@article {1150, title = {Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Jan}, pages = {45-52}, abstract = {

Spirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV(1)) and its ratio to forced vital capacity (FEV(1)/FVC), an indicator of airflow obstruction. This meta-analysis included 20,890 participants of European ancestry from four CHARGE Consortium studies: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study and Rotterdam Study. We identified eight loci associated with FEV(1)/FVC (HHIP, GPR126, ADAM19, AGER-PPT2, FAM13A, PTCH1, PID1 and HTR4) and one locus associated with FEV(1) (INTS12-GSTCD-NPNT) at or near genome-wide significance (P < 5 x 10(-8)) in the CHARGE Consortium dataset. Our findings may offer insights into pulmonary function and pathogenesis of chronic lung disease.

}, keywords = {Databases, Genetic, Female, Forced Expiratory Volume, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Lung, Lung Diseases, Male, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Spirometry, Vital Capacity}, issn = {1546-1718}, doi = {10.1038/ng.500}, author = {Hancock, Dana B and Eijgelsheim, Mark and Wilk, Jemma B and Gharib, Sina A and Loehr, Laura R and Marciante, Kristin D and Franceschini, Nora and van Durme, Yannick M T A and Chen, Ting-Hsu and Barr, R Graham and Schabath, Matthew B and Couper, David J and Brusselle, Guy G and Psaty, Bruce M and van Duijn, Cornelia M and Rotter, Jerome I and Uitterlinden, Andr{\'e} G and Hofman, Albert and Punjabi, Naresh M and Rivadeneira, Fernando and Morrison, Alanna C and Enright, Paul L and North, Kari E and Heckbert, Susan R and Lumley, Thomas and Stricker, Bruno H C and O{\textquoteright}Connor, George T and London, Stephanie J} } @article {1325, title = {Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.}, journal = {Nature}, volume = {478}, year = {2011}, month = {2011 Sep 11}, pages = {103-9}, abstract = {

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>=140 mm Hg systolic blood pressure or >=90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

}, keywords = {Africa, Asia, Blood Pressure, Cardiovascular Diseases, Coronary Artery Disease, Europe, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hypertension, Kidney Diseases, Polymorphism, Single Nucleotide, Stroke}, issn = {1476-4687}, doi = {10.1038/nature10405}, author = {Ehret, Georg B and Munroe, Patricia B and Rice, Kenneth M and Bochud, Murielle and Johnson, Andrew D and Chasman, Daniel I and Smith, Albert V and Tobin, Martin D and Verwoert, Germaine C and Hwang, Shih-Jen and Pihur, Vasyl and Vollenweider, Peter and O{\textquoteright}Reilly, Paul F and Amin, Najaf and Bragg-Gresham, Jennifer L and Teumer, Alexander and Glazer, Nicole L and Launer, Lenore and Zhao, Jing Hua and Aulchenko, Yurii and Heath, Simon and S{\~o}ber, Siim and Parsa, Afshin and Luan, Jian{\textquoteright}an and Arora, Pankaj and Dehghan, Abbas and Zhang, Feng and Lucas, Gavin and Hicks, Andrew A and Jackson, Anne U and Peden, John F and Tanaka, Toshiko and Wild, Sarah H and Rudan, Igor and Igl, Wilmar and Milaneschi, Yuri and Parker, Alex N and Fava, Cristiano and Chambers, John C and Fox, Ervin R and Kumari, Meena and Go, Min Jin and van der Harst, Pim and Kao, Wen Hong Linda and Sj{\"o}gren, Marketa and Vinay, D G and Alexander, Myriam and Tabara, Yasuharu and Shaw-Hawkins, Sue and Whincup, Peter H and Liu, Yongmei and Shi, Gang and Kuusisto, Johanna and Tayo, Bamidele and Seielstad, Mark and Sim, Xueling and Nguyen, Khanh-Dung Hoang and Lehtim{\"a}ki, Terho and Matullo, Giuseppe and Wu, Ying and Gaunt, Tom R and Onland-Moret, N Charlotte and Cooper, Matthew N and Platou, Carl G P and Org, Elin and Hardy, Rebecca and Dahgam, Santosh and Palmen, Jutta and Vitart, Veronique and Braund, Peter S and Kuznetsova, Tatiana and Uiterwaal, Cuno S P M and Adeyemo, Adebowale and Palmas, Walter and Campbell, Harry and Ludwig, Barbara and Tomaszewski, Maciej and Tzoulaki, Ioanna and Palmer, Nicholette D and Aspelund, Thor and Garcia, Melissa and Chang, Yen-Pei C and O{\textquoteright}Connell, Jeffrey R and Steinle, Nanette I and Grobbee, Diederick E and Arking, Dan E and Kardia, Sharon L and Morrison, Alanna C and Hernandez, Dena and Najjar, Samer and McArdle, Wendy L and Hadley, David and Brown, Morris J and Connell, John M and Hingorani, Aroon D and Day, Ian N M and Lawlor, Debbie A and Beilby, John P and Lawrence, Robert W and Clarke, Robert and Hopewell, Jemma C and Ongen, Halit and Dreisbach, Albert W and Li, Yali and Young, J Hunter and Bis, Joshua C and K{\"a}h{\"o}nen, Mika and Viikari, Jorma and Adair, Linda S and Lee, Nanette R and Chen, Ming-Huei and Olden, Matthias and Pattaro, Cristian and Bolton, Judith A Hoffman and K{\"o}ttgen, Anna and Bergmann, Sven and Mooser, Vincent and Chaturvedi, Nish and Frayling, Timothy M and Islam, Muhammad and Jafar, Tazeen H and Erdmann, Jeanette and Kulkarni, Smita R and Bornstein, Stefan R and Gr{\"a}ssler, J{\"u}rgen and Groop, Leif and Voight, Benjamin F and Kettunen, Johannes and Howard, Philip and Taylor, Andrew and Guarrera, Simonetta and Ricceri, Fulvio and Emilsson, Valur and Plump, Andrew and Barroso, In{\^e}s and Khaw, Kay-Tee and Weder, Alan B and Hunt, Steven C and Sun, Yan V and Bergman, Richard N and Collins, Francis S and Bonnycastle, Lori L and Scott, Laura J and Stringham, Heather M and Peltonen, Leena and Perola, Markus and Vartiainen, Erkki and Brand, Stefan-Martin and Staessen, Jan A and Wang, Thomas J and Burton, Paul R and Soler Artigas, Maria and Dong, Yanbin and Snieder, Harold and Wang, Xiaoling and Zhu, Haidong and Lohman, Kurt K and Rudock, Megan E and Heckbert, Susan R and Smith, Nicholas L and Wiggins, Kerri L and Doumatey, Ayo and Shriner, Daniel and Veldre, Gudrun and Viigimaa, Margus and Kinra, Sanjay and Prabhakaran, Dorairaj and Tripathy, Vikal and Langefeld, Carl D and Rosengren, Annika and Thelle, Dag S and Corsi, Anna Maria and Singleton, Andrew and Forrester, Terrence and Hilton, Gina and McKenzie, Colin A and Salako, Tunde and Iwai, Naoharu and Kita, Yoshikuni and Ogihara, Toshio and Ohkubo, Takayoshi and Okamura, Tomonori and Ueshima, Hirotsugu and Umemura, Satoshi and Eyheramendy, Susana and Meitinger, Thomas and Wichmann, H-Erich and Cho, Yoon Shin and Kim, Hyung-Lae and Lee, Jong-Young and Scott, James and Sehmi, Joban S and Zhang, Weihua and Hedblad, Bo and Nilsson, Peter and Smith, George Davey and Wong, Andrew and Narisu, Narisu and Stan{\v c}{\'a}kov{\'a}, Alena and Raffel, Leslie J and Yao, Jie and Kathiresan, Sekar and O{\textquoteright}Donnell, Christopher J and Schwartz, Stephen M and Ikram, M Arfan and Longstreth, W T and Mosley, Thomas H and Seshadri, Sudha and Shrine, Nick R G and Wain, Louise V and Morken, Mario A and Swift, Amy J and Laitinen, Jaana and Prokopenko, Inga and Zitting, Paavo and Cooper, Jackie A and Humphries, Steve E and Danesh, John and Rasheed, Asif and Goel, Anuj and Hamsten, Anders and Watkins, Hugh and Bakker, Stephan J L and van Gilst, Wiek H and Janipalli, Charles S and Mani, K Radha and Yajnik, Chittaranjan S and Hofman, Albert and Mattace-Raso, Francesco U S and Oostra, Ben A and Demirkan, Ayse and Isaacs, Aaron and Rivadeneira, Fernando and Lakatta, Edward G and Orr{\`u}, Marco and Scuteri, Angelo and Ala-Korpela, Mika and Kangas, Antti J and Lyytik{\"a}inen, Leo-Pekka and Soininen, Pasi and Tukiainen, Taru and W{\"u}rtz, Peter and Ong, Rick Twee-Hee and D{\"o}rr, Marcus and Kroemer, Heyo K and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Galan, Pilar and Hercberg, Serge and Lathrop, Mark and Zelenika, Diana and Deloukas, Panos and Mangino, Massimo and Spector, Tim D and Zhai, Guangju and Meschia, James F and Nalls, Michael A and Sharma, Pankaj and Terzic, Janos and Kumar, M V Kranthi and Denniff, Matthew and Zukowska-Szczechowska, Ewa and Wagenknecht, Lynne E and Fowkes, F Gerald R and Charchar, Fadi J and Schwarz, Peter E H and Hayward, Caroline and Guo, Xiuqing and Rotimi, Charles and Bots, Michiel L and Brand, Eva and Samani, Nilesh J and Polasek, Ozren and Talmud, Philippa J and Nyberg, Fredrik and Kuh, Diana and Laan, Maris and Hveem, Kristian and Palmer, Lyle J and van der Schouw, Yvonne T and Casas, Juan P and Mohlke, Karen L and Vineis, Paolo and Raitakari, Olli and Ganesh, Santhi K and Wong, Tien Y and Tai, E Shyong and Cooper, Richard S and Laakso, Markku and Rao, Dabeeru C and Harris, Tamara B and Morris, Richard W and Dominiczak, Anna F and Kivimaki, Mika and Marmot, Michael G and Miki, Tetsuro and Saleheen, Danish and Chandak, Giriraj R and Coresh, Josef and Navis, Gerjan and Salomaa, Veikko and Han, Bok-Ghee and Zhu, Xiaofeng and Kooner, Jaspal S and Melander, Olle and Ridker, Paul M and Bandinelli, Stefania and Gyllensten, Ulf B and Wright, Alan F and Wilson, James F and Ferrucci, Luigi and Farrall, Martin and Tuomilehto, Jaakko and Pramstaller, Peter P and Elosua, Roberto and Soranzo, Nicole and Sijbrands, Eric J G and Altshuler, David and Loos, Ruth J F and Shuldiner, Alan R and Gieger, Christian and Meneton, Pierre and Uitterlinden, Andr{\'e} G and Wareham, Nicholas J and Gudnason, Vilmundur and Rotter, Jerome I and Rettig, Rainer and Uda, Manuela and Strachan, David P and Witteman, Jacqueline C M and Hartikainen, Anna-Liisa and Beckmann, Jacques S and Boerwinkle, Eric and Vasan, Ramachandran S and Boehnke, Michael and Larson, Martin G and Jarvelin, Marjo-Riitta and Psaty, Bruce M and Abecasis, Goncalo R and Chakravarti, Aravinda and Elliott, Paul and van Duijn, Cornelia M and Newton-Cheh, Christopher and Levy, Daniel and Caulfield, Mark J and Johnson, Toby} } @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 {6149, title = {Targeted sequencing in candidate genes for atrial fibrillation: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study.}, journal = {Heart Rhythm}, volume = {11}, year = {2014}, month = {2014 Mar}, pages = {452-7}, abstract = {

BACKGROUND: Genome-wide association studies (GWAS) have identified common genetic variants that predispose to atrial fibrillation (AF). It is unclear whether rare and low-frequency variants in genes implicated by such GWAS confer additional risk of AF.

OBJECTIVE: To study the association of genetic variants with AF at GWAS top loci.

METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study, we selected and sequenced 77 target gene regions from GWAS loci of complex diseases or traits, including 4 genes hypothesized to be related to AF (PRRX1, CAV1, CAV2, and ZFHX3). Sequencing was performed in participants with (n = 948) and without (n = 3330) AF from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Massachusetts General Hospital.

RESULTS: One common variant (rs11265611; P = 1.70 {\texttimes} 10(-6)) intronic to IL6R (interleukin-6 receptor gene) was significantly associated with AF after Bonferroni correction (odds ratio 0.70; 95\% confidence interval 0.58-0.85). The variant was not genotyped or imputed by prior GWAS, but it is in linkage disequilibrium (r(2) = .69) with the single-nucleotide polymorphism, with the strongest association with AF so far at this locus (rs4845625). In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF after Bonferroni correction (P = .01).

CONCLUSIONS: We identified 1 common single-nucleotide polymorphism and 1 gene region that were significantly associated with AF. Future sequencing efforts with larger sample sizes and more comprehensive genome coverage are anticipated to identify additional AF-related variants.

}, keywords = {Aged, Atrial Fibrillation, Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Homeodomain Proteins, Humans, Linkage Disequilibrium, Male, Middle Aged, Polymorphism, Single Nucleotide, Receptors, Interleukin-6}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2013.11.012}, author = {Lin, Honghuang and Sinner, Moritz F and Brody, Jennifer A and Arking, Dan E and Lunetta, Kathryn L and Rienstra, Michiel and Lubitz, Steven A and Magnani, Jared W and Sotoodehnia, Nona and McKnight, Barbara and McManus, David D and Boerwinkle, Eric and Psaty, Bruce M and Rotter, Jerome I and Bis, Joshua C and Gibbs, Richard A and Muzny, Donna and Kovar, Christie L and Morrison, Alanna C and Gupta, Mayetri and Folsom, Aaron R and K{\"a}{\"a}b, Stefan and Heckbert, Susan R and Alonso, Alvaro and Ellinor, Patrick T and Benjamin, Emelia 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 {6860, title = {Integrative pathway genomics of lung function and airflow obstruction.}, journal = {Hum Mol Genet}, volume = {24}, year = {2015}, month = {2015 Dec 1}, pages = {6836-48}, abstract = {

Chronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signaling, proliferation and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less stringent association P-values. Next, we applied pathway enrichment analysis to a meta-analyzed GWAS of airflow obstruction. We identified several biologic modules that functionally overlapped with those associated with pulmonary function. However, differences were also noted, including enrichment of extracellular matrix (ECM) processes specifically in the airflow obstruction study. Network analysis of the ECM module implicated a candidate gene, matrix metalloproteinase 10 (MMP10), as a putative disease target. We used a knockout mouse model to functionally validate MMP10{\textquoteright}s role in influencing lung{\textquoteright}s susceptibility to cigarette smoke-induced emphysema. By integrating pathway analysis with population-based genomics, we unraveled biologic processes underlying pulmonary function traits and identified a candidate gene for obstructive lung disease.

}, keywords = {Airway Obstruction, Animals, Cell Proliferation, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Immune System, Lung, Male, Metabolic Networks and Pathways, Mice, Phenotype, Polymorphism, Single Nucleotide, Signal Transduction}, issn = {1460-2083}, doi = {10.1093/hmg/ddv378}, author = {Gharib, Sina A and Loth, Daan W and Soler Artigas, Maria and Birkland, Timothy P and Wilk, Jemma B and Wain, Louise V and Brody, Jennifer A and Obeidat, Ma{\textquoteright}en and Hancock, Dana B and Tang, Wenbo and Rawal, Rajesh and Boezen, H Marike and Imboden, Medea and Huffman, Jennifer E and Lahousse, Lies and Alves, Alexessander C and Manichaikul, Ani and Hui, Jennie and Morrison, Alanna C and Ramasamy, Adaikalavan and Smith, Albert Vernon and Gudnason, Vilmundur and Surakka, Ida and Vitart, Veronique and Evans, David M and Strachan, David P and Deary, Ian J and Hofman, Albert and Gl{\"a}ser, Sven and Wilson, James F and North, Kari E and Zhao, Jing Hua and Heckbert, Susan R and Jarvis, Deborah L and Probst-Hensch, Nicole and Schulz, Holger and Barr, R Graham and Jarvelin, Marjo-Riitta and O{\textquoteright}Connor, George T and K{\"a}h{\"o}nen, Mika and Cassano, Patricia A and Hysi, Pirro G and Dupuis, Jos{\'e}e and Hayward, Caroline and Psaty, Bruce M and Hall, Ian P and Parks, William C and Tobin, Martin D and London, Stephanie J} } @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 {7004, title = {Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium.}, journal = {PLoS One}, volume = {11}, year = {2016}, month = {2016}, pages = {e0144997}, abstract = {

BACKGROUND: Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.

METHODS: We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5{\texttimes}10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.

RESULTS: In Stage I 15 loci passed the threshold of 5{\texttimes}10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8{\texttimes}10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2{\texttimes}10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2{\texttimes}10-3).

CONCLUSIONS: QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.

}, keywords = {Aged, Cohort Studies, Cooperative Behavior, Coronary Artery Disease, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Myocardial Infarction, Polymorphism, Single Nucleotide, Prospective Studies}, issn = {1932-6203}, doi = {10.1371/journal.pone.0144997}, author = {Dehghan, Abbas and Bis, Joshua C and White, Charles C and Smith, Albert Vernon and Morrison, Alanna C and Cupples, L Adrienne and Trompet, Stella and Chasman, Daniel I and Lumley, Thomas and V{\"o}lker, Uwe and Buckley, Brendan M and Ding, Jingzhong and Jensen, Majken K and Folsom, Aaron R and Kritchevsky, Stephen B and Girman, Cynthia J and Ford, Ian and D{\"o}rr, Marcus and Salomaa, Veikko and Uitterlinden, Andr{\'e} G and Eiriksdottir, Gudny and Vasan, Ramachandran S and Franceschini, Nora and Carty, Cara L and Virtamo, Jarmo and Demissie, Serkalem and Amouyel, Philippe and Arveiler, Dominique and Heckbert, Susan R and Ferrieres, Jean and Ducimetiere, Pierre and Smith, Nicholas L and Wang, Ying A and Siscovick, David S and Rice, Kenneth M and Wiklund, Per-Gunnar and Taylor, Kent D and Evans, Alun and Kee, Frank and Rotter, Jerome I and Karvanen, Juha and Kuulasmaa, Kari and Heiss, Gerardo and Kraft, Peter and Launer, Lenore J and Hofman, Albert and Markus, Marcello R P and Rose, Lynda M and Silander, Kaisa and Wagner, Peter and Benjamin, Emelia J and Lohman, Kurt and Stott, David J and Rivadeneira, Fernando and Harris, Tamara B and Levy, Daniel and Liu, Yongmei and Rimm, Eric B and Jukema, J Wouter and V{\"o}lzke, Henry and Ridker, Paul M and Blankenberg, Stefan and Franco, Oscar H and Gudnason, Vilmundur and Psaty, Bruce M and Boerwinkle, Eric and O{\textquoteright}Donnell, Christopher J} } @article {7594, title = {Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.}, journal = {JAMA Oncol}, volume = {3}, year = {2017}, month = {2017 May 01}, pages = {636-651}, abstract = {

Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.

Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.

Data Sources: Genomewide association studies (GWAS) published up to January 15, 2015.

Study Selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.

Data Extraction and Synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.

Main Outcomes and Measures: Odds ratios (ORs) and 95\% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.

Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95\% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95\% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95\% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95\% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95\% CI, 0.05-0.15]).

Conclusions and Relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.

}, keywords = {Adult, Aged, Aged, 80 and over, Cardiovascular Diseases, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Germ-Line Mutation, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Neoplasms, Polymorphism, Single Nucleotide, Risk Assessment, Telomere, Telomere Homeostasis}, issn = {2374-2445}, doi = {10.1001/jamaoncol.2016.5945}, author = {Haycock, Philip C and Burgess, Stephen and Nounu, Aayah and Zheng, Jie and Okoli, George N and Bowden, Jack and Wade, Kaitlin Hazel and Timpson, Nicholas J and Evans, David M and Willeit, Peter and Aviv, Abraham and Gaunt, Tom R and Hemani, Gibran and Mangino, Massimo and Ellis, Hayley Patricia and Kurian, Kathreena M and Pooley, Karen A and Eeles, Rosalind A and Lee, Jeffrey E and Fang, Shenying and Chen, Wei V and Law, Matthew H and Bowdler, Lisa M and Iles, Mark M and Yang, Qiong and Worrall, Bradford B and Markus, Hugh Stephen and Hung, Rayjean J and Amos, Chris I and Spurdle, Amanda B and Thompson, Deborah J and O{\textquoteright}Mara, Tracy A and Wolpin, Brian and Amundadottir, Laufey and Stolzenberg-Solomon, Rachael and Trichopoulou, Antonia and Onland-Moret, N Charlotte and Lund, Eiliv and Duell, Eric J and Canzian, Federico and Severi, Gianluca and Overvad, Kim and Gunter, Marc J and Tumino, Rosario and Svenson, Ulrika and van Rij, Andre and Baas, Annette F and Bown, Matthew J and Samani, Nilesh J and van t{\textquoteright}Hof, Femke N G and Tromp, Gerard and Jones, Gregory T and Kuivaniemi, Helena and Elmore, James R and Johansson, Mattias and Mckay, James and Scelo, Ghislaine and Carreras-Torres, Robert and Gaborieau, Valerie and Brennan, Paul and Bracci, Paige M and Neale, Rachel E and Olson, Sara H and Gallinger, Steven and Li, Donghui and Petersen, Gloria M and Risch, Harvey A and Klein, Alison P and Han, Jiali and Abnet, Christian C and Freedman, Neal D and Taylor, Philip R and Maris, John M and Aben, Katja K and Kiemeney, Lambertus A and Vermeulen, Sita H and Wiencke, John K and Walsh, Kyle M and Wrensch, Margaret and Rice, Terri and Turnbull, Clare and Litchfield, Kevin and Paternoster, Lavinia and Standl, Marie and Abecasis, Goncalo R and SanGiovanni, John Paul and Li, Yong and Mijatovic, Vladan and Sapkota, Yadav and Low, Siew-Kee and Zondervan, Krina T and Montgomery, Grant W and Nyholt, Dale R and van Heel, David A and Hunt, Karen and Arking, Dan E and Ashar, Foram N and Sotoodehnia, Nona and Woo, Daniel and Rosand, Jonathan and Comeau, Mary E and Brown, W Mark and Silverman, Edwin K and Hokanson, John E and Cho, Michael H and Hui, Jennie and Ferreira, Manuel A and Thompson, Philip J and Morrison, Alanna C and Felix, Janine F and Smith, Nicholas L and Christiano, Angela M and Petukhova, Lynn and Betz, Regina C and Fan, Xing and Zhang, Xuejun and Zhu, Caihong and Langefeld, Carl D and Thompson, Susan D and Wang, Feijie and Lin, Xu and Schwartz, David A and Fingerlin, Tasha and Rotter, Jerome I and Cotch, Mary Frances and Jensen, Richard A and Munz, Matthias and Dommisch, Henrik and Schaefer, Arne S and Han, Fang and Ollila, Hanna M and Hillary, Ryan P and Albagha, Omar and Ralston, Stuart H and Zeng, Chenjie and Zheng, Wei and Shu, Xiao-Ou and Reis, Andre and Uebe, Steffen and H{\"u}ffmeier, Ulrike and Kawamura, Yoshiya and Otowa, Takeshi and Sasaki, Tsukasa and Hibberd, Martin Lloyd and Davila, Sonia and Xie, Gang and Siminovitch, Katherine and Bei, Jin-Xin and Zeng, Yi-Xin and F{\"o}rsti, Asta and Chen, Bowang and Landi, Stefano and Franke, Andre and Fischer, Annegret and Ellinghaus, David and Flores, Carlos and Noth, Imre and Ma, Shwu-Fan and Foo, Jia Nee and Liu, Jianjun and Kim, Jong-Won and Cox, David G and Delattre, Olivier and Mirabeau, Olivier and Skibola, Christine F and Tang, Clara S and Garcia-Barcelo, Merce and Chang, Kai-Ping and Su, Wen-Hui and Chang, Yu-Sun and Martin, Nicholas G and Gordon, Scott and Wade, Tracey D and Lee, Chaeyoung and Kubo, Michiaki and Cha, Pei-Chieng and Nakamura, Yusuke and Levy, Daniel and Kimura, Masayuki and Hwang, Shih-Jen and Hunt, Steven and Spector, Tim and Soranzo, Nicole and Manichaikul, Ani W and Barr, R Graham and Kahali, Bratati and Speliotes, Elizabeth and Yerges-Armstrong, Laura M and Cheng, Ching-Yu and Jonas, Jost B and Wong, Tien Yin and Fogh, Isabella and Lin, Kuang and Powell, John F and Rice, Kenneth and Relton, Caroline L and Martin, Richard M and Davey Smith, George} } @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 {7913, title = {GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 12 03}, pages = {5141}, abstract = {

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

}, keywords = {ADAMTS9 Protein, Amino Acid Oxidoreductases, Carotid Intima-Media Thickness, Coronary Disease, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Lod Score, Plaque, Atherosclerotic, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors}, issn = {2041-1723}, doi = {10.1038/s41467-018-07340-5}, author = {Franceschini, Nora and Giambartolomei, Claudia and de Vries, Paul S and Finan, Chris and Bis, Joshua C and Huntley, Rachael P and Lovering, Ruth C and Tajuddin, Salman M and Winkler, Thomas W and Graff, Misa and Kavousi, Maryam and Dale, Caroline and Smith, Albert V and Hofer, Edith and van Leeuwen, Elisabeth M and Nolte, Ilja M and Lu, Lingyi and Scholz, Markus and Sargurupremraj, Muralidharan and Pitk{\"a}nen, Niina and Franz{\'e}n, Oscar and Joshi, Peter K and Noordam, Raymond and Marioni, Riccardo E and Hwang, Shih-Jen and Musani, Solomon K and Schminke, Ulf and Palmas, Walter and Isaacs, Aaron and Correa, Adolfo and Zonderman, Alan B and Hofman, Albert and Teumer, Alexander and Cox, Amanda J and Uitterlinden, Andr{\'e} G and Wong, Andrew and Smit, Andries J and Newman, Anne B and Britton, Annie and Ruusalepp, Arno and Sennblad, Bengt and Hedblad, Bo and Pasaniuc, Bogdan and Penninx, Brenda W and Langefeld, Carl D and Wassel, Christina L and Tzourio, Christophe and Fava, Cristiano and Baldassarre, Damiano and O{\textquoteright}Leary, Daniel H and Teupser, Daniel and Kuh, Diana and Tremoli, Elena and Mannarino, Elmo and Grossi, Enzo and Boerwinkle, Eric and Schadt, Eric E and Ingelsson, Erik and Veglia, Fabrizio and Rivadeneira, Fernando and Beutner, Frank and Chauhan, Ganesh and Heiss, Gerardo and Snieder, Harold and Campbell, Harry and V{\"o}lzke, Henry and Markus, Hugh S and Deary, Ian J and Jukema, J Wouter and de Graaf, Jacqueline and Price, Jacqueline and Pott, Janne and Hopewell, Jemma C and Liang, Jingjing and Thiery, Joachim and Engmann, Jorgen and Gertow, Karl and Rice, Kenneth and Taylor, Kent D and Dhana, Klodian and Kiemeney, Lambertus A L M and Lind, Lars and Raffield, Laura M and Launer, Lenore J and Holdt, Lesca M and D{\"o}rr, Marcus and Dichgans, Martin and Traylor, Matthew and Sitzer, Matthias and Kumari, Meena and Kivimaki, Mika and Nalls, Mike A and Melander, Olle and Raitakari, Olli and Franco, Oscar H and Rueda-Ochoa, Oscar L and Roussos, Panos and Whincup, Peter H and Amouyel, Philippe and Giral, Philippe and Anugu, Pramod and Wong, Quenna and Malik, Rainer and Rauramaa, Rainer and Burkhardt, Ralph and Hardy, Rebecca and Schmidt, Reinhold and de Mutsert, Ren{\'e}e and Morris, Richard W and Strawbridge, Rona J and Wannamethee, S Goya and H{\"a}gg, Sara and Shah, Sonia and McLachlan, Stela and Trompet, Stella and Seshadri, Sudha and Kurl, Sudhir and Heckbert, Susan R and Ring, Susan and Harris, Tamara B and Lehtim{\"a}ki, Terho and Galesloot, Tessel E and Shah, Tina and de Faire, Ulf and Plagnol, Vincent and Rosamond, Wayne D and Post, Wendy and Zhu, Xiaofeng and Zhang, Xiaoling and Guo, Xiuqing and Saba, Yasaman and Dehghan, Abbas and Seldenrijk, Adrie and Morrison, Alanna C and Hamsten, Anders and Psaty, Bruce M and van Duijn, Cornelia M and Lawlor, Deborah A and Mook-Kanamori, Dennis O and Bowden, Donald W and Schmidt, Helena and Wilson, James F and Wilson, James G and Rotter, Jerome I and Wardlaw, Joanna M and Deanfield, John and Halcox, Julian and Lyytik{\"a}inen, Leo-Pekka and Loeffler, Markus and Evans, Michele K and Debette, Stephanie and Humphries, Steve E and V{\"o}lker, Uwe and Gudnason, Vilmundur and Hingorani, Aroon D and Bj{\"o}rkegren, Johan L M and Casas, Juan P and O{\textquoteright}Donnell, Christopher J} } @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 {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 {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 {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 {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 {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 {9702, title = {Machine learning models for predicting blood pressure phenotypes by combining multiple polygenic risk scores.}, journal = {Sci Rep}, volume = {14}, year = {2024}, month = {2024 May 30}, pages = {12436}, 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. In summary, non-linear ML models improves BP prediction in models incorporating diverse populations.

}, keywords = {Blood Pressure, Female, Genetic Predisposition to Disease, Genetic Risk Score, Genome-Wide Association Study, Humans, Hypertension, Machine Learning, Male, Middle Aged, Models, Genetic, Multifactorial Inheritance, Phenotype, Risk Factors}, issn = {2045-2322}, doi = {10.1038/s41598-024-62945-9}, 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 Mitchell, 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 Ida Chen, Yii-Der and Sofer, Tamar} } @article {9787, title = {Rare variant contribution to the heritability of coronary artery disease.}, journal = {Nat Commun}, volume = {15}, year = {2024}, month = {2024 Oct 09}, pages = {8741}, abstract = {

Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3\% assuming a prevalence of 8.2\%. Ultra-rare (minor allele frequency <= 0.1\%) variants with low linkage disequilibrium (LD) score contribute ~50\% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

}, keywords = {Case-Control Studies, Coronary Artery Disease, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Middle Aged, Polymorphism, Single Nucleotide, White People, Whole Genome Sequencing}, issn = {2041-1723}, doi = {10.1038/s41467-024-52939-6}, author = {Rocheleau, Ghislain and Clarke, Shoa L and Auguste, Ga{\"e}lle and Hasbani, Natalie R and Morrison, Alanna C and Heath, Adam S and Bielak, Lawrence F and Iyer, Kruthika R and Young, Erica P and Stitziel, Nathan O and Jun, Goo and Laurie, Cecelia and Broome, Jai G and Khan, Alyna T and Arnett, Donna K and Becker, Lewis C and Bis, Joshua C and Boerwinkle, Eric and Bowden, Donald W and Carson, April P and Ellinor, Patrick T and Fornage, Myriam and Franceschini, Nora and Freedman, Barry I and Heard-Costa, Nancy L and Hou, Lifang and Chen, Yii-Der Ida and Kenny, Eimear E and Kooperberg, Charles and Kral, Brian G and Loos, Ruth J F and Lutz, Sharon M and Manson, JoAnn E and Martin, Lisa W and Mitchell, Braxton D and Nassir, Rami and Palmer, Nicholette D and Post, Wendy S and Preuss, Michael H and Psaty, Bruce M and Raffield, Laura M and Regan, Elizabeth A and Rich, Stephen S and Smith, Jennifer A and Taylor, Kent D and Yanek, Lisa R and Young, Kendra A and Hilliard, Austin T and Tcheandjieu, Catherine and Peyser, Patricia A and Vasan, Ramachandran S and Rotter, Jerome I and Miller, Clint L and Assimes, Themistocles L and de Vries, Paul S and Do, Ron} } @article {9898, title = {Rare damaging CCR2 variants are associated with lower lifetime cardiovascular risk.}, journal = {Genome Med}, volume = {17}, year = {2025}, month = {2025 Mar 21}, pages = {27}, abstract = {

BACKGROUND: Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease.

METHODS: Computationally predicted damaging or loss-of-function (REVEL > 0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested in migration and cAMP assays. Validated damaging variants were tested for association with cardiovascular endpoints, atherosclerosis burden, and vascular risk factors. Significant associations were replicated in six independent datasets (n = 1,062,595).

RESULTS: Carriers of 45 predicted damaging or loss-of-function CCR2 variants (n = 787 individuals) were at lower risk of myocardial infarction and coronary artery disease. One of these variants (M249K, n = 585, 0.15\% of European ancestry individuals) was associated with lower monocyte count and with both decreased downstream signaling and chemoattraction in response to CCL2. While M249K showed no association with conventional vascular risk factors, it was consistently associated with a lower risk of myocardial infarction (odds ratio [OR]: 0.66, 95\% confidence interval [CI]: 0.54-0.81, p = 6.1 {\texttimes} 10) and coronary artery disease (OR: 0.74, 95\%CI: 0.63-0.87, p = 2.9 {\texttimes} 10) in the UK Biobank and in six replication cohorts. In a phenome-wide association study, there was no evidence of a higher risk of infections among M249K carriers.

CONCLUSIONS: Carriers of an experimentally confirmed damaging CCR2 variant are at a lower lifetime risk of myocardial infarction and coronary artery disease without carrying a higher risk of infections. Our findings provide genetic support for the translational potential of CCR2-targeting as an atheroprotective approach.

}, keywords = {Aged, Cardiovascular Diseases, Chemokine CCL2, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Monocytes, Receptors, CCR2}, issn = {1756-994X}, doi = {10.1186/s13073-025-01456-2}, author = {Georgakis, Marios K and Malik, Rainer and Bounkari, Omar El and Hasbani, Natalie R and Li, Jiang and Huffman, Jennifer E and Shakt, Gabrielle and Tack, Reinier W P and Kimball, Tamara N and Asare, Yaw 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 Bernhagen, J{\"u}rgen and Anderson, Christopher D and Damrauer, Scott M and Zand, Ramin and Rotter, Jerome I and de Vries, Paul S and Dichgans, Martin} }