya, Toshiharu and Tanaka, Toshiko and Ferrucci, Luigi and Bandinelli, Stefania and Virtanen, Jyrki K and Voutilainen, Ari and Jayasena, Tharusha and Thalamuthu, Anbupalam and Poljak, Anne and Bustamante, Sonia and Sachdev, Perminder S and Senn, Mackenzie K and Rich, Stephen S and Tsai, Michael Y and Wood, Alexis C and Laakso, Markku and Lankinen, Maria and Yang, Xiaowei and Sun, Liang and Li, Huaixing and Lin, Xu and Nowak, Christoph and Arnl{\"o}v, Johan and Riserus, Ulf and Lind, Lars and Le Goff, M{\'e}lanie and Samieri, Cecilia and Helmer, Catherine and Qian, Frank and Micha, Renata and Tin, Adrienne and K{\"o}ttgen, Anna and de Boer, Ian H and Siscovick, David S and Mozaffarian, Dariush and Wu, Jason HY} } @article {9285, title = {Association of Rare Protein-Truncating DNA Variants in APOB or PCSK9 With Low-density Lipoprotein Cholesterol Level and Risk of Coronary Heart Disease.}, journal = {JAMA Cardiol}, year = {2023}, month = {2023 Feb 01}, abstract = {

IMPORTANCE: Protein-truncating variants (PTVs) in apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are associated with significantly lower low-density lipoprotein (LDL) cholesterol concentrations. The association of these PTVs with coronary heart disease (CHD) warrants further characterization in large, multiracial prospective cohort studies.

OBJECTIVE: To evaluate the association of PTVs in APOB and PCSK9 with LDL cholesterol concentrations and CHD risk.

DESIGN, SETTING, AND PARTICIPANTS: This studied included participants from 5 National Heart, Lung, and Blood Institute (NHLBI) studies and the UK Biobank. NHLBI study participants aged 5 to 84 years were recruited between 1971 and 2002 across the US and underwent whole-genome sequencing. UK Biobank participants aged 40 to 69 years were recruited between 2006 and 2010 in the UK and underwent whole-exome sequencing. Data were analyzed from June 2021 to October 2022.

EXPOSURES: PTVs in APOB and PCSK9.

MAIN OUTCOMES AND MEASURES: Estimated untreated LDL cholesterol levels and CHD.

RESULTS: Among 19 073 NHLBI participants (10 598 [55.6\%] female; mean [SD] age, 52 [17] years), 139 (0.7\%) carried an APOB or PCSK9 PTV, which was associated with 49 mg/dL (95\% CI, 43-56) lower estimated untreated LDL cholesterol level. Over a median (IQR) follow-up of 21.5 (13.9-29.4) years, incident CHD was observed in 12 of 139 carriers (8.6\%) vs 3029 of 18 934 noncarriers (16.0\%), corresponding to an adjusted hazard ratio of 0.51 (95\% CI, 0.28-0.89; P = .02). Among 190 464 UK Biobank participants (104 831 [55.0\%] female; mean [SD] age, 57 [8] years), 662 (0.4\%) carried a PTV, which was associated with 45 mg/dL (95\% CI, 42-47) lower estimated untreated LDL cholesterol level. Estimated CHD risk by age 75 years was 3.7\% (95\% CI, 2.0-5.3) in carriers vs 7.0\% (95\% CI, 6.9-7.2) in noncarriers, corresponding to an adjusted hazard ratio of 0.51 (95\% CI, 0.32-0.81; P = .004).

CONCLUSIONS AND RELEVANCE: Among 209 537 individuals in this study, 0.4\% carried an APOB or PCSK9 PTV that was associated with less exposure to LDL cholesterol and a 49\% lower risk of CHD.

}, issn = {2380-6591}, doi = {10.1001/jamacardio.2022.5271}, author = {Dron, Jacqueline S and Patel, Aniruddh P and Zhang, Yiyi and Jurgens, Sean J and Maamari, Dimitri J and Wang, Minxian and Boerwinkle, Eric and Morrison, Alanna C and de Vries, Paul S and Fornage, Myriam and Hou, Lifang and Lloyd-Jones, Donald M and Psaty, Bruce M and Tracy, Russell P and Bis, Joshua C and Vasan, Ramachandran S and Levy, Daniel and Heard-Costa, Nancy and Rich, Stephen S and Guo, Xiuqing and Taylor, Kent D and Gibbs, Richard A and Rotter, Jerome I and Willer, Cristen J and Oelsner, Elizabeth C and Moran, Andrew E and Peloso, Gina M and Natarajan, Pradeep and Khera, Amit V} } @article {9388, title = {Association of Severe Hypercholesterolemia and Familial Hypercholesterolemia Genotype With Risk of Coronary Heart Disease.}, journal = {Circulation}, volume = {147}, year = {2023}, month = {2023 May 16}, pages = {1556-1559}, keywords = {Coronary Disease, Genotype, Humans, Hypercholesterolemia, Hyperlipoproteinemia Type II}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.123.064168}, author = {Zhang, Yiyi and Dron, Jacqueline S and Bellows, Brandon K and Khera, Amit V and Liu, Junxiu and Balte, Pallavi P and Oelsner, Elizabeth C and Amr, Sami Samir and Lebo, Matthew S and Nagy, Anna and Peloso, Gina M and Natarajan, Pradeep and Rotter, Jerome I and Willer, Cristen and Boerwinkle, Eric and Ballantyne, Christie M and Lutsey, Pamela L and Fornage, Myriam and Lloyd-Jones, Donald M and Hou, Lifang and Psaty, Bruce M and Bis, Joshua C and Floyd, James S and Vasan, Ramachandran S and Heard-Costa, Nancy L and Carson, April P and Hall, Michael E and Rich, Stephen S and Guo, Xiuqing and Kazi, Dhruv S and de Ferranti, Sarah D and Moran, Andrew E} } @article {9479, title = {Carriers of rare damaging genetic variants are at lower risk of atherosclerotic disease.}, journal = {medRxiv}, year = {2023}, month = {2023 Aug 16}, abstract = {

BACKGROUND: The CCL2/CCR2 axis governs monocyte trafficking and recruitment to atherosclerotic lesions. Human genetic analyses and population-based studies support an association between circulating CCL2 levels and atherosclerosis. Still, it remains unknown whether pharmacological targeting of CCR2, the main CCL2 receptor, would provide protection against human atherosclerotic disease.

METHODS: In whole-exome sequencing data from 454,775 UK Biobank participants (40-69 years), we identified predicted loss-of-function (LoF) or damaging missense (REVEL score >0.5) variants within the gene. We prioritized variants associated with lower monocyte count (p<0.05) and tested associations with vascular risk factors and risk of atherosclerotic disease over a mean follow-up of 14 years. The results were replicated in a pooled cohort of three independent datasets (TOPMed, deCODE and Penn Medicine BioBank; total n=441,445) and the effect of the most frequent damaging variant was experimentally validated.

RESULTS: A total of 45 predicted LoF or damaging missense variants were identified in the gene, 4 of which were also significantly associated with lower monocyte count, but not with other white blood cell counts. Heterozygous carriers of these variants were at a lower risk of a combined atherosclerosis outcome, showed a lower burden of atherosclerosis across four vascular beds, and were at a lower lifetime risk of coronary artery disease and myocardial infarction. There was no evidence of association with vascular risk factors including LDL-cholesterol, blood pressure, glycemic status, or C-reactive protein. Using a cAMP assay, we found that cells transfected with the most frequent damaging variant (3:46358273:T:A, M249K, 547 carriers, frequency: 0.14\%) show a decrease in signaling in response to CCL2. The associations of the M249K variant with myocardial infarction were consistent across cohorts (OR : 0.62 95\%CI: 0.39-0.96; OR : 0.64 95\%CI: 0.34-1.19; OR : 0.64 95\%CI: 0.45-0.90). In a phenome-wide association study, we found no evidence for higher risk of common infections or mortality among carriers of damaging variants.

CONCLUSIONS: Heterozygous carriers of damaging variants have a lower burden of atherosclerosis and lower lifetime risk of myocardial infarction. In conjunction with previous evidence from experimental and epidemiological studies, our findings highlight the translational potential of CCR2-targeting as an atheroprotective approach.

}, doi = {10.1101/2023.08.14.23294063}, author = {Georgakis, Marios K and Malik, Rainer and Hasbani, Natalie R and Shakt, Gabrielle and Morrison, Alanna C and Tsao, Noah L and Judy, Renae and Mitchell, Braxton D and Xu, Huichun and Montasser, May E and Do, Ron and Kenny, Eimear E and Loos, Ruth J F and Terry, James G and Carr, John Jeffrey and Bis, Joshua C and Psaty, Bruce M and Longstreth, W T and Young, Kendra A and Lutz, Sharon M and Cho, Michael H and Broome, Jai and Khan, Alyna T and Wang, Fei Fei and Heard-Costa, Nancy and Seshadri, Sudha and Vasan, Ramachandran S and Palmer, Nicholette D and Freedman, Barry I and Bowden, Donald W and Yanek, Lisa R and Kral, Brian G and Becker, Lewis C and Peyser, Patricia A and Bielak, Lawrence F and Ammous, Farah and Carson, April P and Hall, Michael E and Raffield, Laura M and Rich, Stephen S and Post, Wendy S and Tracy, Russel P and Taylor, Kent D and Guo, Xiuqing and Mahaney, Michael C and Curran, Joanne E and Blangero, John and Clarke, Shoa L and Haessler, Jeffrey W and Hu, Yao and Assimes, Themistocles L and Kooperberg, Charles and Damrauer, Scott M and Rotter, Jerome I and de Vries, Paul S and Dichgans, Martin} } @article {9506, title = {Clonal Hematopoiesis of Indeterminate Potential (CHIP) and Incident Type 2 Diabetes Risk.}, journal = {Diabetes Care}, year = {2023}, month = {2023 Sep 27}, abstract = {

OBJECTIVE: Clonal hematopoiesis of indeterminate potential (CHIP) is an aging-related accumulation of somatic mutations in hematopoietic stem cells, leading to clonal expansion. CHIP presence has been implicated in atherosclerotic coronary heart disease (CHD) and all-cause mortality, but its association with incident type 2 diabetes (T2D) is unknown. We hypothesized that CHIP is associated with elevated risk of T2D.

RESEARCH DESIGN AND METHODS: CHIP was derived from whole-genome sequencing of blood DNA in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) prospective cohorts. We performed analysis for 17,637 participants from six cohorts, without prior T2D, cardiovascular disease, or cancer. We evaluated baseline CHIP versus no CHIP prevalence with incident T2D, including associations with DNMT3A, TET2, ASXL1, JAK2, and TP53 variants. We estimated multivariable-adjusted hazard ratios (HRs) and 95\% confidence intervals (CIs) with adjustment for age, sex, BMI, smoking, alcohol, education, self-reported race/ethnicity, and combined cohorts{\textquoteright} estimates via fixed-effects meta-analysis.

RESULTS: Mean (SD) age was 63.4 (11.5) years, 76\% were female, and CHIP prevalence was 6.0\% (n = 1,055) at baseline. T2D was diagnosed in n = 2,467 over mean follow-up of 9.8 years. Participants with CHIP had 23\% (CI = 1.04, 1.45) higher risk of T2D than those with no CHIP. Specifically, higher risk was for TET2 (HR 1.48; CI = 1.05, 2.08) and ASXL1 (HR 1.76; CI = 1.03, 2.99) mutations; DNMT3A was nonsignificant (HR 1.15; CI = 0.93, 1.43). Statistical power was limited for JAK2 and TP53 analyses.

CONCLUSIONS: CHIP was associated with higher incidence of T2D. CHIP mutations located on genes implicated in CHD and mortality were also related to T2D, suggesting shared aging-related pathology.

}, issn = {1935-5548}, doi = {10.2337/dc23-0805}, author = {Tobias, Deirdre K and Manning, Alisa K and Wessel, Jennifer and Raghavan, Sridharan and Westerman, Kenneth E and Bick, Alexander G and DiCorpo, Daniel and Whitsel, Eric A and Collins, Jason and Correa, Adolfo and Cupples, L Adrienne and Dupuis, Jos{\'e}e and Goodarzi, Mark O and Guo, Xiuqing and Howard, Barbara and Lange, Leslie A and Liu, Simin and Raffield, Laura M and Reiner, Alex P and Rich, Stephen S and Taylor, Kent D and Tinker, Lesley and Wilson, James G and Wu, Peitao and Carson, April P and Vasan, Ramachandran S and Fornage, Myriam and Psaty, Bruce M and Kooperberg, Charles and Rotter, Jerome I and Meigs, James and Manson, JoAnn E} } @article {9588, title = {Determinants of mosaic chromosomal alteration fitness.}, journal = {medRxiv}, year = {2023}, month = {2023 Oct 21}, abstract = {

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well-understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our estimates of mCA fitness were correlated (R = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using a theoretical probability distribution. Individuals with lymphoid-associated mCAs had a significantly higher white blood cell count and faster clonal expansion rate. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified , , and locus variants as modulators of mCA clonal expansion rate.

}, doi = {10.1101/2023.10.20.23297280}, author = {Pershad, Yash and Mack, Taralynn and Poisner, Hannah and Jakubek, Yasminka A and Stilp, Adrienne M and Mitchell, Braxton D and Lewis, Joshua P and Boerwinkle, Eric and Loos, Ruth J and Chami, Nathalie and Wang, Zhe and Barnes, Kathleen and Pankratz, Nathan and Fornage, Myriam and Redline, Susan and Psaty, Bruce M and Bis, Joshua C and Shojaie, Ali and Silverman, Edwin K and Cho, Michael H and Yun, Jeong and DeMeo, Dawn and Levy, Daniel and Johnson, Andrew and Mathias, Rasika and Taub, Margaret and Arnett, Donna and North, Kari and Raffield, Laura M and Carson, April and Doyle, Margaret F and Rich, Stephen S and Rotter, Jerome I and Guo, Xiuqing and Cox, Nancy and Roden, Dan M and Franceschini, Nora and Desai, Pinkal and Reiner, Alex and Auer, Paul L and Scheet, Paul and Jaiswal, Siddhartha and Weinstock, Joshua S and Bick, Alexander G} } @article {9379, title = {Evaluating the use of blood pressure polygenic risk scores across race/ethnic background groups.}, journal = {Nat Commun}, volume = {14}, year = {2023}, month = {2023 Jun 02}, pages = {3202}, abstract = {

We assess performance and limitations of polygenic risk scores (PRSs) for multiple blood pressure (BP) phenotypes in diverse population groups. We compare "clumping-and-thresholding" (PRSice2) and LD-based (LDPred2) methods to construct PRSs from each of multiple GWAS, as well as multi-PRS approaches that sum PRSs with and without weights, including PRS-CSx. We use datasets from the MGB Biobank, TOPMed study, UK biobank, and from All of Us to train, assess, and validate PRSs in groups defined by self-reported race/ethnic background (Asian, Black, Hispanic/Latino, and White). For both SBP and DBP, the PRS-CSx based PRS, constructed as a weighted sum of PRSs developed from multiple independent GWAS, perform best across all race/ethnic backgrounds. Stratified analysis in All of Us shows that PRSs are better predictive of BP in females compared to males, individuals without obesity, and middle-aged (40-60 years) compared to older and younger individuals.

}, keywords = {Blood Pressure, Ethnicity, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance, Population Health, Risk Factors}, issn = {2041-1723}, doi = {10.1038/s41467-023-38990-9}, author = {Kurniansyah, Nuzulul and Goodman, Matthew O and Khan, Alyna T and Wang, Jiongming and Feofanova, Elena and Bis, Joshua C and Wiggins, Kerri L and Huffman, Jennifer E and Kelly, Tanika and Elfassy, Tali and Guo, Xiuqing and Palmas, Walter and Lin, Henry J and Hwang, Shih-Jen and Gao, Yan and Young, Kendra and Kinney, Gregory L and Smith, Jennifer A and Yu, Bing and Liu, Simin and Wassertheil-Smoller, Sylvia and Manson, JoAnn E and Zhu, Xiaofeng and Chen, Yii-Der Ida and Lee, I-Te and Gu, C Charles and Lloyd-Jones, Donald M and Z{\"o}llner, Sebastian and Fornage, Myriam and Kooperberg, Charles and Correa, Adolfo and Psaty, Bruce M and Arnett, Donna K and Isasi, Carmen R and Rich, Stephen S and Kaplan, Robert C and Redline, Susan and Mitchell, Braxton D and Franceschini, Nora and Levy, Daniel and Rotter, Jerome I and Morrison, Alanna C and Sofer, Tamar} } @article {9535, title = {Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci.}, journal = {Front Genet}, volume = {14}, year = {2023}, month = {2023}, pages = {1235337}, abstract = {

Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant ( < 5 {\texttimes} 10) and suggestive ( < 1 {\texttimes} 10) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (), brain (), and liver () biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

}, issn = {1664-8021}, doi = {10.3389/fgene.2023.1235337}, author = {de Las Fuentes, Lisa and Schwander, Karen L and Brown, Michael R and Bentley, Amy R and Winkler, Thomas W and Sung, Yun Ju and Munroe, Patricia B and Miller, Clint L and Aschard, Hugo and Aslibekyan, Stella and Bartz, Traci M and Bielak, Lawrence F and Chai, Jin Fang and Cheng, Ching-Yu and Dorajoo, Rajkumar and Feitosa, Mary F and Guo, Xiuqing and Hartwig, Fernando P and Horimoto, Andrea and Kolcic, Ivana and Lim, Elise and Liu, Yongmei and Manning, Alisa K and Marten, Jonathan and Musani, Solomon K and Noordam, Raymond and Padmanabhan, Sandosh and Rankinen, Tuomo and Richard, Melissa A and Ridker, Paul M and Smith, Albert V and Vojinovic, Dina and Zonderman, Alan B and Alver, Maris and Boissel, Mathilde and Christensen, Kaare and Freedman, Barry I and Gao, Chuan and Giulianini, Franco and Harris, Sarah E and He, Meian and Hsu, Fang-Chi and Kuhnel, Brigitte and Laguzzi, Federica and Li, Xiaoyin and Lyytik{\"a}inen, Leo-Pekka and Nolte, Ilja M and Poveda, Alaitz and Rauramaa, Rainer and Riaz, Muhammad and Robino, Antonietta and Sofer, Tamar and Takeuchi, Fumihiko and Tayo, Bamidele O and van der Most, Peter J and Verweij, Niek and Ware, Erin B and Weiss, Stefan and Wen, Wanqing and Yanek, Lisa R and Zhan, Yiqiang and Amin, Najaf and Arking, Dan E and Ballantyne, Christie and Boerwinkle, Eric and Brody, Jennifer A and Broeckel, Ulrich and Campbell, Archie and Canouil, Micka{\"e}l and Chai, Xiaoran and Chen, Yii-Der Ida and Chen, Xu and Chitrala, Kumaraswamy Naidu and Concas, Maria Pina and de Faire, Ulf and de Mutsert, Ren{\'e}e and de Silva, H Janaka and de Vries, Paul S and Do, Ahn and Faul, Jessica D and Fisher, Virginia and Floyd, James S and Forrester, Terrence and Friedlander, Yechiel and Girotto, Giorgia and Gu, C Charles and Hallmans, G{\"o}ran and Heikkinen, Sami and Heng, Chew-Kiat and Homuth, Georg and Hunt, Steven and Ikram, M Arfan and Jacobs, David R and Kavousi, Maryam and Khor, Chiea Chuen and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Komulainen, Pirjo and Langefeld, Carl D and Liang, Jingjing and Liu, Kiang and Liu, Jianjun and Lohman, Kurt and M{\"a}gi, Reedik and Manichaikul, Ani W and McKenzie, Colin A and Meitinger, Thomas and Milaneschi, Yuri and Nauck, Matthias and Nelson, Christopher P and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Pereira, Alexandre C and Perls, Thomas and Peters, Annette and Polasek, Ozren and Raitakari, Olli T and Rice, Kenneth and Rice, Treva K and Rich, Stephen S and Sabanayagam, Charumathi and Schreiner, Pamela J and Shu, Xiao-Ou and Sidney, Stephen and Sims, Mario and Smith, Jennifer A and Starr, John M and Strauch, Konstantin and Tai, E Shyong and Taylor, Kent D and Tsai, Michael Y and Uitterlinden, Andr{\'e} G and van Heemst, Diana and Waldenberger, Melanie and Wang, Ya-Xing and Wei, Wen-Bin and Wilson, Gregory and Xuan, Deng and Yao, Jie and Yu, Caizheng and Yuan, Jian-Min and Zhao, Wei and Becker, Diane M and Bonnefond, Am{\'e}lie and Bowden, Donald W and Cooper, Richard S and Deary, Ian J and Divers, Jasmin and Esko, T{\~o}nu and Franks, Paul W and Froguel, Philippe and Gieger, Christian and Jonas, Jost B and Kato, Norihiro and Lakka, Timo A and Leander, Karin and Lehtim{\"a}ki, Terho and Magnusson, Patrik K E and North, Kari E and Ntalla, Ioanna and Penninx, Brenda and Samani, Nilesh J and Snieder, Harold and Spedicati, Beatrice and van der Harst, Pim and V{\"o}lzke, Henry and Wagenknecht, Lynne E and Weir, David R and Wojczynski, Mary K and Wu, Tangchun and Zheng, Wei and Zhu, Xiaofeng and Bouchard, Claude and Chasman, Daniel I and Evans, Michele K and Fox, Ervin R and Gudnason, Vilmundur and Hayward, Caroline and Horta, Bernardo L and Kardia, Sharon L R and Krieger, Jose Eduardo and Mook-Kanamori, Dennis O and Peyser, Patricia A and Province, Michael M and Psaty, Bruce M and Rudan, Igor and Sim, Xueling and Smith, Blair H and van Dam, Rob M and van Duijn, Cornelia M and Wong, Tien Yin and Arnett, Donna K and Rao, Dabeeru C and Gauderman, James and Liu, Ching-Ti and Morrison, Alanna C and Rotter, Jerome I and Fornage, Myriam} } @article {9286, title = {Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants.}, journal = {bioRxiv}, year = {2023}, month = {2023 Jan 31}, abstract = {

Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-seq data in GTEx v8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased WGS data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants.

}, doi = {10.1101/2023.01.31.526505}, author = {Einson, Jonah and Glinos, Dafni and Boerwinkle, Eric and Castaldi, Peter and Darbar, Dawood and de Andrade, Mariza and Ellinor, Patrick and Fornage, Myriam and Gabriel, Stacey and Germer, Soren and Gibbs, Richard and Hersh, Craig P and Johnsen, Jill and Kaplan, Robert and Konkle, Barbara A and Kooperberg, Charles and Nassir, Rami and Loos, Ruth J F and Meyers, Deborah A and Mitchell, Braxton D and Psaty, Bruce and Vasan, Ramachandran S and Rich, Stephen S and Rienstra, Michael and Rotter, Jerome I and Saferali, Aabida and Shoemaker, M Benjamin and Silverman, Edwin and Smith, Albert Vernon and Mohammadi, Pejman and Castel, Stephane E and Iossifov, Ivan and Lappalainen, Tuuli} } @article {9419, title = {The genetic determinants of recurrent somatic mutations in 43,693 blood genomes.}, journal = {Sci Adv}, volume = {9}, year = {2023}, month = {2023 Apr 28}, pages = {eabm4945}, abstract = {

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.

}, keywords = {Germ-Line Mutation, Hematopoiesis, Humans, Middle Aged, Mutation, Mutation, Missense, Phenotype}, issn = {2375-2548}, doi = {10.1126/sciadv.abm4945}, author = {Weinstock, Joshua S and Laurie, Cecelia A and Broome, Jai G and Taylor, Kent D and Guo, Xiuqing and Shuldiner, Alan R and O{\textquoteright}Connell, Jeffrey R and Lewis, Joshua P and Boerwinkle, Eric and Barnes, Kathleen C and Chami, Nathalie and Kenny, Eimear E and Loos, Ruth J F and Fornage, Myriam and Redline, Susan and Cade, Brian E and Gilliland, Frank D and Chen, Zhanghua and Gauderman, W James and Kumar, Rajesh and Grammer, Leslie and Schleimer, Robert P and Psaty, Bruce M and Bis, Joshua C and Brody, Jennifer A and Silverman, Edwin K and Yun, Jeong H and Qiao, Dandi and Weiss, Scott T and Lasky-Su, Jessica and DeMeo, Dawn L and Palmer, Nicholette D and Freedman, Barry I and Bowden, Donald W and Cho, Michael H and Vasan, Ramachandran S and Johnson, Andrew D and Yanek, Lisa R and Becker, Lewis C and Kardia, Sharon and He, Jiang and Kaplan, Robert and Heckbert, Susan R and Smith, Nicholas L and Wiggins, Kerri L and Arnett, Donna K and Irvin, Marguerite R and Tiwari, Hemant and Correa, Adolfo and Raffield, Laura M and Gao, Yan and de Andrade, Mariza and Rotter, Jerome I and Rich, Stephen S and Manichaikul, Ani W and Konkle, Barbara A and Johnsen, Jill M and Wheeler, Marsha M and Custer, Brian S and Duggirala, Ravindranath and Curran, Joanne E and Blangero, John and Gui, Hongsheng and Xiao, Shujie and Williams, L Keoki and Meyers, Deborah A and Li, Xingnan and Ortega, Victor and McGarvey, Stephen and Gu, C Charles and Chen, Yii-Der Ida and Lee, Wen-Jane and Shoemaker, M Benjamin and Darbar, Dawood and Roden, Dan and Albert, Christine and Kooperberg, Charles and Desai, Pinkal and Blackwell, Thomas W and Abecasis, Goncalo R and Smith, Albert V and Kang, Hyun M and Mathias, Rasika and Natarajan, Pradeep and Jaiswal, Siddhartha and Reiner, Alexander P and Bick, Alexander G} } @article {9586, title = {Machine learning models for blood pressure phenotypes combining multiple polygenic risk scores.}, journal = {medRxiv}, year = {2023}, month = {2023 Dec 14}, abstract = {

We construct non-linear machine learning (ML) prediction models for systolic and diastolic blood pressure (SBP, DBP) using demographic and clinical variables and polygenic risk scores (PRSs). We developed a two-model ensemble, consisting of a baseline model, where prediction is based on demographic and clinical variables only, and a genetic model, where we also include PRSs. We evaluate the use of a linear versus a non-linear model at both the baseline and the genetic model levels and assess the improvement in performance when incorporating multiple PRSs. We report the ensemble model{\textquoteright}s performance as percentage variance explained (PVE) on a held-out test dataset. A non-linear baseline model improved the PVEs from 28.1\% to 30.1\% (SBP) and 14.3\% to 17.4\% (DBP) compared with a linear baseline model. Including seven PRSs in the genetic model computed based on the largest available GWAS of SBP/DBP improved the genetic model PVE from 4.8\% to 5.1\% (SBP) and 4.7\% to 5\% (DBP) compared to using a single PRS. Adding additional 14 PRSs computed based on two independent GWASs further increased the genetic model PVE to 6.3\% (SBP) and 5.7\% (DBP). PVE differed across self-reported race/ethnicity groups, with primarily all non-White groups benefitting from the inclusion of additional PRSs.

}, doi = {10.1101/2023.12.13.23299909}, author = {Hrytsenko, Yana and Shea, Benjamin and Elgart, Michael and Kurniansyah, Nuzulul and Lyons, Genevieve and Morrison, Alanna C and Carson, April P and Haring, Bernhard and Mitchel, Braxton D and Psaty, Bruce M and Jaeger, Byron C and Gu, C Charles and Kooperberg, Charles and Levy, Daniel and Lloyd-Jones, Donald and Choi, Eunhee and Brody, Jennifer A and Smith, Jennifer A and Rotter, Jerome I and Moll, Matthew and Fornage, Myriam and Simon, Noah and Castaldi, Peter and Casanova, Ramon and Chung, Ren-Hua and Kaplan, Robert and Loos, Ruth J F and Kardia, Sharon L R and Rich, Stephen S and Redline, Susan and Kelly, Tanika and O{\textquoteright}Connor, Timothy and Zhao, Wei and Kim, Wonji and Guo, Xiuqing and Der Ida Chen, Yii and Sofer, Tamar} } @article {9538, title = {Mosaic chromosomal alterations in blood across ancestries using whole-genome sequencing.}, journal = {Nat Genet}, volume = {55}, year = {2023}, month = {2023 Nov}, pages = {1912-1919}, abstract = {

Megabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. Although further studies in diverse populations will be needed to replicate our findings, we report three loci associated with loss of chromosome X, associations between autosomal mCAs and rare variants in DCPS, ADM17, PPP1R16B and TET2 and ancestry-specific variants in ATM and MPL with mCAs in cis.

}, keywords = {Black People, Genome, Human, Genome-Wide Association Study, Hispanic or Latino, Humans, Mosaicism, Precision Medicine}, issn = {1546-1718}, doi = {10.1038/s41588-023-01553-1}, author = {Jakubek, Yasminka A and Zhou, Ying and Stilp, Adrienne and Bacon, Jason and Wong, Justin W and Ozcan, Zuhal and Arnett, Donna and Barnes, Kathleen and Bis, Joshua C and Boerwinkle, Eric and Brody, Jennifer A and Carson, April P and Chasman, Daniel I and Chen, Jiawen and Cho, Michael and Conomos, Matthew P and Cox, Nancy and Doyle, Margaret F and Fornage, Myriam and Guo, Xiuqing and Kardia, Sharon L R and Lewis, Joshua P and Loos, Ruth J F and Ma, Xiaolong and Machiela, Mitchell J and Mack, Taralynn M and Mathias, Rasika A and Mitchell, Braxton D and Mychaleckyj, Josyf C and North, Kari and Pankratz, Nathan and Peyser, Patricia A and Preuss, Michael H and Psaty, Bruce and Raffield, Laura M and Vasan, Ramachandran S and Redline, Susan and Rich, Stephen S and Rotter, Jerome I and Silverman, Edwin K and Smith, Jennifer A and Smith, Aaron P and Taub, Margaret and Taylor, Kent D and Yun, Jeong and Li, Yun and Desai, Pinkal and Bick, Alexander G and Reiner, Alexander P and Scheet, Paul and Auer, Paul L} } @article {9385, title = {Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications.}, journal = {medRxiv}, year = {2023}, month = {2023 Mar 31}, abstract = {

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7\% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P<5{\texttimes}10 ) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.

}, doi = {10.1101/2023.03.31.23287839}, author = {Suzuki, Ken and Hatzikotoulas, Konstantinos and Southam, Lorraine and Taylor, Henry J and Yin, Xianyong and Lorenz, Kim M and Mandla, Ravi and Huerta-Chagoya, Alicia and Rayner, Nigel W and Bocher, Ozvan and Ana Luiza de, S V Arruda and Sonehara, Kyuto and Namba, Shinichi and Lee, Simon S K and Preuss, Michael H and Petty, Lauren E and Schroeder, Philip and Vanderwerff, Brett and Kals, Mart and Bragg, Fiona and Lin, Kuang and Guo, Xiuqing and Zhang, Weihua and Yao, Jie and Kim, Young Jin and Graff, Mariaelisa and Takeuchi, Fumihiko and Nano, Jana and Lamri, Amel and Nakatochi, Masahiro and Moon, Sanghoon and Scott, Robert A and Cook, James P and Lee, Jung-Jin and Pan, Ian and Taliun, Daniel and Parra, Esteban J and Chai, Jin-Fang and Bielak, Lawrence F and Tabara, Yasuharu and Hai, Yang and Thorleifsson, Gudmar and Grarup, Niels and Sofer, Tamar and Wuttke, Matthias and Sarnowski, Chloe and Gieger, Christian and Nousome, Darryl and Trompet, Stella and Kwak, Soo-Heon and Long, Jirong and Sun, Meng and Tong, Lin and Chen, Wei-Min and Nongmaithem, Suraj S and Noordam, Raymond and Lim, Victor J Y and Tam, Claudia H T and Joo, Yoonjung Yoonie and Chen, Chien-Hsiun and Raffield, Laura M and Prins, Bram Peter and Nicolas, Aude and Yanek, Lisa R and Chen, Guanjie and Brody, Jennifer A and Kabagambe, Edmond and An, Ping and Xiang, Anny H and Choi, Hyeok Sun and Cade, Brian E and Tan, Jingyi and Alaine Broadaway, K and Williamson, Alice and Kamali, Zoha and Cui, Jinrui and Adair, Linda S and Adeyemo, Adebowale and Aguilar-Salinas, Carlos A and Ahluwalia, Tarunveer S and Anand, Sonia S and Bertoni, Alain and Bork-Jensen, Jette and Brandslund, Ivan and Buchanan, Thomas A and Burant, Charles F and Butterworth, Adam S and Canouil, Micka{\"e}l and Chan, Juliana C N and Chang, Li-Ching and Chee, Miao-Li and Chen, Ji and Chen, Shyh-Huei and Chen, Yuan-Tsong and Chen, Zhengming and Chuang, Lee-Ming and Cushman, Mary and Danesh, John and Das, Swapan K and Janaka de Silva, H and Dedoussis, George and Dimitrov, Latchezar and Doumatey, Ayo P and Du, Shufa and Duan, Qing and Eckardt, Kai-Uwe and Emery, Leslie S and Evans, Daniel S and Evans, Michele K and Fischer, Krista and Floyd, James S and Ford, Ian and Franco, Oscar H and Frayling, Timothy M and Freedman, Barry I and Genter, Pauline and Gerstein, Hertzel C and Giedraitis, Vilmantas and Gonz{\'a}lez-Villalpando, Clicerio and Gonzalez-Villalpando, Maria Elena and Gordon-Larsen, Penny and Gross, Myron and Guare, Lindsay A and Hackinger, Sophie and Han, Sohee and Hattersley, Andrew T and Herder, Christian and Horikoshi, Momoko and Howard, Annie-Green and Hsueh, Willa and Huang, Mengna and Huang, Wei and Hung, Yi-Jen and Hwang, Mi Yeong and Hwu, Chii-Min and Ichihara, Sahoko and Ikram, Mohammad Arfan and Ingelsson, Martin and Islam, Md Tariqul and Isono, Masato and Jang, Hye-Mi and Jasmine, Farzana and Jiang, Guozhi and Jonas, Jost B and J{\o}rgensen, Torben and Kandeel, Fouad R and Kasturiratne, Anuradhani and Katsuya, Tomohiro and Kaur, Varinderpal and Kawaguchi, Takahisa and Keaton, Jacob M and Kho, Abel N and Khor, Chiea-Chuen and Kibriya, Muhammad G and Kim, Duk-Hwan and Kronenberg, Florian and Kuusisto, Johanna and L{\"a}ll, Kristi and Lange, Leslie A and Lee, Kyung Min and Lee, Myung-Shik and Lee, Nanette R and Leong, Aaron and Li, Liming and Li, Yun and Li-Gao, Ruifang and Lithgart, Symen and Lindgren, Cecilia M and Linneberg, Allan and Liu, Ching-Ti and Liu, Jianjun and Locke, Adam E and Louie, Tin and Luan, Jian{\textquoteright}an and Luk, Andrea O and Luo, Xi and Lv, Jun and Lynch, Julie A and Lyssenko, Valeriya and Maeda, Shiro and Mamakou, Vasiliki and Mansuri, Sohail Rafik and Matsuda, Koichi and Meitinger, Thomas and Metspalu, Andres and Mo, Huan and Morris, Andrew D and Nadler, Jerry L and Nalls, Michael A and Nayak, Uma and Ntalla, Ioanna and Okada, Yukinori and Orozco, Lorena and Patel, Sanjay R and Patil, Snehal and Pei, Pei and Pereira, Mark A and Peters, Annette and Pirie, Fraser J and Polikowsky, Hannah G and Porneala, Bianca and Prasad, Gauri and Rasmussen-Torvik, Laura J and Reiner, Alexander P and Roden, Michael and Rohde, Rebecca and Roll, Katheryn and Sabanayagam, Charumathi and Sandow, Kevin and Sankareswaran, Alagu and Sattar, Naveed and Sch{\"o}nherr, Sebastian and Shahriar, Mohammad and Shen, Botong and Shi, Jinxiu and Shin, Dong Mun and Shojima, Nobuhiro and Smith, Jennifer A and So, Wing Yee and Stan{\v c}{\'a}kov{\'a}, Alena and Steinthorsdottir, Valgerdur and Stilp, Adrienne M and Strauch, Konstantin and Taylor, Kent D and Thorand, Barbara and Thorsteinsdottir, Unnur and Tomlinson, Brian and Tran, Tam C and Tsai, Fuu-Jen and Tuomilehto, Jaakko and Tusi{\'e}-Luna, Teresa and Udler, Miriam S and Valladares-Salgado, Adan and van Dam, Rob M and van Klinken, Jan B and Varma, Rohit and Wacher-Rodarte, Niels and Wheeler, Eleanor and Wickremasinghe, Ananda R and van Dijk, Ko Willems and Witte, Daniel R and Yajnik, Chittaranjan S and Yamamoto, Ken and Yamamoto, Kenichi and Yoon, Kyungheon and Yu, Canqing and Yuan, Jian-Min and Yusuf, Salim and Zawistowski, Matthew and Zhang, Liang and Zheng, Wei and Project, Biobank Japan and BioBank, Penn Medicine and Center, Regeneron Genetics and Consortium, eMERGE and Raffel, Leslie J and Igase, Michiya and Ipp, Eli and Redline, Susan and Cho, Yoon Shin and Lind, Lars and Province, Michael A and Fornage, Myriam and Hanis, Craig L and Ingelsson, Erik and Zonderman, Alan B and Psaty, Bruce M and Wang, Ya-Xing and Rotimi, Charles N and Becker, Diane M and Matsuda, Fumihiko and Liu, Yongmei and Yokota, Mitsuhiro and Kardia, Sharon L R and Peyser, Patricia A and Pankow, James S and Engert, James C and Bonnefond, Am{\'e}lie and Froguel, Philippe and Wilson, James G and Sheu, Wayne H H and Wu, Jer-Yuarn and Geoffrey Hayes, M and Ma, Ronald C W and Wong, Tien-Yin and Mook-Kanamori, Dennis O and Tuomi, Tiinamaija and Chandak, Giriraj R and Collins, Francis S and Bharadwaj, Dwaipayan and Par{\'e}, Guillaume and Sale, Mich{\`e}le M and Ahsan, Habibul and Motala, Ayesha A and Shu, Xiao-Ou and Park, Kyong-Soo and Jukema, J Wouter and Cruz, Miguel and Chen, Yii-Der Ida and Rich, Stephen S and McKean-Cowdin, Roberta and Grallert, Harald and Cheng, Ching-Yu and Ghanbari, Mohsen and Tai, E-Shyong and Dupuis, Jos{\'e}e and Kato, Norihiro and Laakso, Markku and K{\"o}ttgen, Anna and Koh, Woon-Puay and Bowden, Donald W and Palmer, Colin N A and Kooner, Jaspal S and Kooperberg, Charles and Liu, Simin and North, Kari E and Saleheen, Danish and Hansen, Torben and Pedersen, Oluf and Wareham, Nicholas J and Lee, Juyoung and Kim, Bong-Jo and Millwood, Iona Y and Walters, Robin G and Stefansson, Kari and Goodarzi, Mark O and Mohlke, Karen L and Langenberg, Claudia and Haiman, Christopher A and Loos, Ruth J F and Florez, Jose C and Rader, Daniel J and Ritchie, Marylyn D and Z{\"o}llner, Sebastian and M{\"a}gi, Reedik and Denny, Joshua C and Yamauchi, Toshimasa and Kadowaki, Takashi and Chambers, John C and Ng, Maggie C Y and Sim, Xueling and Below, Jennifer E and Tsao, Philip S and Chang, Kyong-Mi and McCarthy, Mark I and Meigs, James B and Mahajan, Anubha and Spracklen, Cassandra N and Mercader, Josep M and Boehnke, Michael and Rotter, Jerome I and Vujkovic, Marijana and Voight, Benjamin F and Morris, Andrew P and Zeggini, Eleftheria} } @article {9412, title = {Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing.}, journal = {Nat Genet}, volume = {55}, year = {2023}, month = {2023 Feb}, pages = {291-300}, abstract = {

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55\% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

}, keywords = {Biology, Drug Repositioning, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Tobacco Use, Transcriptome}, issn = {1546-1718}, doi = {10.1038/s41588-022-01282-x}, author = {Chen, Fang and Wang, Xingyan and Jang, Seon-Kyeong and Quach, Bryan C and Weissenkampen, J Dylan and Khunsriraksakul, Chachrit and Yang, Lina and Sauteraud, Renan and Albert, Christine M and Allred, Nicholette D D and Arnett, Donna K and Ashley-Koch, Allison E and Barnes, Kathleen C and Barr, R Graham and Becker, Diane M and Bielak, Lawrence F and Bis, Joshua C and Blangero, John and Boorgula, Meher Preethi and Chasman, Daniel I and Chavan, Sameer and Chen, Yii-der I and Chuang, Lee-Ming and Correa, Adolfo and Curran, Joanne E and David, Sean P and Fuentes, Lisa de Las and Deka, Ranjan and Duggirala, Ravindranath and Faul, Jessica D and Garrett, Melanie E and Gharib, Sina A and Guo, Xiuqing and Hall, Michael E and Hawley, Nicola L and He, Jiang and Hobbs, Brian D and Hokanson, John E and Hsiung, Chao A and Hwang, Shih-Jen and Hyde, Thomas M and Irvin, Marguerite R and Jaffe, Andrew E and Johnson, Eric O and Kaplan, Robert and Kardia, Sharon L R and Kaufman, Joel D and Kelly, Tanika N and Kleinman, Joel E and Kooperberg, Charles and Lee, I-Te and Levy, Daniel and Lutz, Sharon M and Manichaikul, Ani W and Martin, Lisa W and Marx, Olivia and McGarvey, Stephen T and Minster, Ryan L and Moll, Matthew and Moussa, Karine A and Naseri, Take and North, Kari E and Oelsner, Elizabeth C and Peralta, Juan M and Peyser, Patricia A and Psaty, Bruce M and Rafaels, Nicholas and Raffield, Laura M and Reupena, Muagututi{\textquoteright}a Sefuiva and Rich, Stephen S and Rotter, Jerome I and Schwartz, David A and Shadyab, Aladdin H and Sheu, Wayne H-H and Sims, Mario and Smith, Jennifer A and Sun, Xiao and Taylor, Kent D and Telen, Marilyn J and Watson, Harold and Weeks, Daniel E and Weir, David R and Yanek, Lisa R and Young, Kendra A and Young, Kristin L and Zhao, Wei and Hancock, Dana B and Jiang, Bibo and Vrieze, Scott and Liu, Dajiang J} } @article {9239, title = {Powerful, scalable and resource-efficient meta-analysis of rare variant associations in large whole genome sequencing studies.}, journal = {Nat Genet}, volume = {55}, year = {2023}, month = {2023 Jan}, pages = {154-164}, abstract = {

Meta-analysis of whole genome sequencing/whole exome sequencing (WGS/WES) studies provides an attractive solution to the problem of collecting large sample sizes for discovering rare variants associated with complex phenotypes. Existing rare variant meta-analysis approaches are not scalable to biobank-scale WGS data. Here we present MetaSTAAR, a powerful and resource-efficient rare variant meta-analysis framework for large-scale WGS/WES studies. MetaSTAAR accounts for relatedness and population structure, can analyze both quantitative and dichotomous traits and boosts the power of rare variant tests by incorporating multiple variant functional annotations. Through meta-analysis of four lipid traits in 30,138 ancestrally diverse samples from 14 studies of the Trans Omics for Precision Medicine (TOPMed) Program, we show that MetaSTAAR performs rare variant meta-analysis at scale and produces results comparable to using pooled data. Additionally, we identified several conditionally significant rare variant associations with lipid traits. We further demonstrate that MetaSTAAR is scalable to biobank-scale cohorts through meta-analysis of TOPMed WGS data and UK Biobank WES data of ~200,000 samples.

}, keywords = {Exome Sequencing, Genome-Wide Association Study, Lipids, Phenotype, Whole Genome Sequencing}, issn = {1546-1718}, doi = {10.1038/s41588-022-01225-6}, author = {Li, Xihao and Quick, Corbin and Zhou, Hufeng and Gaynor, Sheila M and Liu, Yaowu and Chen, Han and Selvaraj, Margaret Sunitha and Sun, Ryan and Dey, Rounak and Arnett, Donna K and Bielak, Lawrence F and Bis, Joshua C and Blangero, John and Boerwinkle, Eric and Bowden, Donald W and Brody, Jennifer A and Cade, Brian E and Correa, Adolfo and Cupples, L Adrienne and Curran, Joanne E and de Vries, Paul S and Duggirala, Ravindranath and Freedman, Barry I and G{\"o}ring, Harald H H and Guo, Xiuqing and Haessler, Jeffrey and Kalyani, Rita R and Kooperberg, Charles and Kral, Brian G and Lange, Leslie A and Manichaikul, Ani and Martin, Lisa W and McGarvey, Stephen T and Mitchell, Braxton D and Montasser, May E and Morrison, Alanna C and Naseri, Take and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Peyser, Patricia A and Psaty, Bruce M and Raffield, Laura M and Redline, Susan and Reiner, Alexander P and Reupena, Muagututi{\textquoteright}a Sefuiva and Rice, Kenneth M and Rich, Stephen S and Sitlani, Colleen M and Smith, Jennifer A and Taylor, Kent D and Vasan, Ramachandran S and Willer, Cristen J and Wilson, James G and Yanek, Lisa R and Zhao, Wei and Rotter, Jerome I and Natarajan, Pradeep and Peloso, Gina M and Li, Zilin and Lin, Xihong} } @article {9418, title = {Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed Whole Genome Sequencing Study.}, journal = {medRxiv}, year = {2023}, month = {2023 Jun 29}, abstract = {

Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions. Large-scale whole genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess the associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with blood lipid levels (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare variant aggregate association tests using the STAAR (variant-Set Test for Association using Annotation infoRmation) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare coding variants in nearby protein coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a {\textpm}500 kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73\%) were conditionally independent of common regulatory variations and rare protein coding variations at the same loci. We replicated 34 out of 61 (56\%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNA, implicating new therapeutic opportunities.

}, doi = {10.1101/2023.06.28.23291966}, author = {Wang, Yuxuan and Selvaraj, Margaret Sunitha and Li, Xihao and Li, Zilin and Holdcraft, Jacob A and Arnett, Donna K and Bis, Joshua C and Blangero, John and Boerwinkle, Eric and Bowden, Donald W and Cade, Brian E and Carlson, Jenna C and Carson, April P and Chen, Yii-Der Ida and Curran, Joanne E and de Vries, Paul S and Dutcher, Susan K and Ellinor, Patrick T and Floyd, James S and Fornage, Myriam and Freedman, Barry I and Gabriel, Stacey and Germer, Soren and Gibbs, Richard A and Guo, Xiuqing and He, Jiang and Heard-Costa, Nancy and Hildalgo, Bertha and Hou, Lifang and Irvin, Marguerite R and Joehanes, Roby and Kaplan, Robert C and Kardia, Sharon Lr and Kelly, Tanika N and Kim, Ryan and Kooperberg, Charles and Kral, Brian G and Levy, Daniel and Li, Changwei and Liu, Chunyu and Lloyd-Jone, Don and Loos, Ruth Jf and Mahaney, Michael C and Martin, Lisa W and Mathias, Rasika A and Minster, Ryan L and Mitchell, Braxton D and Montasser, May E and Morrison, Alanna C and Murabito, Joanne M and Naseri, Take and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Preuss, Michael H and Psaty, Bruce M and Raffield, Laura M and Rao, Dabeeru C and Redline, Susan and Reiner, Alexander P and Rich, Stephen S and Ruepena, Muagututi{\textquoteright}a Sefuiva and Sheu, Wayne H-H and Smith, Jennifer A and Smith, Albert and Tiwari, Hemant K and Tsai, Michael Y and Viaud-Martinez, Karine A and Wang, Zhe and Yanek, Lisa R and Zhao, Wei and Rotter, Jerome I and Lin, Xihong and Natarajan, Pradeep and Peloso, Gina M} } @article {9543, title = {A statistical framework for powerful multi-trait rare variant analysis in large-scale whole-genome sequencing studies.}, journal = {bioRxiv}, year = {2023}, month = {2023 Nov 02}, abstract = {

Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally-scalable analytical pipeline for functionally-informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides) in 61,861 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered new associations with lipid traits missed by single-trait analysis, including rare variants within an enhancer of and an intergenic region on chromosome 1.

}, doi = {10.1101/2023.10.30.564764}, author = {Li, Xihao and Chen, Han and Selvaraj, Margaret Sunitha and Van Buren, Eric and Zhou, Hufeng and Wang, Yuxuan and Sun, Ryan and McCaw, Zachary R and Yu, Zhi and Arnett, Donna K and Bis, Joshua C and Blangero, John and Boerwinkle, Eric and Bowden, Donald W and Brody, Jennifer A and Cade, Brian E and Carson, April P and Carlson, Jenna C and Chami, Nathalie and Chen, Yii-Der Ida and Curran, Joanne E and de Vries, Paul S and Fornage, Myriam and Franceschini, Nora and Freedman, Barry I and Gu, Charles and Heard-Costa, Nancy L and He, Jiang and Hou, Lifang and Hung, Yi-Jen and Irvin, Marguerite R and Kaplan, Robert C and Kardia, Sharon L R and Kelly, Tanika and Konigsberg, Iain and Kooperberg, Charles and Kral, Brian G and Li, Changwei and Loos, Ruth J F and Mahaney, Michael C and Martin, Lisa W and Mathias, Rasika A and Minster, Ryan L and Mitchell, Braxton D and Montasser, May E and Morrison, Alanna C and Palmer, Nicholette D and Peyser, Patricia A and Psaty, Bruce M and Raffield, Laura M and Redline, Susan and Reiner, Alexander P and Rich, Stephen S and Sitlani, Colleen M and Smith, Jennifer A and Taylor, Kent D and Tiwari, Hemant and Vasan, Ramachandran S and Wang, Zhe and Yanek, Lisa R and Yu, Bing and Rice, Kenneth M and Rotter, Jerome I and Peloso, Gina M and Natarajan, Pradeep and Li, Zilin and Liu, Zhonghua and Lin, Xihong} } @article {9450, title = {Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus.}, journal = {medRxiv}, year = {2023}, month = {2023 Jul 28}, abstract = {

BACKGROUND: Type 2 diabetes mellitus (T2D) confers a two- to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD.

METHODS: From 16 studies of the Cohorts for Heart \& Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level estimated effect sizes were combined using inverse variance weighted fixed effects meta-analysis. We also tested 204 known CAD variants for association with incident CVD among patients with T2D.

RESULTS: A total of 49,230 participants with T2D were included in the analyses (31,118 European ancestries and 18,112 non-European ancestries) which consisted of 8,956 incident CVD cases over a range of mean follow-up duration between 3.2 and 33.7 years (event rate 18.2\%). We identified three novel, distinct genetic loci for incident CVD among individuals with T2D that reached the threshold for genome-wide significance ( <5.0{\texttimes}10 ): rs147138607 (intergenic variant between and ) with a hazard ratio (HR) 1.23, 95\% confidence interval (CI) 1.15 - 1.32, =3.6{\texttimes}10 , rs11444867 (intergenic variant near ) with HR 1.89, 95\% CI 1.52 - 2.35, =9.9{\texttimes}10 , and rs335407 (intergenic variant between and ) HR 1.25, 95\% CI 1.16 - 1.35, =1.5{\texttimes}10 . Among 204 known CAD loci, 32 were associated with incident CVD in people with T2D with <0.05, and 5 were significant after Bonferroni correction ( <0.00024, 0.05/204). A polygenic score of these 204 variants was significantly associated with incident CVD with HR 1.14 (95\% CI 1.12 - 1.16) per 1 standard deviation increase ( =1.0{\texttimes}10 ).

CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

CLINICAL PERSPECTIVE: We conducted a large-scale multi-ancestry time-to-event GWAS to identify genetic variants associated with CVD among people with T2D. Three variants were significantly associated with incident CVD in people with T2D: rs147138607 (intergenic variant between and ), rs11444867 (intergenic variant near ), and rs335407 (intergenic variant between and ). A polygenic score composed of known CAD variants identified in the general population was significantly associated with the risk of CVD in people with T2D. There are genetic risk factors specific to T2D that could at least partially explain the excess risk of CVD in people with T2D.In addition, we show that people with T2D have enrichment of known CAD association signals which could also explain the excess risk of CVD.

}, doi = {10.1101/2023.07.25.23293180}, author = {Kwak, Soo Heon and Hernandez-Cancela, Ryan B and DiCorpo, Daniel A and Condon, David E and Merino, Jordi and Wu, Peitao and Brody, Jennifer A and Yao, Jie and Guo, Xiuqing and Ahmadizar, Fariba and Meyer, Mariah and Sincan, Murat and Mercader, Josep M and Lee, Sujin and Haessler, Jeffrey and Vy, Ha My T and Lin, Zhaotong and Armstrong, Nicole D and Gu, Shaopeng and Tsao, Noah L and Lange, Leslie A and Wang, Ningyuan and Wiggins, Kerri L and Trompet, Stella and Liu, Simin and Loos, Ruth J F and Judy, Renae and Schroeder, Philip H and Hasbani, Natalie R and Bos, Maxime M and Morrison, Alanna C and Jackson, Rebecca D and Reiner, Alexander P and Manson, JoAnn E and Chaudhary, Ninad S and Carmichael, Lynn K and Chen, Yii-Der Ida and Taylor, Kent D and Ghanbari, Mohsen and van Meurs, Joyce and Pitsillides, Achilleas N and Psaty, Bruce M and Noordam, Raymond and Do, Ron and Park, Kyong Soo and Jukema, J Wouter and Kavousi, Maryam and Correa, Adolfo and Rich, Stephen S and Damrauer, Scott M and Hajek, Catherine and Cho, Nam H and Irvin, Marguerite R and Pankow, James S and Nadkarni, Girish N and Sladek, Robert and Goodarzi, Mark O and Florez, Jose C and Chasman, Daniel I and Heckbert, Susan R and Kooperberg, Charles and Dupuis, Jos{\'e}e and Malhotra, Rajeev and de Vries, Paul S and Liu, Ching-Ti and Rotter, Jerome I and Meigs, James B} } @article {9544, title = {A Type 1 Diabetes Polygenic Score Is Not Associated With Prevalent Type 2 Diabetes in Large Population Studies.}, journal = {J Endocr Soc}, volume = {7}, year = {2023}, month = {2023 Oct 09}, pages = {bvad123}, abstract = {

CONTEXT: Both type 1 diabetes (T1D) and type 2 diabetes (T2D) have significant genetic contributions to risk and understanding their overlap can offer clinical insight.

OBJECTIVE: We examined whether a T1D polygenic score (PS) was associated with a diagnosis of T2D in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

METHODS: We constructed a T1D PS using 79 known single nucleotide polymorphisms associated with T1D risk. We analyzed 13 792 T2D cases and 14 169 controls from CHARGE cohorts to determine the association between the T1D PS and T2D prevalence. We validated findings in an independent sample of 2256 T2D cases and 27 052 controls from the Mass General Brigham Biobank (MGB Biobank). As secondary analyses in 5228 T2D cases from CHARGE, we used multivariable regression models to assess the association of the T1D PS with clinical outcomes associated with T1D.

RESULTS: The T1D PS was not associated with T2D both in CHARGE ( = .15) and in the MGB Biobank ( = .87). The partitioned human leukocyte antigens only PS was associated with T2D in CHARGE (OR 1.02 per 1 SD increase in PS, 95\% CI 1.01-1.03, = .006) but not in the MGB Biobank. The T1D PS was weakly associated with insulin use (OR 1.007, 95\% CI 1.001-1.012, = .03) in CHARGE T2D cases but not with other outcomes.

CONCLUSION: In large biobank samples, a common variant PS for T1D was not consistently associated with prevalent T2D. However, possible heterogeneity in T2D cannot be ruled out and future studies are needed do subphenotyping.

}, issn = {2472-1972}, doi = {10.1210/jendso/bvad123}, author = {Srinivasan, Shylaja and Wu, Peitao and Mercader, Josep M and Udler, Miriam S and Porneala, Bianca C and Bartz, Traci M and Floyd, James S and Sitlani, Colleen and Guo, Xiquing and Haessler, Jeffrey and Kooperberg, Charles and Liu, Jun and Ahmad, Shahzad and van Duijn, Cornelia and Liu, Ching-Ti and Goodarzi, Mark O and Florez, Jose C and Meigs, James B and Rotter, Jerome I and Rich, Stephen S and Dupuis, Jos{\'e}e and Leong, Aaron} } @article {9537, title = {Type 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis.}, journal = {Circ Genom Precis Med}, year = {2023}, month = {2023 Nov 28}, pages = {e004176}, abstract = {

BACKGROUND: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D.

METHODS: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program. We included first-order T2D interaction terms in each model to determine whether CAD loci were modified by T2D. The genetic main and interaction effects were assessed using a joint test to determine whether a CAD variant, or gene-based rare variant set, was associated with the respective subclinical atherosclerosis measures and then further determined whether these loci had a significant interaction test.

RESULTS: Using a Bonferroni-corrected significance threshold of <1.6{\texttimes}10, we identified 3 genes (, , and ) associated with CAC and 2 genes ( and ) associated with carotid intima-media thickness and carotid plaque, respectively, through gene-based rare variant set analysis. Both and also had significantly different associations for CAC in T2D cases versus controls. No significant interaction tests were identified through the candidate single-variant analysis.

CONCLUSIONS: These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.123.004176}, author = {Hasbani, Natalie R and Westerman, Kenneth E and Heon Kwak, Soo and Chen, Han and Li, Xihao and DiCorpo, Daniel and Wessel, Jennifer and Bis, Joshua C and Sarnowski, Chloe and Wu, Peitao and Bielak, Lawrence F and Guo, Xiuqing and Heard-Costa, Nancy and Kinney, Gregory and Mahaney, Michael C and Montasser, May E and Palmer, Nicholette D and Raffield, Laura M and Terry, James G and Yanek, Lisa R and Bon, Jessica and Bowden, Donald W and Brody, Jennifer A and Duggirala, Ravindranath and Jacobs, David R and Kalyani, Rita R and Lange, Leslie A and Mitchell, Braxton D and Smith, Jennifer A and Taylor, Kent D and Carson, April and Curran, Joanne E and Fornage, Myriam and Freedman, Barry I and Gabriel, Stacey and Gibbs, Richard A and Gupta, Namrata and Kardia, Sharon L R and Kral, Brian G and Momin, Zeineen and Newman, Anne B and Post, Wendy S and Viaud-Martinez, Karine A and Young, Kendra A and Becker, Lewis C and Bertoni, Alain and Blangero, John and Carr, John J and Pratte, Katherine and Psaty, Bruce M and Rich, Stephen S and Wu, Joseph C and Malhotra, Rajeev and Peyser, Patricia A and Morrison, Alanna C and Vasan, Ramachandran S and Lin, Xihong and Rotter, Jerome I and Meigs, James B and Manning, Alisa K and de Vries, Paul S} } @article {9449, title = {Whole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles.}, journal = {medRxiv}, year = {2023}, month = {2023 Jun 12}, abstract = {

UNLABELLED: Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole genome sequencing (WGS) data provides better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the NHLBI{\textquoteright}s Trans-Omics for Precision Medicine (TOPMed) program (n=32,572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=131,340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, four are driven by common variants of small effect with reported MAF at least 10\% higher in African populations. Three ( , and signals contain predicted deleterious missense variants. Two loci, and , each harbor two conditionally distinct, non-coding variants. The gene region encoding the protein chain subunits ( ), contains 7 distinct signals, including one novel signal driven by rs28577061, a variant common (MAF=0.180) in African reference panels but extremely rare (MAF=0.008) in Europeans. Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.

KEY POINTS: Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 conditionally distinct variants (20 novel).Sufficient power achieved to identify signal driven by African population variant.Links to (1) liver enzyme, blood cell and lipid genetic signals, (2) liver regulatory elements, and (3) thrombotic and inflammatory disease.

}, doi = {10.1101/2023.06.07.23291095}, author = {Huffman, Jennifer E and Nicolas, Jayna and Hahn, Julie and Heath, Adam S and Raffield, Laura M and Yanek, Lisa R and Brody, Jennifer A and Thibord, Florian and Almasy, Laura and Bartz, Traci M and Bielak, Lawrence F and Bowler, Russell P and Carrasquilla, Germ{\'a}n D and Chasman, Daniel I and Chen, Ming-Huei and Emmert, David B and Ghanbari, Mohsen and Haessle, Jeffery and Hottenga, Jouke-Jan and Kleber, Marcus E and Le, Ngoc-Quynh and Lee, Jiwon and Lewis, Joshua P and Li-Gao, Ruifang and Luan, Jian{\textquoteright}an and Malmberg, Anni and Mangino, Massimo and Marioni, Riccardo E and Martinez-Perez, Angel and Pankratz, Nathan and Polasek, Ozren and Richmond, Anne and Rodriguez, Benjamin At and Rotter, Jerome I and Steri, Maristella and Suchon, Pierre and Trompet, Stella and Weiss, Stefan and Zare, Marjan and Auer, Paul and Cho, Michael H and Christofidou, Paraskevi and Davies, Gail and de Geus, Eco and Deleuze, Jean-Francois and Delgado, Graciela E and Ekunwe, Lynette and Faraday, Nauder and G{\"o}gele, Martin and Greinacher, Andreas and He, Gao and Howard, Tom and Joshi, Peter K and Kilpel{\"a}inen, Tuomas O and Lahti, Jari and Linneberg, Allan and Naitza, Silvia and Noordam, Raymond and Pa{\"u}ls-Verg{\'e}s, Ferran and Rich, Stephen S and Rosendaal, Frits R and Rudan, Igor and Ryan, Kathleen A and Souto, Juan Carlos and van Rooij, Frank Ja and Wang, Heming and Zhao, Wei and Becker, Lewis C and Beswick, Andrew and Brown, Michael R and Cade, Brian E and Campbell, Harry and Cho, Kelly and Crapo, James D and Curran, Joanne E and de Maat, Moniek Pm and Doyle, Margaret and Elliott, Paul and Floyd, James S and Fuchsberger, Christian and Grarup, Niels and Guo, Xiuqing and Harris, Sarah E and Hou, Lifang and Kolcic, Ivana and Kooperberg, Charles and Menni, Cristina and Nauck, Matthias and O{\textquoteright}Connell, Jeffrey R and Orr{\`u}, Valeria and Psaty, Bruce M and R{\"a}ikk{\"o}nen, Katri and Smith, Jennifer A and Soria, Jos{\'e} Manuel and Stott, David J and van Hylckama Vlieg, Astrid and Watkins, Hugh and Willemsen, Gonneke and Wilson, Peter and Ben-Shlomo, Yoav and Blangero, John and Boomsma, Dorret and Cox, Simon R and Dehghan, Abbas and Eriksson, Johan G and Fiorillo, Edoardo and Fornage, Myriam and Hansen, Torben and Hayward, Caroline and Ikram, M Arfan and Jukema, J Wouter and Kardia, Sharon Lr and Lange, Leslie A and M{\"a}rz, Winfried and Mathias, Rasika A and Mitchell, Braxton D and Mook-Kanamori, Dennis O and Morange, Pierre-Emmanuel and Pedersen, Oluf and Pramstaller, Peter P and Redline, Susan and Reiner, Alexander and Ridker, Paul M and Silverman, Edwin K and Spector, Tim D and V{\"o}lker, Uwe and Wareham, Nick and Wilson, James F and Yao, Jie and Tr{\'e}gou{\"e}t, David-Alexandre and Johnson, Andrew D and Wolberg, Alisa S and de Vries, Paul S and Sabater-Lleal, Maria and Morrison, Alanna C and Smith, Nicholas L} } @article {9581, title = {Whole genome sequence analysis of apparent treatment resistant hypertension status in participants from the Trans-Omics for Precision Medicine program.}, journal = {Front Genet}, volume = {14}, year = {2023}, month = {2023}, pages = {1278215}, abstract = {

Apparent treatment-resistant hypertension (aTRH) is characterized by the use of four or more antihypertensive (AHT) classes to achieve blood pressure (BP) control. In the current study, we conducted single-variant and gene-based analyses of aTRH among individuals from 12 Trans-Omics for Precision Medicine cohorts with whole-genome sequencing data. Cases were defined as individuals treated for hypertension (HTN) taking three different AHT classes, with average systolic BP >= 140 or diastolic BP >= 90~mmHg, or four or more medications regardless of BP ( = 1,705). A normotensive control group was defined as individuals with BP < 140/90~mmHg ( = 22,079), not on AHT medication. A second control group comprised individuals who were treatment responsive on one AHT medication with BP < 140/ 90~mmHg ( = 5,424). Logistic regression with kinship adjustment using the Scalable and Accurate Implementation of Generalized mixed models (SAIGE) was performed, adjusting for age, sex, and genetic ancestry. We assessed variants using SKAT-O in rare-variant analyses. Single-variant and gene-based tests were conducted in a pooled multi-ethnicity stratum, as well as self-reported ethnic/racial strata (European and African American). One variant in the known HTN locus, , was a top finding in the multi-ethnic analysis ( = 8.23E-07) for the normotensive control group [rs12476527, odds ratio (95\% confidence interval) = 0.80 (0.74-0.88)]. This variant was replicated in the Vanderbilt University Medical Center{\textquoteright}s DNA repository data. Aggregate gene-based signals included the genes and . Additional work validating these loci in larger, more diverse populations, is warranted to determine whether these regions influence the pathobiology of aTRH.

}, issn = {1664-8021}, doi = {10.3389/fgene.2023.1278215}, author = {Armstrong, Nicole D and Srinivasasainagendra, Vinodh and Ammous, Farah and Assimes, Themistocles L and Beitelshees, Amber L and Brody, Jennifer and Cade, Brian E and Ida Chen, Yii-Der and Chen, Han and de Vries, Paul S and Floyd, James S and Franceschini, Nora and Guo, Xiuqing and Hellwege, Jacklyn N and House, John S and Hwu, Chii-Min and Kardia, Sharon L R and Lange, Ethan M and Lange, Leslie A and McDonough, Caitrin W and Montasser, May E and O{\textquoteright}Connell, Jeffrey R and Shuey, Megan M and Sun, Xiao and Tanner, Rikki M and Wang, Zhe and Zhao, Wei and Carson, April P and Edwards, Todd L and Kelly, Tanika N and Kenny, Eimear E and Kooperberg, Charles and Loos, Ruth J F and Morrison, Alanna C and Motsinger-Reif, Alison and Psaty, Bruce M and Rao, Dabeeru C and Redline, Susan and Rich, Stephen S and Rotter, Jerome I and Smith, Jennifer A and Smith, Albert V and Irvin, Marguerite R and Arnett, Donna K} } @article {9484, title = {WHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE.}, journal = {medRxiv}, year = {2023}, month = {2023 Aug 22}, abstract = {

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51\% were of non-European population groups. We discovered 18 BMI-associated signals ( < 5 {\texttimes} 10 ). Notably, we identified and replicated a novel low frequency single nucleotide polymorphism (SNP) in that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the and loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.

}, doi = {10.1101/2023.08.21.23293271}, author = {Zhang, Xinruo and Brody, Jennifer A and Graff, Mariaelisa and Highland, Heather M and Chami, Nathalie and Xu, Hanfei and Wang, Zhe and Ferrier, Kendra and Chittoor, Geetha and Josyula, Navya S and Li, Xihao and Li, Zilin and Allison, Matthew A and Becker, Diane M and Bielak, Lawrence F and Bis, Joshua C and Boorgula, Meher Preethi and Bowden, Donald W and Broome, Jai G and Buth, Erin J and Carlson, Christopher S and Chang, Kyong-Mi and Chavan, Sameer and Chiu, Yen-Feng and Chuang, Lee-Ming and Conomos, Matthew P and DeMeo, Dawn L and Du, Margaret and Duggirala, Ravindranath and Eng, Celeste and Fohner, Alison E and Freedman, Barry I and Garrett, Melanie E and Guo, Xiuqing and Haiman, Chris and Heavner, Benjamin D and Hidalgo, Bertha and Hixson, James E and Ho, Yuk-Lam and Hobbs, Brian D and Hu, Donglei and Hui, Qin and Hwu, Chii-Min and Jackson, Rebecca D and Jain, Deepti and Kalyani, Rita R and Kardia, Sharon L R and Kelly, Tanika N and Lange, Ethan M and LeNoir, Michael and Li, Changwei and Marchand, Loic Le and McDonald, Merry-Lynn N and McHugh, Caitlin P and Morrison, Alanna C and Naseri, Take and O{\textquoteright}Connell, Jeffrey and O{\textquoteright}Donnell, Christopher J and Palmer, Nicholette D and Pankow, James S and Perry, James A and Peters, Ulrike and Preuss, Michael H and Rao, D C and Regan, Elizabeth A and Reupena, Sefuiva M and Roden, Dan M and Rodriguez-Santana, Jose and Sitlani, Colleen M and Smith, Jennifer A and Tiwari, Hemant K and Vasan, Ramachandran S and Wang, Zeyuan and Weeks, Daniel E and Wessel, Jennifer and Wiggins, Kerri L and Wilkens, Lynne R and Wilson, Peter W F and Yanek, Lisa R and Yoneda, Zachary T and Zhao, Wei and Z{\"o}llner, Sebastian and Arnett, Donna K and Ashley-Koch, Allison E and Barnes, Kathleen C and Blangero, John and Boerwinkle, Eric and Burchard, Esteban G and Carson, April P and Chasman, Daniel I and Chen, Yii-Der Ida and Curran, Joanne E and Fornage, Myriam and Gordeuk, Victor R and He, Jiang and Heckbert, Susan R and Hou, Lifang and Irvin, Marguerite R and Kooperberg, Charles and Minster, Ryan L and Mitchell, Braxton D and Nouraie, Mehdi and Psaty, Bruce M and Raffield, Laura M and Reiner, Alexander P and Rich, Stephen S and Rotter, Jerome I and Shoemaker, M Benjamin and Smith, Nicholas L and Taylor, Kent D and Telen, Marilyn J and Weiss, Scott T and Zhang, Yingze and Costa, Nancy Heard- and Sun, Yan V and Lin, Xihong and Cupples, L Adrienne and Lange, Leslie A and Liu, Ching-Ti and Loos, Ruth J F and North, Kari E and Justice, Anne E} } @article {9500, title = {Whole Genome Sequencing Based Analysis of Inflammation Biomarkers in the Trans-Omics for Precision Medicine (TOPMed) Consortium.}, journal = {bioRxiv}, year = {2023}, month = {2023 Sep 12}, abstract = {

Inflammation biomarkers can provide valuable insight into the role of inflammatory processes in many diseases and conditions. Sequencing based analyses of such biomarkers can also serve as an exemplar of the genetic architecture of quantitative traits. To evaluate the biological insight, which can be provided by a multi-ancestry, whole-genome based association study, we performed a comprehensive analysis of 21 inflammation biomarkers from up to 38,465 individuals with whole-genome sequencing from the Trans-Omics for Precision Medicine (TOPMed) program. We identified 22 distinct single-variant associations across 6 traits - E-selectin, intercellular adhesion molecule 1, interleukin-6, lipoprotein-associated phospholipase A2 activity and mass, and P-selectin - that remained significant after conditioning on previously identified associations for these inflammatory biomarkers. We further expanded upon known biomarker associations by pairing the single-variant analysis with a rare variant set-based analysis that further identified 19 significant rare variant set-based associations with 5 traits. These signals were distinct from both significant single variant association signals within TOPMed and genetic signals observed in prior studies, demonstrating the complementary value of performing both single and rare variant analyses when analyzing quantitative traits. We also confirm several previously reported signals from semi-quantitative proteomics platforms. Many of these signals demonstrate the extensive allelic heterogeneity and ancestry-differentiated variant-trait associations common for inflammation biomarkers, a characteristic we hypothesize will be increasingly observed with well-powered, large-scale analyses of complex traits.

}, doi = {10.1101/2023.09.10.555215}, author = {Jiang, Min-Zhi and Gaynor, Sheila M and Li, Xihao and Van Buren, Eric and Stilp, Adrienne and Buth, Erin and Wang, Fei Fei and Manansala, Regina and Gogarten, Stephanie M and Li, Zilin and Polfus, Linda M and Salimi, Shabnam and Bis, Joshua C and Pankratz, Nathan and Yanek, Lisa R and Durda, Peter and Tracy, Russell P and Rich, Stephen S and Rotter, Jerome I and Mitchell, Braxton D and Lewis, Joshua P and Psaty, Bruce M and Pratte, Katherine A and Silverman, Edwin K and Kaplan, Robert C and Avery, Christy and North, Kari and Mathias, Rasika A and Faraday, Nauder and Lin, Honghuang and Wang, Biqi and Carson, April P and Norwood, Arnita F and Gibbs, Richard A and Kooperberg, Charles and Lundin, Jessica and Peters, Ulrike and Dupuis, Jos{\'e}e and Hou, Lifang and Fornage, Myriam and Benjamin, Emelia J and Reiner, Alexander P and Bowler, Russell P and Lin, Xihong and Auer, Paul L and Raffield, Laura M} } @article {9580, title = {Association analysis of mitochondrial DNA heteroplasmic variants: methods and application.}, journal = {medRxiv}, year = {2024}, month = {2024 Jan 13}, abstract = {

We rigorously assessed a comprehensive association testing framework for heteroplasmy, employing both simulated and real-world data. This framework employed a variant allele fraction (VAF) threshold and harnessed multiple gene-based tests for robust identification and association testing of heteroplasmy. Our simulation studies demonstrated that gene-based tests maintained an appropriate type I error rate at α=0.001. Notably, when 5\% or more heteroplasmic variants within a target region were linked to an outcome, burden-extension tests (including the adaptive burden test, variable threshold burden test, and z-score weighting burden test) outperformed the sequence kernel association test (SKAT) and the original burden test. Applying this framework, we conducted association analyses on whole-blood derived heteroplasmy in 17,507 individuals of African and European ancestries (31\% of African Ancestry, mean age of 62, with 58\% women) with whole genome sequencing data. We performed both cohort- and ancestry-specific association analyses, followed by meta-analysis on bothpooled samples and within each ancestry group. Our results suggest that mtDNA-Enco ded genes/regions are likely to exhibit varying rates in somatic aging, with the notably strong associations observed between heteroplasmy in the and genes ( <0.001) and advance aging by the Original Burden test. In contrast, SKAT identified significant associations ( <0.001) between diabetes and the aggregated effects of heteroplasmy in several protein-coding genes. Further research is warranted to validate these findings. In summary, our proposed statistical framework represents a valuable tool for facilitating association testing of heteroplasmy with disease traits in large human populations.

}, doi = {10.1101/2024.01.12.24301233}, author = {Sun, Xianbang and Bulekova, Katia and Yang, Jian and Lai, Meng and Pitsillides, Achilleas N and Liu, Xue and Zhang, Yuankai and Guo, Xiuqing and Yong, Qian and Raffield, Laura M and Rotter, Jerome I and Rich, Stephen S and Abecasis, Goncalo and Carson, April P and Vasan, Ramachandran S and Bis, Joshua C and Psaty, Bruce M and Boerwinkle, Eric and Fitzpatrick, Annette L and Satizabal, Claudia L and Arking, Dan E and Ding, Jun and Levy, Daniel and Liu, Chunyu} } @article {9620, title = {Familial Hypercholesterolemia Variant and Cardiovascular Risk in Individuals With Elevated Cholesterol.}, journal = {JAMA Cardiol}, year = {2024}, month = {2024 Jan 31}, abstract = {

IMPORTANCE: Familial hypercholesterolemia (FH) is a genetic disorder that often results in severely high low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease (CHD). However, the impact of FH variants on CHD risk among individuals with moderately elevated LDL-C is not well quantified.

OBJECTIVE: To assess CHD risk associated with FH variants among individuals with moderately (130-189 mg/dL) and severely (>=190 mg/dL) elevated LDL-C and to quantify excess CHD deaths attributable to FH variants in US adults.

DESIGN, SETTING, AND PARTICIPANTS: A total of 21 426 individuals without preexisting CHD from 6 US cohort studies (Atherosclerosis Risk in Communities study, Coronary Artery Risk Development in Young Adults study, Cardiovascular Health Study, Framingham Heart Study Offspring cohort, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis) were included, 63 of whom had an FH variant. Data were collected from 1971 to 2018, and the median (IQR) follow-up was 18 (13-28) years. Data were analyzed from March to May 2023.

EXPOSURES: LDL-C, cumulative past LDL-C, FH variant status.

MAIN OUTCOMES AND MEASURES: Cox proportional hazards models estimated associations between FH variants and incident CHD. The Cardiovascular Disease Policy Model projected excess CHD deaths associated with FH variants in US adults.

RESULTS: Of the 21 426 individuals without preexisting CHD (mean [SD] age 52.1 [15.5] years; 12 041 [56.2\%] female), an FH variant was found in 22 individuals with moderately elevated LDL-C (0.3\%) and in 33 individuals with severely elevated LDL-C (2.5\%). The adjusted hazard ratios for incident CHD comparing those with and without FH variants were 2.9 (95\% CI, 1.4-6.0) and 2.6 (95\% CI, 1.4-4.9) among individuals with moderately and severely elevated LDL-C, respectively. The association between FH variants and CHD was slightly attenuated when further adjusting for baseline LDL-C level, whereas the association was no longer statistically significant after adjusting for cumulative past LDL-C exposure. Among US adults 20 years and older with no history of CHD and LDL-C 130 mg/dL or higher, more than 417 000 carry an FH variant and were projected to experience more than 12 000 excess CHD deaths in those with moderately elevated LDL-C and 15 000 in those with severely elevated LDL-C compared with individuals without an FH variant.

CONCLUSIONS AND RELEVANCE: In this pooled cohort study, the presence of FH variants was associated with a 2-fold higher CHD risk, even when LDL-C was only moderately elevated. The increased CHD risk appeared to be largely explained by the higher cumulative LDL-C exposure in individuals with an FH variant compared to those without. Further research is needed to assess the value of adding genetic testing to traditional phenotypic FH screening.

}, issn = {2380-6591}, doi = {10.1001/jamacardio.2023.5366}, author = {Zhang, Yiyi and Dron, Jacqueline S and Bellows, Brandon K and Khera, Amit V and Liu, Junxiu and Balte, Pallavi P and Oelsner, Elizabeth C and Amr, Sami Samir and Lebo, Matthew S and Nagy, Anna and Peloso, Gina M and Natarajan, Pradeep and Rotter, Jerome I and Willer, Cristen and Boerwinkle, Eric and Ballantyne, Christie M and Lutsey, Pamela L and Fornage, Myriam and Lloyd-Jones, Donald M and Hou, Lifang and Psaty, Bruce M and Bis, Joshua C and Floyd, James S and Vasan, Ramachandran S and Heard-Costa, Nancy L and Carson, April P and Hall, Michael E and Rich, Stephen S and Guo, Xiuqing and Kazi, Dhruv S and de Ferranti, Sarah D and Moran, Andrew E} } @article {9619, title = {Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.}, journal = {Nature}, year = {2024}, month = {2024 Feb 19}, abstract = {

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes and molecular mechanisms that are often specific to cell type. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7\% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 {\texttimes} 10) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

}, issn = {1476-4687}, doi = {10.1038/s41586-024-07019-6}, author = {Suzuki, Ken and Hatzikotoulas, Konstantinos and Southam, Lorraine and Taylor, Henry J and Yin, Xianyong and Lorenz, Kim M and Mandla, Ravi and Huerta-Chagoya, Alicia and Melloni, Giorgio E M and Kanoni, Stavroula and Rayner, Nigel W and Bocher, Ozvan and Arruda, Ana Luiza and Sonehara, Kyuto and Namba, Shinichi and Lee, Simon S K and Preuss, Michael H and Petty, Lauren E and Schroeder, Philip and Vanderwerff, Brett and Kals, Mart and Bragg, Fiona and Lin, Kuang and Guo, Xiuqing and Zhang, Weihua and Yao, Jie and Kim, Young Jin and Graff, Mariaelisa and Takeuchi, Fumihiko and Nano, Jana and Lamri, Amel and Nakatochi, Masahiro and Moon, Sanghoon and Scott, Robert A and Cook, James P and Lee, Jung-Jin and Pan, Ian and Taliun, Daniel and Parra, Esteban J and Chai, Jin-Fang and Bielak, Lawrence F and Tabara, Yasuharu and Hai, Yang and Thorleifsson, Gudmar and Grarup, Niels and Sofer, Tamar and Wuttke, Matthias and Sarnowski, Chloe and Gieger, Christian and Nousome, Darryl and Trompet, Stella and Kwak, Soo-Heon and Long, Jirong and Sun, Meng and Tong, Lin and Chen, Wei-Min and Nongmaithem, Suraj S and Noordam, Raymond and Lim, Victor J Y and Tam, Claudia H T and Joo, Yoonjung Yoonie and Chen, Chien-Hsiun and Raffield, Laura M and Prins, Bram Peter and Nicolas, Aude and Yanek, Lisa R and Chen, Guanjie and Brody, Jennifer A and Kabagambe, Edmond and An, Ping and Xiang, Anny H and Choi, Hyeok Sun and Cade, Brian E and Tan, Jingyi and Broadaway, K Alaine and Williamson, Alice and Kamali, Zoha and Cui, Jinrui and Thangam, Manonanthini and Adair, Linda S and Adeyemo, Adebowale and Aguilar-Salinas, Carlos A and Ahluwalia, Tarunveer S and Anand, Sonia S and Bertoni, Alain and Bork-Jensen, Jette and Brandslund, Ivan and Buchanan, Thomas A and Burant, Charles F and Butterworth, Adam S and Canouil, Micka{\"e}l and Chan, Juliana C N and Chang, Li-Ching and Chee, Miao-Li and Chen, Ji and Chen, Shyh-Huei and Chen, Yuan-Tsong and Chen, Zhengming and Chuang, Lee-Ming and Cushman, Mary and Danesh, John and Das, Swapan K and de Silva, H Janaka and Dedoussis, George and Dimitrov, Latchezar and Doumatey, Ayo P and Du, Shufa and Duan, Qing and Eckardt, Kai-Uwe and Emery, Leslie S and Evans, Daniel S and Evans, Michele K and Fischer, Krista and Floyd, James S and Ford, Ian and Franco, Oscar H and Frayling, Timothy M and Freedman, Barry I and Genter, Pauline and Gerstein, Hertzel C and Giedraitis, Vilmantas and Gonz{\'a}lez-Villalpando, Clicerio and Gonzalez-Villalpando, Maria Elena and Gordon-Larsen, Penny and Gross, Myron and Guare, Lindsay A and Hackinger, Sophie and Hakaste, Liisa and Han, Sohee and Hattersley, Andrew T and Herder, Christian and Horikoshi, Momoko and Howard, Annie-Green and Hsueh, Willa and Huang, Mengna and Huang, Wei and Hung, Yi-Jen and Hwang, Mi Yeong and Hwu, Chii-Min and Ichihara, Sahoko and Ikram, Mohammad Arfan and Ingelsson, Martin and Islam, Md Tariqul and Isono, Masato and Jang, Hye-Mi and Jasmine, Farzana and Jiang, Guozhi and Jonas, Jost B and J{\o}rgensen, Torben and Kamanu, Frederick K and Kandeel, Fouad R and Kasturiratne, Anuradhani and Katsuya, Tomohiro and Kaur, Varinderpal and Kawaguchi, Takahisa and Keaton, Jacob M and Kho, Abel N and Khor, Chiea-Chuen and Kibriya, Muhammad G and Kim, Duk-Hwan and Kronenberg, Florian and Kuusisto, Johanna and L{\"a}ll, Kristi and Lange, Leslie A and Lee, Kyung Min and Lee, Myung-Shik and Lee, Nanette R and Leong, Aaron and Li, Liming and Li, Yun and Li-Gao, Ruifang and Ligthart, Symen and Lindgren, Cecilia M and Linneberg, Allan and Liu, Ching-Ti and Liu, Jianjun and Locke, Adam E and Louie, Tin and Luan, Jian{\textquoteright}an and Luk, Andrea O and Luo, Xi and Lv, Jun and Lynch, Julie A and Lyssenko, Valeriya and Maeda, Shiro and Mamakou, Vasiliki and Mansuri, Sohail Rafik and Matsuda, Koichi and Meitinger, Thomas and Melander, Olle and Metspalu, Andres and Mo, Huan and Morris, Andrew D and Moura, Filipe A and Nadler, Jerry L and Nalls, Michael A and Nayak, Uma and Ntalla, Ioanna and Okada, Yukinori and Orozco, Lorena and Patel, Sanjay R and Patil, Snehal and Pei, Pei and Pereira, Mark A and Peters, Annette and Pirie, Fraser J and Polikowsky, Hannah G and Porneala, Bianca and Prasad, Gauri and Rasmussen-Torvik, Laura J and Reiner, Alexander P and Roden, Michael and Rohde, Rebecca and Roll, Katheryn and Sabanayagam, Charumathi and Sandow, Kevin and Sankareswaran, Alagu and Sattar, Naveed and Sch{\"o}nherr, Sebastian and Shahriar, Mohammad and Shen, Botong and Shi, Jinxiu and Shin, Dong Mun and Shojima, Nobuhiro and Smith, Jennifer A and So, Wing Yee and Stan{\v c}{\'a}kov{\'a}, Alena and Steinthorsdottir, Valgerdur and Stilp, Adrienne M and Strauch, Konstantin and Taylor, Kent D and Thorand, Barbara and Thorsteinsdottir, Unnur and Tomlinson, Brian and Tran, Tam C and Tsai, Fuu-Jen and Tuomilehto, Jaakko and Tusi{\'e}-Luna, Teresa and Udler, Miriam S and Valladares-Salgado, Adan and van Dam, Rob M and van Klinken, Jan B and Varma, Rohit and Wacher-Rodarte, Niels and Wheeler, Eleanor and Wickremasinghe, Ananda R and van Dijk, Ko Willems and Witte, Daniel R and Yajnik, Chittaranjan S and Yamamoto, Ken and Yamamoto, Kenichi and Yoon, Kyungheon and Yu, Canqing and Yuan, Jian-Min and Yusuf, Salim and Zawistowski, Matthew and Zhang, Liang and Zheng, Wei and Raffel, Leslie J and Igase, Michiya and Ipp, Eli and Redline, Susan and Cho, Yoon Shin and Lind, Lars and Province, Michael A and Fornage, Myriam and Hanis, Craig L and Ingelsson, Erik and Zonderman, Alan B and Psaty, Bruce M and Wang, Ya-Xing and Rotimi, Charles N and Becker, Diane M and Matsuda, Fumihiko and Liu, Yongmei and Yokota, Mitsuhiro and Kardia, Sharon L R and Peyser, Patricia A and Pankow, James S and Engert, James C and Bonnefond, Am{\'e}lie and Froguel, Philippe and Wilson, James G and Sheu, Wayne H H and Wu, Jer-Yuarn and Hayes, M Geoffrey and Ma, Ronald C W and Wong, Tien-Yin and Mook-Kanamori, Dennis O and Tuomi, Tiinamaija and Chandak, Giriraj R and Collins, Francis S and Bharadwaj, Dwaipayan and Par{\'e}, Guillaume and Sale, Mich{\`e}le M and Ahsan, Habibul and Motala, Ayesha A and Shu, Xiao-Ou and Park, Kyong-Soo and Jukema, J Wouter and Cruz, Miguel and Chen, Yii-Der Ida and Rich, Stephen S and McKean-Cowdin, Roberta and Grallert, Harald and Cheng, Ching-Yu and Ghanbari, Mohsen and Tai, E-Shyong and Dupuis, Jos{\'e}e and Kato, Norihiro and Laakso, Markku and K{\"o}ttgen, Anna and Koh, Woon-Puay and Bowden, Donald W and Palmer, Colin N A and Kooner, Jaspal S and Kooperberg, Charles and Liu, Simin and North, Kari E and Saleheen, Danish and Hansen, Torben and Pedersen, Oluf and Wareham, Nicholas J and Lee, Juyoung and Kim, Bong-Jo and Millwood, Iona Y and Walters, Robin G and Stefansson, Kari and Ahlqvist, Emma and Goodarzi, Mark O and Mohlke, Karen L and Langenberg, Claudia and Haiman, Christopher A and Loos, Ruth J F and Florez, Jose C and Rader, Daniel J and Ritchie, Marylyn D and Z{\"o}llner, Sebastian and M{\"a}gi, Reedik and Marston, Nicholas A and Ruff, Christian T and van Heel, David A and Finer, Sarah and Denny, Joshua C and Yamauchi, Toshimasa and Kadowaki, Takashi and Chambers, John C and Ng, Maggie C Y and Sim, Xueling and Below, Jennifer E and Tsao, Philip S and Chang, Kyong-Mi and McCarthy, Mark I and Meigs, James B and Mahajan, Anubha and Spracklen, Cassandra N and Mercader, Josep M and Boehnke, Michael and Rotter, Jerome I and Vujkovic, Marijana and Voight, Benjamin F and Morris, Andrew P and Zeggini, Eleftheria} } @article {9642, title = {A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations.}, journal = {medRxiv}, year = {2024}, month = {2024 Mar 08}, abstract = {

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to genes involved in neurological, thyroidal, bone metabolism, and hematopoietic pathways. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausibility of distinct influences of both sleep duration extremes in cardiovascular health. With several of our loci reflecting specificity towards population background or sex, our discovery sheds light on the importance of embracing granularity when addressing heterogeneity entangled in gene-environment interactions, and in therapeutic design approaches for blood pressure management.

}, doi = {10.1101/2024.03.07.24303870}, author = {Nagarajan, Pavithra and Winkler, Thomas W and Bentley, Amy R and Miller, Clint L and Kraja, Aldi T and Schwander, Karen and Lee, Songmi and Wang, Wenyi and Brown, Michael R and Morrison, John L and Giri, Ayush and O{\textquoteright}Connell, Jeffrey R and Bartz, Traci M and de Las Fuentes, Lisa and Gudmundsdottir, Valborg and Guo, Xiuqing and Harris, Sarah E and Huang, Zhijie and Kals, Mart and Kho, Minjung and Lefevre, Christophe and Luan, Jian{\textquoteright}an and Lyytik{\"a}inen, Leo-Pekka and Mangino, Massimo and Milaneschi, Yuri and Palmer, Nicholette D and Rao, Varun and Rauramaa, Rainer and Shen, Botong and Stadler, Stefan and Sun, Quan and Tang, Jingxian and Th{\'e}riault, S{\'e}bastien and van der Graaf, Adriaan and van der Most, Peter J and Wang, Yujie and Weiss, Stefan and Westerman, Kenneth E and Yang, Qian and Yasuharu, Tabara and Zhao, Wei and Zhu, Wanying and Altschul, Drew and Ansari, Md Abu Yusuf and Anugu, Pramod and Argoty-Pantoja, Anna D and Arzt, Michael and Aschard, Hugues and Attia, John R and Bazzanno, Lydia and Breyer, Max A and Brody, Jennifer A and Cade, Brian E and Chen, Hung-Hsin and Ida Chen, Yii-Der and Chen, Zekai and de Vries, Paul S and Dimitrov, Latchezar M and Do, Anh and Du, Jiawen and Dupont, Charles T and Edwards, Todd L and Evans, Michele K and Faquih, Tariq and Felix, Stephan B and Fisher-Hoch, Susan P and Floyd, James S and Graff, Mariaelisa and Gu, Charles and Gu, Dongfeng and Hairston, Kristen G and Hanley, Anthony J and Heid, Iris M and Heikkinen, Sami and Highland, Heather M and Hood, Michelle M and K{\"a}h{\"o}nen, Mika and Karvonen-Gutierrez, Carrie A and Kawaguchi, Takahisa and Kazuya, Setoh and Kelly, Tanika N and Komulainen, Pirjo and Levy, Daniel and Lin, Henry J and Liu, Peter Y and Marques-Vidal, Pedro and McCormick, Joseph B and Mei, Hao and Meigs, James B and Menni, Cristina and Nam, Kisung and Nolte, Ilja M and Pacheco, Natasha L and Petty, Lauren E and Polikowsky, Hannah G and Province, Michael A and Psaty, Bruce M and Raffield, Laura M and Raitakari, Olli T and Rich, Stephen S and Riha, Renata L and Risch, Lorenz and Risch, Martin and Ruiz-Narvaez, Edward A and Scott, Rodney J and Sitlani, Colleen M and Smith, Jennifer A and Sofer, Tamar and Teder-Laving, Maris and V{\"o}lker, Uwe and Vollenweider, Peter and Wang, Guanchao and van Dijk, Ko Willems and Wilson, Otis D and Xia, Rui and Yao, Jie and Young, Kristin L and Zhang, Ruiyuan and Zhu, Xiaofeng and Below, Jennifer E and B{\"o}ger, Carsten A and Conen, David and Cox, Simon R and D{\"o}rr, Marcus and Feitosa, Mary F and Fox, Ervin R and Franceschini, Nora and Gharib, Sina A and Gudnason, Vilmundur and Harlow, Sioban D and He, Jiang and Holliday, Elizabeth G and Kutalik, Zolt{\'a}n and Lakka, Timo A and Lawlor, Deborah A and Lee, Seunggeun and Lehtim{\"a}ki, Terho and Li, Changwei and Liu, Ching-Ti and M{\"a}gi, Reedik and Matsuda, Fumihiko and Morrison, Alanna C and Penninx, Brenda Wjh and Peyser, Patricia A and Rotter, Jerome I and Snieder, Harold and Spector, Tim D and Wagenknecht, Lynne E and Wareham, Nicholas J and Zonderman, Alan B and North, Kari E and Fornage, Myriam and Hung, Adriana M and Manning, Alisa K and Gauderman, James and Chen, Han and Munroe, Patricia B and Rao, Dabeeru C and van Heemst, Diana and Redline, Susan and Noordam, Raymond and Wang, Heming} } @article {9646, title = {Methylation patterns associated with C-reactive protein in racially and ethnically diverse populations.}, journal = {Epigenetics}, volume = {19}, year = {2024}, month = {2024 Dec}, pages = {2333668}, abstract = {

Systemic low-grade inflammation is a feature of chronic disease. C-reactive protein (CRP) is a common biomarker of inflammation and used as an indicator of disease risk; however, the role of inflammation in disease is not completely understood. Methylation is an epigenetic modification in the DNA which plays a pivotal role in gene expression. In this study we evaluated differential DNA methylation patterns associated with blood CRP level to elucidate biological pathways and genetic regulatory mechanisms to improve the understanding of chronic inflammation. The racially and ethnically diverse participants in this study were included as 50\% White, 41\% Black or African American, 7\% Hispanic or Latino/a, and 2\% Native Hawaiian, Asian American, American Indian, or Alaska Native (total = 13,433) individuals. We replicated 113 CpG sites from 87 unique loci, of which five were novel (, , and cg03282312), across a discovery set of 1,150 CpG sites associated with CRP level ( < 1.2E-7). The downstream pathways affected by DNA methylation included the identification of and CpG-gene transcript pairs which contributed to the innate immune response gene enrichment pathway along with , , and . Gene enrichment analysis also identified the nuclear factor-kappaB transcription pathway. Using two-sample Mendelian randomization (MR) we inferred methylation at three CpG sites as causal for CRP levels using both White and Black or African American MR instrument variables. Overall, we identified novel CpG sites and gene transcripts that could be valuable in understanding the specific cellular processes and pathogenic mechanisms involved in inflammation.

}, keywords = {C-Reactive Protein, CpG Islands, DNA, DNA Methylation, Epigenesis, Genetic, Genome-Wide Association Study, Humans, Inflammation, Intracellular Signaling Peptides and Proteins}, issn = {1559-2308}, doi = {10.1080/15592294.2024.2333668}, author = {Lundin, Jessica I and Peters, Ulrike and Hu, Yao and Ammous, Farah and Avery, Christy L and Benjamin, Emelia J and Bis, Joshua C and Brody, Jennifer A and Carlson, Chris and Cushman, Mary and Gignoux, Chris and Guo, Xiuqing and Haessler, Jeff and Haiman, Chris and Joehanes, Roby and Kasela, Silva and Kenny, Eimear and Lapalainien, Tuuli and Levy, Daniel and Liu, Chunyu and Liu, Yongmei and Loos, Ruth J F and Lu, Ake and Matise, Tara and North, Kari E and Park, Sungshim L and Ratliff, Scott M and Reiner, Alex and Rich, Stephen S and Rotter, Jerome I and Smith, Jennifer A and Sotoodehnia, Nona and Tracy, Russell and Van den Berg, David and Xu, Huichun and Ye, Ting and Zhao, Wei and Raffield, Laura M and Kooperberg, Charles} }