@article {1284, title = {Genetic predictors of fibrin D-dimer levels in healthy adults.}, journal = {Circulation}, volume = {123}, year = {2011}, month = {2011 May 03}, pages = {1864-72}, abstract = {

BACKGROUND: Fibrin fragment D-dimer, one of several peptides produced when crosslinked fibrin is degraded by plasmin, is the most widely used clinical marker of activated blood coagulation. To identity genetic loci influencing D-dimer levels, we performed the first large-scale, genome-wide association search.

METHODS AND RESULTS: A genome-wide investigation of the genomic correlates of plasma D-dimer levels was conducted among 21 052 European-ancestry adults. Plasma levels of D-dimer were measured independently in each of 13 cohorts. Each study analyzed the association between ≈2.6 million genotyped and imputed variants across the 22 autosomal chromosomes and natural-log{\textendash}transformed D-dimer levels using linear regression in additive genetic models adjusted for age and sex. Among all variants, 74 exceeded the genome-wide significance threshold and marked 3 regions. At 1p22, rs12029080 (P=6.4{\texttimes}10(-52)) was 46.0 kb upstream from F3, coagulation factor III (tissue factor). At 1q24, rs6687813 (P=2.4{\texttimes}10(-14)) was 79.7 kb downstream of F5, coagulation factor V. At 4q32, rs13109457 (P=2.9{\texttimes}10(-18)) was located between 2 fibrinogen genes: 10.4 kb downstream from FGG and 3.0 kb upstream from FGA. Variants were associated with a 0.099-, 0.096-, and 0.061-unit difference, respectively, in natural-log{\textendash}transformed D-dimer and together accounted for 1.8\% of the total variance. When adjusted for nonsynonymous substitutions in F5 and FGA loci known to be associated with D-dimer levels, there was no evidence of an additional association at either locus.

CONCLUSIONS: Three genes were associated with fibrin D-dimer levels. Of these 3, the F3 association was the strongest, and has not been previously reported.

}, keywords = {Adult, Aged, Blood Coagulation, European Continental Ancestry Group, Factor V, Female, Fibrin Fibrinogen Degradation Products, Fibrinogen, Genetic Testing, Genome-Wide Association Study, Humans, Male, Middle Aged, Reference Values, Thromboplastin}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.110.009480}, author = {Smith, Nicholas L and Huffman, Jennifer E and Strachan, David P and Huang, Jie and Dehghan, Abbas and Trompet, Stella and Lopez, Lorna M and Shin, So-Youn and Baumert, Jens and Vitart, Veronique and Bis, Joshua C and Wild, Sarah H and Rumley, Ann and Yang, Qiong and Uitterlinden, Andr{\'e} G and Stott, David J and Davies, Gail and Carter, Angela M and Thorand, Barbara and Polasek, Ozren and McKnight, Barbara and Campbell, Harry and Rudnicka, Alicja R and Chen, Ming-Huei and Buckley, Brendan M and Harris, Sarah E and Peters, Annette and Pulanic, Drazen and Lumley, Thomas and de Craen, Anton J M and Liewald, David C and Gieger, Christian and Campbell, Susan and Ford, Ian and Gow, Alan J and Luciano, Michelle and Porteous, David J and Guo, Xiuqing and Sattar, Naveed and Tenesa, Albert and Cushman, Mary and Slagboom, P Eline and Visscher, Peter M and Spector, Tim D and Illig, Thomas and Rudan, Igor and Bovill, Edwin G and Wright, Alan F and McArdle, Wendy L and Tofler, Geoffrey and Hofman, Albert and Westendorp, Rudi G J and Starr, John M and Grant, Peter J and Karakas, Mahir and Hastie, Nicholas D and Psaty, Bruce M and Wilson, James F and Lowe, Gordon D O and O{\textquoteright}Donnell, Christopher J and Witteman, Jacqueline C M and Jukema, J Wouter and Deary, Ian J and Soranzo, Nicole and Koenig, Wolfgang and Hayward, Caroline} } @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 {1323, title = {Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque.}, journal = {Nat Genet}, volume = {43}, year = {2011}, month = {2011 Sep 11}, pages = {940-7}, abstract = {

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 {\texttimes} 10(-8)). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.

}, keywords = {Adult, Aged, Aging, Atherosclerosis, Carotid Intima-Media Thickness, Cohort Studies, Coronary Artery Disease, European Continental Ancestry Group, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Genotype, Heart, Humans, Middle Aged, Phenotype, Plaque, Atherosclerotic, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1546-1718}, doi = {10.1038/ng.920}, author = {Bis, Joshua C and Kavousi, Maryam and Franceschini, Nora and Isaacs, Aaron and Abecasis, Goncalo R and Schminke, Ulf and Post, Wendy S and Smith, Albert V and Cupples, L Adrienne and Markus, Hugh S and Schmidt, Reinhold and Huffman, Jennifer E and Lehtim{\"a}ki, Terho and Baumert, Jens and M{\"u}nzel, Thomas and Heckbert, Susan R and Dehghan, Abbas and North, Kari and Oostra, Ben and Bevan, Steve and Stoegerer, Eva-Maria and Hayward, Caroline and Raitakari, Olli and Meisinger, Christa and Schillert, Arne and Sanna, Serena and V{\"o}lzke, Henry and Cheng, Yu-Ching and Thorsson, Bolli and Fox, Caroline S and Rice, Kenneth and Rivadeneira, Fernando and Nambi, Vijay and Halperin, Eran and Petrovic, Katja E and Peltonen, Leena and Wichmann, H Erich and Schnabel, Renate B and D{\"o}rr, Marcus and Parsa, Afshin and Aspelund, Thor and Demissie, Serkalem and Kathiresan, Sekar and Reilly, Muredach P and Taylor, Kent and Uitterlinden, Andre and Couper, David J and Sitzer, Matthias and K{\"a}h{\"o}nen, Mika and Illig, Thomas and Wild, Philipp S and Orr{\`u}, Marco and L{\"u}demann, Jan and Shuldiner, Alan R and Eiriksdottir, Gudny and White, Charles C and Rotter, Jerome I and Hofman, Albert and Seissler, Jochen and Zeller, Tanja and Usala, Gianluca and Ernst, Florian and Launer, Lenore J and D{\textquoteright}Agostino, Ralph B and O{\textquoteright}Leary, Daniel H and Ballantyne, Christie and Thiery, Joachim and Ziegler, Andreas and Lakatta, Edward G and Chilukoti, Ravi Kumar and Harris, Tamara B and Wolf, Philip A and Psaty, Bruce M and Polak, Joseph F and Li, Xia and Rathmann, Wolfgang and Uda, Manuela and Boerwinkle, Eric and Klopp, Norman and Schmidt, Helena and Wilson, James F and Viikari, Jorma and Koenig, Wolfgang and Blankenberg, Stefan and Newman, Anne B and Witteman, Jacqueline and Heiss, Gerardo and Duijn, Cornelia van and Scuteri, Angelo and Homuth, Georg and Mitchell, Braxton D and Gudnason, Vilmundur and O{\textquoteright}Donnell, Christopher J} } @article {1359, title = {Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies.}, journal = {Circ Cardiovasc Genet}, volume = {5}, year = {2012}, month = {2012 Feb 01}, pages = {100-12}, abstract = {

BACKGROUND: Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.

METHODS AND RESULTS: Continuous ABI and PAD (ABI <=0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ≈2.5 million single nucleotide polymorphisms (SNPs) in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed effects inverse variance weighted meta-analyses. There were a total of 41 692 participants of European ancestry (≈60\% women, mean ABI 1.02 to 1.19), including 3409 participants with PAD and with genome-wide association study data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β=-0.006, P=2.46{\texttimes}10(-8)). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16 717). The association for rs10757269 strengthened in the combined discovery and replication analysis (P=2.65{\texttimes}10(-9)). No other SNP associations for ABI or PAD achieved genome-wide significance. However, 2 previously reported candidate genes for PAD and 1 SNP associated with coronary artery disease were associated with ABI: DAB21P (rs13290547, P=3.6{\texttimes}10(-5)), CYBA (rs3794624, P=6.3{\texttimes}10(-5)), and rs1122608 (LDLR, P=0.0026).

CONCLUSIONS: Genome-wide association studies in more than 40 000 individuals identified 1 genome wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for coronary artery disease are associated with ABI.

}, keywords = {Adult, Age Factors, Aged, Aged, 80 and over, Alleles, Ankle Brachial Index, Chromosomes, Human, Pair 9, Cohort Studies, Cyclin-Dependent Kinase Inhibitor p15, Female, Genome-Wide Association Study, Genotype, HapMap Project, Humans, Logistic Models, Male, Middle Aged, Peripheral Vascular Diseases, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Sex Factors}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.111.961292}, author = {Murabito, Joanne M and White, Charles C and Kavousi, Maryam and Sun, Yan V and Feitosa, Mary F and Nambi, Vijay and Lamina, Claudia and Schillert, Arne and Coassin, Stefan and Bis, Joshua C and Broer, Linda and Crawford, Dana C and Franceschini, Nora and Frikke-Schmidt, Ruth and Haun, Margot and Holewijn, Suzanne and Huffman, Jennifer E and Hwang, Shih-Jen and Kiechl, Stefan and Kollerits, Barbara and Montasser, May E and Nolte, Ilja M and Rudock, Megan E and Senft, Andrea and Teumer, Alexander and van der Harst, Pim and Vitart, Veronique and Waite, Lindsay L and Wood, Andrew R and Wassel, Christina L and Absher, Devin M and Allison, Matthew A and Amin, Najaf and Arnold, Alice and Asselbergs, Folkert W and Aulchenko, Yurii and Bandinelli, Stefania and Barbalic, Maja and Boban, Mladen and Brown-Gentry, Kristin and Couper, David J and Criqui, Michael H and Dehghan, Abbas and den Heijer, Martin and Dieplinger, Benjamin and Ding, Jingzhong and D{\"o}rr, Marcus and Espinola-Klein, Christine and Felix, Stephan B and Ferrucci, Luigi and Folsom, Aaron R and Fraedrich, Gustav and Gibson, Quince and Goodloe, Robert and Gunjaca, Grgo and Haltmayer, Meinhard and Heiss, Gerardo and Hofman, Albert and Kieback, Arne and Kiemeney, Lambertus A and Kolcic, Ivana and Kullo, Iftikhar J and Kritchevsky, Stephen B and Lackner, Karl J and Li, Xiaohui and Lieb, Wolfgang and Lohman, Kurt and Meisinger, Christa and Melzer, David and Mohler, Emile R and Mudnic, Ivana and Mueller, Thomas and Navis, Gerjan and Oberhollenzer, Friedrich and Olin, Jeffrey W and O{\textquoteright}Connell, Jeff and O{\textquoteright}Donnell, Christopher J and Palmas, Walter and Penninx, Brenda W and Petersmann, Astrid and Polasek, Ozren and Psaty, Bruce M and Rantner, Barbara and Rice, Ken and Rivadeneira, Fernando and Rotter, Jerome I and Seldenrijk, Adrie and Stadler, Marietta and Summerer, Monika and Tanaka, Toshiko and Tybjaerg-Hansen, Anne and Uitterlinden, Andr{\'e} G and van Gilst, Wiek H and Vermeulen, Sita H and Wild, Sarah H and Wild, Philipp S and Willeit, Johann and Zeller, Tanja and Zemunik, Tatijana and Zgaga, Lina and Assimes, Themistocles L and Blankenberg, Stefan and Boerwinkle, Eric and Campbell, Harry and Cooke, John P and de Graaf, Jacqueline and Herrington, David and Kardia, Sharon L R and Mitchell, Braxton D and Murray, Anna and M{\"u}nzel, Thomas and Newman, Anne B and Oostra, Ben A and Rudan, Igor and Shuldiner, Alan R and Snieder, Harold and van Duijn, Cornelia M and V{\"o}lker, Uwe and Wright, Alan F and Wichmann, H-Erich and Wilson, James F and Witteman, Jacqueline C M and Liu, Yongmei and Hayward, Caroline and Borecki, Ingrid B and Ziegler, Andreas and North, Kari E and Cupples, L Adrienne and Kronenberg, Florian} } @article {6175, title = {FTO genotype is associated with phenotypic variability of body mass index.}, journal = {Nature}, volume = {490}, year = {2012}, month = {2012 Oct 11}, pages = {267-72}, abstract = {

There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using \~{}170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7\%, corresponding to a difference of \~{}0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.

}, keywords = {Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Body Height, Body Mass Index, Co-Repressor Proteins, Female, Genetic Variation, Genome-Wide Association Study, Humans, Male, Nerve Tissue Proteins, Phenotype, Polymorphism, Single Nucleotide, Proteins, Repressor Proteins}, issn = {1476-4687}, doi = {10.1038/nature11401}, author = {Yang, Jian and Loos, Ruth J F and Powell, Joseph E and Medland, Sarah E and Speliotes, Elizabeth K and Chasman, Daniel I and Rose, Lynda M and Thorleifsson, Gudmar and Steinthorsdottir, Valgerdur and M{\"a}gi, Reedik and Waite, Lindsay and Smith, Albert Vernon and Yerges-Armstrong, Laura M and Monda, Keri L and Hadley, David and Mahajan, Anubha and Li, Guo and Kapur, Karen and Vitart, Veronique and Huffman, Jennifer E and Wang, Sophie R and Palmer, Cameron and Esko, T{\~o}nu and Fischer, Krista and Zhao, Jing Hua and Demirkan, Ayse and Isaacs, Aaron and Feitosa, Mary F and Luan, Jian{\textquoteright}an and Heard-Costa, Nancy L and White, Charles and Jackson, Anne U and Preuss, Michael and Ziegler, Andreas and Eriksson, Joel and Kutalik, Zolt{\'a}n and Frau, Francesca and Nolte, Ilja M and van Vliet-Ostaptchouk, Jana V and Hottenga, Jouke-Jan and Jacobs, Kevin B and Verweij, Niek and Goel, Anuj and Medina-G{\'o}mez, Carolina and Estrada, Karol and Bragg-Gresham, Jennifer Lynn and Sanna, Serena and Sidore, Carlo and Tyrer, Jonathan and Teumer, Alexander and Prokopenko, Inga and Mangino, Massimo and Lindgren, Cecilia M and Assimes, Themistocles L and Shuldiner, Alan R and Hui, Jennie and Beilby, John P and McArdle, Wendy L and Hall, Per and Haritunians, Talin and Zgaga, Lina and Kolcic, Ivana and Polasek, Ozren and Zemunik, Tatijana and Oostra, Ben A and Junttila, M Juhani and Gr{\"o}nberg, Henrik and Schreiber, Stefan and Peters, Annette and Hicks, Andrew A and Stephens, Jonathan and Foad, Nicola S and Laitinen, Jaana and Pouta, Anneli and Kaakinen, Marika and Willemsen, Gonneke and Vink, Jacqueline M and Wild, Sarah H and Navis, Gerjan and Asselbergs, Folkert W and Homuth, Georg and John, Ulrich and Iribarren, Carlos and Harris, Tamara and Launer, Lenore and Gudnason, Vilmundur and O{\textquoteright}Connell, Jeffrey R and Boerwinkle, Eric and Cadby, Gemma and Palmer, Lyle J and James, Alan L and Musk, Arthur W and Ingelsson, Erik and Psaty, Bruce M and Beckmann, Jacques S and Waeber, G{\'e}rard and Vollenweider, Peter and Hayward, Caroline and Wright, Alan F and Rudan, Igor and Groop, Leif C and Metspalu, Andres and Khaw, Kay Tee and van Duijn, Cornelia M and Borecki, Ingrid B and Province, Michael A and Wareham, Nicholas J and Tardif, Jean-Claude and Huikuri, Heikki V and Cupples, L Adrienne and Atwood, Larry D and Fox, Caroline S and Boehnke, Michael and Collins, Francis S and Mohlke, Karen L and Erdmann, Jeanette and Schunkert, Heribert and Hengstenberg, Christian and Stark, Klaus and Lorentzon, Mattias and Ohlsson, Claes and Cusi, Daniele and Staessen, Jan A and van der Klauw, Melanie M and Pramstaller, Peter P and Kathiresan, Sekar and Jolley, Jennifer D and Ripatti, Samuli and Jarvelin, Marjo-Riitta and de Geus, Eco J C and Boomsma, Dorret I and Penninx, Brenda and Wilson, James F and Campbell, Harry and Chanock, Stephen J and van der Harst, Pim and Hamsten, Anders and Watkins, Hugh and Hofman, Albert and Witteman, Jacqueline C and Zillikens, M Carola and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Zillikens, M Carola and Kiemeney, Lambertus A and Vermeulen, Sita H and Abecasis, Goncalo R and Schlessinger, David and Schipf, Sabine and Stumvoll, Michael and T{\"o}njes, Anke and Spector, Tim D and North, Kari E and Lettre, Guillaume and McCarthy, Mark I and Berndt, Sonja I and Heath, Andrew C and Madden, Pamela A F and Nyholt, Dale R and Montgomery, Grant W and Martin, Nicholas G and McKnight, Barbara and Strachan, David P and Hill, William G and Snieder, Harold and Ridker, Paul M and Thorsteinsdottir, Unnur and Stefansson, Kari and Frayling, Timothy M and Hirschhorn, Joel N and Goddard, Michael E and Visscher, Peter M} } @article {6152, title = {Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 May}, pages = {501-12}, abstract = {

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

}, keywords = {Anthropometry, Body Height, Body Mass Index, Case-Control Studies, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Obesity, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Waist-Hip Ratio}, issn = {1546-1718}, doi = {10.1038/ng.2606}, author = {Berndt, Sonja I and Gustafsson, Stefan and M{\"a}gi, Reedik and Ganna, Andrea and Wheeler, Eleanor and Feitosa, Mary F and Justice, Anne E and Monda, Keri L and Croteau-Chonka, Damien C and Day, Felix R and Esko, T{\~o}nu and Fall, Tove and Ferreira, Teresa and Gentilini, Davide and Jackson, Anne U and Luan, Jian{\textquoteright}an and Randall, Joshua C and Vedantam, Sailaja and Willer, Cristen J and Winkler, Thomas W and Wood, Andrew R and Workalemahu, Tsegaselassie and Hu, Yi-Juan and Lee, Sang Hong and Liang, Liming and Lin, Dan-Yu and Min, Josine L and Neale, Benjamin M and Thorleifsson, Gudmar and Yang, Jian and Albrecht, Eva and Amin, Najaf and Bragg-Gresham, Jennifer L and Cadby, Gemma and den Heijer, Martin and Eklund, Niina and Fischer, Krista and Goel, Anuj and Hottenga, Jouke-Jan and Huffman, Jennifer E and Jarick, Ivonne and Johansson, Asa and Johnson, Toby and Kanoni, Stavroula and Kleber, Marcus E and K{\"o}nig, Inke R and Kristiansson, Kati and Kutalik, Zolt{\'a}n and Lamina, Claudia and Lecoeur, C{\'e}cile and Li, Guo and Mangino, Massimo and McArdle, Wendy L and Medina-G{\'o}mez, Carolina and M{\"u}ller-Nurasyid, Martina and Ngwa, Julius S and Nolte, Ilja M and Paternoster, Lavinia and Pechlivanis, Sonali and Perola, Markus and Peters, Marjolein J and Preuss, Michael and Rose, Lynda M and Shi, Jianxin and Shungin, Dmitry and Smith, Albert Vernon and Strawbridge, Rona J and Surakka, Ida and Teumer, Alexander and Trip, Mieke D and Tyrer, Jonathan and van Vliet-Ostaptchouk, Jana V and Vandenput, Liesbeth and Waite, Lindsay L and Zhao, Jing Hua and Absher, Devin and Asselbergs, Folkert W and Atalay, Mustafa and Attwood, Antony P and Balmforth, Anthony J and Basart, Hanneke and Beilby, John and Bonnycastle, Lori L and Brambilla, Paolo and Bruinenberg, Marcel and Campbell, Harry and Chasman, Daniel I and Chines, Peter S and Collins, Francis S and Connell, John M and Cookson, William O and de Faire, Ulf and de Vegt, Femmie and Dei, Mariano and Dimitriou, Maria and Edkins, Sarah and Estrada, Karol and Evans, David M and Farrall, Martin and Ferrario, Marco M and Ferrieres, Jean and Franke, Lude and Frau, Francesca and Gejman, Pablo V and Grallert, Harald and Gr{\"o}nberg, Henrik and Gudnason, Vilmundur and Hall, Alistair S and Hall, Per and Hartikainen, Anna-Liisa and Hayward, Caroline and Heard-Costa, Nancy L and Heath, Andrew C and Hebebrand, Johannes and Homuth, Georg and Hu, Frank B and Hunt, Sarah E and Hypp{\"o}nen, Elina and Iribarren, Carlos and Jacobs, Kevin B and Jansson, John-Olov and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kathiresan, Sekar and Kee, Frank and Khaw, Kay-Tee and Kivimaki, Mika and Koenig, Wolfgang and Kraja, Aldi T and Kumari, Meena and Kuulasmaa, Kari and Kuusisto, Johanna and Laitinen, Jaana H and Lakka, Timo A and Langenberg, Claudia and Launer, Lenore J and Lind, Lars and Lindstr{\"o}m, Jaana and Liu, Jianjun and Liuzzi, Antonio and Lokki, Marja-Liisa and Lorentzon, Mattias and Madden, Pamela A and Magnusson, Patrik K and Manunta, Paolo and Marek, Diana and M{\"a}rz, Winfried and Mateo Leach, Irene and McKnight, Barbara and Medland, Sarah E and Mihailov, Evelin and Milani, Lili and Montgomery, Grant W and Mooser, Vincent and M{\"u}hleisen, Thomas W and Munroe, Patricia B and Musk, Arthur W and Narisu, Narisu and Navis, Gerjan and Nicholson, George and Nohr, Ellen A and Ong, Ken K and Oostra, Ben A and Palmer, Colin N A and Palotie, Aarno and Peden, John F and Pedersen, Nancy and Peters, Annette and Polasek, Ozren and Pouta, Anneli and Pramstaller, Peter P and Prokopenko, Inga and P{\"u}tter, Carolin and Radhakrishnan, Aparna and Raitakari, Olli and Rendon, Augusto and Rivadeneira, Fernando and Rudan, Igor and Saaristo, Timo E and Sambrook, Jennifer G and Sanders, Alan R and Sanna, Serena and Saramies, Jouko and Schipf, Sabine and Schreiber, Stefan and Schunkert, Heribert and Shin, So-Youn and Signorini, Stefano and Sinisalo, Juha and Skrobek, Boris and Soranzo, Nicole and Stan{\v c}{\'a}kov{\'a}, Alena and Stark, Klaus and Stephens, Jonathan C and Stirrups, Kathleen and Stolk, Ronald P and Stumvoll, Michael and Swift, Amy J and Theodoraki, Eirini V and Thorand, Barbara and Tr{\'e}gou{\"e}t, David-Alexandre and Tremoli, Elena and van der Klauw, Melanie M and van Meurs, Joyce B J and Vermeulen, Sita H and Viikari, Jorma and Virtamo, Jarmo and Vitart, Veronique and Waeber, G{\'e}rard and Wang, Zhaoming and Widen, Elisabeth and Wild, Sarah H and Willemsen, Gonneke and Winkelmann, Bernhard R and Witteman, Jacqueline C M and Wolffenbuttel, Bruce H R and Wong, Andrew and Wright, Alan F and Zillikens, M Carola and Amouyel, Philippe and Boehm, Bernhard O and Boerwinkle, Eric and Boomsma, Dorret I and Caulfield, Mark J and Chanock, Stephen J and Cupples, L Adrienne and Cusi, Daniele and Dedoussis, George V and Erdmann, Jeanette and Eriksson, Johan G and Franks, Paul W and Froguel, Philippe and Gieger, Christian and Gyllensten, Ulf and Hamsten, Anders and Harris, Tamara B and Hengstenberg, Christian and Hicks, Andrew A and Hingorani, Aroon and Hinney, Anke and Hofman, Albert and Hovingh, Kees G and Hveem, Kristian and Illig, Thomas and Jarvelin, Marjo-Riitta and J{\"o}ckel, Karl-Heinz and Keinanen-Kiukaanniemi, Sirkka M and Kiemeney, Lambertus A and Kuh, Diana and Laakso, Markku and Lehtim{\"a}ki, Terho and Levinson, Douglas F and Martin, Nicholas G and Metspalu, Andres and Morris, Andrew D and Nieminen, Markku S and Nj{\o}lstad, Inger and Ohlsson, Claes and Oldehinkel, Albertine J and Ouwehand, Willem H and Palmer, Lyle J and Penninx, Brenda and Power, Chris and Province, Michael A and Psaty, Bruce M and Qi, Lu and Rauramaa, Rainer and Ridker, Paul M and Ripatti, Samuli and Salomaa, Veikko and Samani, Nilesh J and Snieder, Harold and S{\o}rensen, Thorkild I A and Spector, Timothy D and Stefansson, Kari and T{\"o}njes, Anke and Tuomilehto, Jaakko and Uitterlinden, Andr{\'e} G and Uusitupa, Matti and van der Harst, Pim and Vollenweider, Peter and Wallaschofski, Henri and Wareham, Nicholas J and Watkins, Hugh and Wichmann, H-Erich and Wilson, James F and Abecasis, Goncalo R and Assimes, Themistocles L and Barroso, In{\^e}s and Boehnke, Michael and Borecki, Ingrid B and Deloukas, Panos and Fox, Caroline S and Frayling, Timothy and Groop, Leif C and Haritunian, Talin and Heid, Iris M and Hunter, David and Kaplan, Robert C and Karpe, Fredrik and Moffatt, Miriam F and Mohlke, Karen L and O{\textquoteright}Connell, Jeffrey R and Pawitan, Yudi and Schadt, Eric E and Schlessinger, David and Steinthorsdottir, Valgerdur and Strachan, David P and Thorsteinsdottir, Unnur and van Duijn, Cornelia M and Visscher, Peter M and Di Blasio, Anna Maria and Hirschhorn, Joel N and Lindgren, Cecilia M and Morris, Andrew P and Meyre, David and Scherag, Andre and McCarthy, Mark I and Speliotes, Elizabeth K and North, Kari E and Loos, Ruth J F and Ingelsson, Erik} } @article {6155, title = {Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease.}, journal = {Circulation}, volume = {128}, year = {2013}, month = {2013 Sep 17}, pages = {1310-24}, abstract = {

BACKGROUND: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34\% to 50\%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2\%) of its variation.

METHODS AND RESULTS: We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5{\texttimes}10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7\% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism.

CONCLUSIONS: We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.

}, keywords = {Adolescent, Adult, African Continental Ancestry Group, Aged, Aged, 80 and over, Cardiovascular Diseases, Coronary Artery Disease, European Continental Ancestry Group, Female, Fibrinogen, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Hispanic Americans, Humans, Male, Middle Aged, Myocardial Infarction, Polymorphism, Single Nucleotide, Risk Factors, Stroke, Venous Thromboembolism, Young Adult}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.113.002251}, author = {Sabater-Lleal, Maria and Huang, Jie and Chasman, Daniel and Naitza, Silvia and Dehghan, Abbas and Johnson, Andrew D and Teumer, Alexander and Reiner, Alex P and Folkersen, Lasse and Basu, Saonli and Rudnicka, Alicja R and Trompet, Stella and M{\"a}larstig, Anders and Baumert, Jens and Bis, Joshua C and Guo, Xiuqing and Hottenga, Jouke J and Shin, So-Youn and Lopez, Lorna M and Lahti, Jari and Tanaka, Toshiko and Yanek, Lisa R and Oudot-Mellakh, Tiphaine and Wilson, James F and Navarro, Pau and Huffman, Jennifer E and Zemunik, Tatijana and Redline, Susan and Mehra, Reena and Pulanic, Drazen and Rudan, Igor and Wright, Alan F and Kolcic, Ivana and Polasek, Ozren and Wild, Sarah H and Campbell, Harry and Curb, J David and Wallace, Robert and Liu, Simin and Eaton, Charles B and Becker, Diane M and Becker, Lewis C and Bandinelli, Stefania and R{\"a}ikk{\"o}nen, Katri and Widen, Elisabeth and Palotie, Aarno and Fornage, Myriam and Green, David and Gross, Myron and Davies, Gail and Harris, Sarah E and Liewald, David C and Starr, John M and Williams, Frances M K and Grant, Peter J and Spector, Timothy D and Strawbridge, Rona J and Silveira, Angela and Sennblad, Bengt and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Franco, Oscar H and Hofman, Albert and van Dongen, Jenny and Willemsen, Gonneke and Boomsma, Dorret I and Yao, Jie and Swords Jenny, Nancy and Haritunians, Talin and McKnight, Barbara and Lumley, Thomas and Taylor, Kent D and Rotter, Jerome I and Psaty, Bruce M and Peters, Annette and Gieger, Christian and Illig, Thomas and Grotevendt, Anne and Homuth, Georg and V{\"o}lzke, Henry and Kocher, Thomas and Goel, Anuj and Franzosi, Maria Grazia and Seedorf, Udo and Clarke, Robert and Steri, Maristella and Tarasov, Kirill V and Sanna, Serena and Schlessinger, David and Stott, David J and Sattar, Naveed and Buckley, Brendan M and Rumley, Ann and Lowe, Gordon D and McArdle, Wendy L and Chen, Ming-Huei and Tofler, Geoffrey H and Song, Jaejoon and Boerwinkle, Eric and Folsom, Aaron R and Rose, Lynda M and Franco-Cereceda, Anders and Teichert, Martina and Ikram, M Arfan and Mosley, Thomas H and Bevan, Steve and Dichgans, Martin and Rothwell, Peter M and Sudlow, Cathie L M and Hopewell, Jemma C and Chambers, John C and Saleheen, Danish and Kooner, Jaspal S and Danesh, John and Nelson, Christopher P and Erdmann, Jeanette and Reilly, Muredach P and Kathiresan, Sekar and Schunkert, Heribert and Morange, Pierre-Emmanuel and Ferrucci, Luigi and Eriksson, Johan G and Jacobs, David and Deary, Ian J and Soranzo, Nicole and Witteman, Jacqueline C M and de Geus, Eco J C and Tracy, Russell P and Hayward, Caroline and Koenig, Wolfgang and Cucca, Francesco and Jukema, J Wouter and Eriksson, Per and Seshadri, Sudha and Markus, Hugh S and Watkins, Hugh and Samani, Nilesh J and Wallaschofski, Henri and Smith, Nicholas L and Tregouet, David and Ridker, Paul M and Tang, Weihong and Strachan, David P and Hamsten, Anders and O{\textquoteright}Donnell, Christopher J} } @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 {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 {6367, title = {Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {34}, year = {2014}, month = {2014 May}, pages = {1093-101}, abstract = {

OBJECTIVE: Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases. We conducted a meta-analysis of genome-wide association studies to identify novel correlates of circulating levels of tPA.

APPROACH AND RESULTS: Fourteen cohort studies with tPA measures (N=26 929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels (P<5.0{\texttimes}10(-8)). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9{\texttimes}10(-14)) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3{\texttimes}10(-9)) is intronic to POLB and <200 kb away from the tPA encoding the gene PLAT. We identified a nonsynonymous SNP (rs2020921) in modest linkage disequilibrium with rs3136739 (r(2)=0.50) within exon 5 of PLAT (P=2.0{\texttimes}10(-8)). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0{\texttimes}10(-9)) within intron 7 of STX2. We further found evidence for the association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased the release of tPA from vascular endothelial cells, whereas silencing STX2 increased the tPA release. Through an in silico lookup, we found no associations of the 3 lead SNPs with coronary artery disease or stroke.

CONCLUSIONS: We identified 3 loci associated with circulating tPA levels, the PLAT region, STXBP5, and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release.

}, keywords = {Aged, Cells, Cultured, Coronary Artery Disease, Endothelial Cells, Europe, Female, Gene Expression Regulation, Gene Silencing, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Nerve Tissue Proteins, Phenotype, Polymorphism, Single Nucleotide, R-SNARE Proteins, Risk Factors, Stroke, Syntaxin 1, Tissue Plasminogen Activator, Transfection, United States, Up-Regulation}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.113.302088}, author = {Huang, Jie and Huffman, Jennifer E and Yamakuchi, Munekazu and Yamkauchi, Munekazu and Trompet, Stella and Asselbergs, Folkert W and Sabater-Lleal, Maria and Tr{\'e}gou{\"e}t, David-Alexandre and Chen, Wei-Min and Smith, Nicholas L and Kleber, Marcus E and Shin, So-Youn and Becker, Diane M and Tang, Weihong and Dehghan, Abbas and Johnson, Andrew D and Truong, Vinh and Folkersen, Lasse and Yang, Qiong and Oudot-Mellkah, Tiphaine and Buckley, Brendan M and Moore, Jason H and Williams, Frances M K and Campbell, Harry and Silbernagel, G{\"u}nther and Vitart, Veronique and Rudan, Igor and Tofler, Geoffrey H and Navis, Gerjan J and DeStefano, Anita and Wright, Alan F and Chen, Ming-Huei and de Craen, Anton J M and Worrall, Bradford B and Rudnicka, Alicja R and Rumley, Ann and Bookman, Ebony B and Psaty, Bruce M and Chen, Fang and Keene, Keith L and Franco, Oscar H and B{\"o}hm, Bernhard O and Uitterlinden, Andr{\'e} G and Carter, Angela M and Jukema, J Wouter and Sattar, Naveed and Bis, Joshua C and Ikram, Mohammad A and Sale, Mich{\`e}le M and McKnight, Barbara and Fornage, Myriam and Ford, Ian and Taylor, Kent and Slagboom, P Eline and McArdle, Wendy L and Hsu, Fang-Chi and Franco-Cereceda, Anders and Goodall, Alison H and Yanek, Lisa R and Furie, Karen L and Cushman, Mary and Hofman, Albert and Witteman, Jacqueline C M and Folsom, Aaron R and Basu, Saonli and Matijevic, Nena and van Gilst, Wiek H and Wilson, James F and Westendorp, Rudi G J and Kathiresan, Sekar and Reilly, Muredach P and Tracy, Russell P and Polasek, Ozren and Winkelmann, Bernhard R and Grant, Peter J and Hillege, Hans L and Cambien, Francois and Stott, David J and Lowe, Gordon D and Spector, Timothy D and Meigs, James B and M{\"a}rz, Winfried and Eriksson, Per and Becker, Lewis C and Morange, Pierre-Emmanuel and Soranzo, Nicole and Williams, Scott M and Hayward, Caroline and van der Harst, Pim and Hamsten, Anders and Lowenstein, Charles J and Strachan, David P and O{\textquoteright}Donnell, Christopher J} } @article {6667, title = {No evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e111156}, abstract = {

Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2 {\texttimes} 10(-8). This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.

}, keywords = {Alcohol Drinking, Body Mass Index, Fibrinogen, Gene-Environment Interaction, Genomics, Humans, Smoking}, issn = {1932-6203}, doi = {10.1371/journal.pone.0111156}, author = {Baumert, Jens and Huang, Jie and McKnight, Barbara and Sabater-Lleal, Maria and Steri, Maristella and Chu, Audrey Y and Trompet, Stella and Lopez, Lorna M and Fornage, Myriam and Teumer, Alexander and Tang, Weihong and Rudnicka, Alicja R and M{\"a}larstig, Anders and Hottenga, Jouke-Jan and Kavousi, Maryam and Lahti, Jari and Tanaka, Toshiko and Hayward, Caroline and Huffman, Jennifer E and Morange, Pierre-Emmanuel and Rose, Lynda M and Basu, Saonli and Rumley, Ann and Stott, David J and Buckley, Brendan M and de Craen, Anton J M and Sanna, Serena and Masala, Marco and Biffar, Reiner and Homuth, Georg and Silveira, Angela and Sennblad, Bengt and Goel, Anuj and Watkins, Hugh and M{\"u}ller-Nurasyid, Martina and R{\"u}ckerl, Regina and Taylor, Kent and Chen, Ming-Huei and de Geus, Eco J C and Hofman, Albert and Witteman, Jacqueline C M and de Maat, Moniek P M and Palotie, Aarno and Davies, Gail and Siscovick, David S and Kolcic, Ivana and Wild, Sarah H and Song, Jaejoon and McArdle, Wendy L and Ford, Ian and Sattar, Naveed and Schlessinger, David and Grotevendt, Anne and Franzosi, Maria Grazia and Illig, Thomas and Waldenberger, Melanie and Lumley, Thomas and Tofler, Geoffrey H and Willemsen, Gonneke and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and R{\"a}ikk{\"o}nen, Katri and Chasman, Daniel I and Folsom, Aaron R and Lowe, Gordon D and Westendorp, Rudi G J and Slagboom, P Eline and Cucca, Francesco and Wallaschofski, Henri and Strawbridge, Rona J and Seedorf, Udo and Koenig, Wolfgang and Bis, Joshua C and Mukamal, Kenneth J and van Dongen, Jenny and Widen, Elisabeth and Franco, Oscar H and Starr, John M and Liu, Kiang and Ferrucci, Luigi and Polasek, Ozren and Wilson, James F and Oudot-Mellakh, Tiphaine and Campbell, Harry and Navarro, Pau and Bandinelli, Stefania and Eriksson, Johan and Boomsma, Dorret I and Dehghan, Abbas and Clarke, Robert and Hamsten, Anders and Boerwinkle, Eric and Jukema, J Wouter and Naitza, Silvia and Ridker, Paul M and V{\"o}lzke, Henry and Deary, Ian J and Reiner, Alexander P and Tr{\'e}gou{\"e}t, David-Alexandre and O{\textquoteright}Donnell, Christopher J and Strachan, David P and Peters, Annette and Smith, Nicholas L} } @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 {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 {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 {6788, title = {Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF.}, journal = {Blood}, volume = {126}, year = {2015}, month = {2015 Sep 10}, pages = {e19-29}, abstract = {

Fibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] >=0.01 and <0.05) and rare (MAF <0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76,000 participants of 4 ancestries. We identified 12 novel associations of low-frequency (n = 2) and rare (n = 10) variants across the fibrinogen, FVII, FVIII, and vWF traits that were independent of previously identified associations. Novel loci were found within previously reported genes and had effect sizes much larger than and independent of previously identified common variants. In addition, associations at KCNT1, HID1, and KATNB1 identified new candidate genes related to hemostasis for follow-up replication and functional genomic analysis. Newly identified low-frequency and rare-variant associations accounted for modest amounts of trait variance and therefore are unlikely to increase predicted trait heritability but provide new information for understanding individual variation in hemostasis pathways.

}, keywords = {Cohort Studies, Factor VII, Factor VIII, Fibrinogen, Gene Frequency, Genetic Association Studies, Genetic Variation, Humans, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Potassium Channels, von Willebrand Factor}, issn = {1528-0020}, doi = {10.1182/blood-2015-02-624551}, author = {Huffman, Jennifer E and de Vries, Paul S and Morrison, Alanna C and Sabater-Lleal, Maria and Kacprowski, Tim and Auer, Paul L and Brody, Jennifer A and Chasman, Daniel I and Chen, Ming-Huei and Guo, Xiuqing and Lin, Li-An and Marioni, Riccardo E and M{\"u}ller-Nurasyid, Martina and Yanek, Lisa R and Pankratz, Nathan and Grove, Megan L and de Maat, Moniek P M and Cushman, Mary and Wiggins, Kerri L and Qi, Lihong and Sennblad, Bengt and Harris, Sarah E and Polasek, Ozren and Riess, Helene and Rivadeneira, Fernando and Rose, Lynda M and Goel, Anuj and Taylor, Kent D and Teumer, Alexander and Uitterlinden, Andr{\'e} G and Vaidya, Dhananjay and Yao, Jie and Tang, Weihong and Levy, Daniel and Waldenberger, Melanie and Becker, Diane M and Folsom, Aaron R and Giulianini, Franco and Greinacher, Andreas and Hofman, Albert and Huang, Chiang-Ching and Kooperberg, Charles and Silveira, Angela and Starr, John M and Strauch, Konstantin and Strawbridge, Rona J and Wright, Alan F and McKnight, Barbara and Franco, Oscar H and Zakai, Neil and Mathias, Rasika A and Psaty, Bruce M and Ridker, Paul M and Tofler, Geoffrey H and V{\"o}lker, Uwe and Watkins, Hugh and Fornage, Myriam and Hamsten, Anders and Deary, Ian J and Boerwinkle, Eric and Koenig, Wolfgang and Rotter, Jerome I and Hayward, Caroline and Dehghan, Abbas and Reiner, Alex P and O{\textquoteright}Donnell, Christopher J and Smith, Nicholas L} } @article {7145, title = {An Empirical Comparison of Joint and Stratified Frameworks for Studying G {\texttimes} E Interactions: Systolic Blood Pressure and Smoking in the CHARGE Gene-Lifestyle Interactions Working Group.}, journal = {Genet Epidemiol}, volume = {40}, year = {2016}, month = {2016 Jul}, pages = {404-15}, abstract = {

Studying gene-environment (G {\texttimes} E) interactions is important, as they extend our knowledge of the genetic architecture of complex traits and may help to identify novel variants not detected via analysis of main effects alone. The main statistical framework for studying G {\texttimes} E interactions uses a single regression model that includes both the genetic main and G {\texttimes} E interaction effects (the "joint" framework). The alternative "stratified" framework combines results from genetic main-effect analyses carried out separately within the exposed and unexposed groups. Although there have been several investigations using theory and simulation, an empirical comparison of the two frameworks is lacking. Here, we compare the two frameworks using results from genome-wide association studies of systolic blood pressure for 3.2 million low frequency and 6.5 million common variants across 20 cohorts of European ancestry, comprising 79,731 individuals. Our cohorts have sample sizes ranging from 456 to 22,983 and include both family-based and population-based samples. In cohort-specific analyses, the two frameworks provided similar inference for population-based cohorts. The agreement was reduced for family-based cohorts. In meta-analyses, agreement between the two frameworks was less than that observed in cohort-specific analyses, despite the increased sample size. In meta-analyses, agreement depended on (1) the minor allele frequency, (2) inclusion of family-based cohorts in meta-analysis, and (3) filtering scheme. The stratified framework appears to approximate the joint framework well only for common variants in population-based cohorts. We conclude that the joint framework is the preferred approach and should be used to control false positives when dealing with low-frequency variants and/or family-based cohorts.

}, issn = {1098-2272}, doi = {10.1002/gepi.21978}, author = {Sung, Yun Ju and Winkler, Thomas W and Manning, Alisa K and Aschard, Hugues and Gudnason, Vilmundur and Harris, Tamara B and Smith, Albert V and Boerwinkle, Eric and Brown, Michael R and Morrison, Alanna C and Fornage, Myriam and Lin, Li-An and Richard, Melissa and Bartz, Traci M and Psaty, Bruce M and Hayward, Caroline and Polasek, Ozren and Marten, Jonathan and Rudan, Igor and Feitosa, Mary F and Kraja, Aldi T and Province, Michael A and Deng, Xuan and Fisher, Virginia A and Zhou, Yanhua and Bielak, Lawrence F and Smith, Jennifer and Huffman, Jennifer E and Padmanabhan, Sandosh and Smith, Blair H and Ding, Jingzhong and Liu, Yongmei and Lohman, Kurt and Bouchard, Claude and Rankinen, Tuomo and Rice, Treva K and Arnett, Donna and Schwander, Karen and Guo, Xiuqing and Palmas, Walter and Rotter, Jerome I and Alfred, Tamuno and Bottinger, Erwin P and Loos, Ruth J F and Amin, Najaf and Franco, Oscar H and van Duijn, Cornelia M and Vojinovic, Dina and Chasman, Daniel I and Ridker, Paul M and Rose, Lynda M and Kardia, Sharon and Zhu, Xiaofeng and Rice, Kenneth and Borecki, Ingrid B and Rao, Dabeeru C and Gauderman, W James and Cupples, L Adrienne} } @article {7136, title = {General Framework for Meta-Analysis of Haplotype Association Tests.}, journal = {Genet Epidemiol}, volume = {40}, year = {2016}, month = {2016 Apr}, pages = {244-52}, abstract = {

For complex traits, most associated single nucleotide variants (SNV) discovered to date have a small effect, and detection of association is only possible with large sample sizes. Because of patient confidentiality concerns, it is often not possible to pool genetic data from multiple cohorts, and meta-analysis has emerged as the method of choice to combine results from multiple studies. Many meta-analysis methods are available for single SNV analyses. As new approaches allow the capture of low frequency and rare genetic variation, it is of interest to jointly consider multiple variants to improve power. However, for the analysis of haplotypes formed by multiple SNVs, meta-analysis remains a challenge, because different haplotypes may be observed across studies. We propose a two-stage meta-analysis approach to combine haplotype analysis results. In the first stage, each cohort estimate haplotype effect sizes in a regression framework, accounting for relatedness among observations if appropriate. For the second stage, we use a multivariate generalized least square meta-analysis approach to combine haplotype effect estimates from multiple cohorts. Haplotype-specific association tests and a global test of independence between haplotypes and traits are obtained within our framework. We demonstrate through simulation studies that we control the type-I error rate, and our approach is more powerful than inverse variance weighted meta-analysis of single SNV analysis when haplotype effects are present. We replicate a published haplotype association between fasting glucose-associated locus (G6PC2) and fasting glucose in seven studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and we provide more precise haplotype effect estimates.

}, issn = {1098-2272}, doi = {10.1002/gepi.21959}, author = {Wang, Shuai and Zhao, Jing Hua and An, Ping and Guo, Xiuqing and Jensen, Richard A and Marten, Jonathan and Huffman, Jennifer E and Meidtner, Karina and Boeing, Heiner and Campbell, Archie and Rice, Kenneth M and Scott, Robert A and Yao, Jie and Schulze, Matthias B and Wareham, Nicholas J and Borecki, Ingrid B and Province, Michael A and Rotter, Jerome I and Hayward, Caroline and Goodarzi, Mark O and Meigs, James B and Dupuis, Jos{\'e}e} } @article {7168, title = {Genetic variants in RBFOX3 are associated with sleep latency.}, journal = {Eur J Hum Genet}, volume = {24}, year = {2016}, month = {2016 Oct}, pages = {1488-95}, abstract = {

Time to fall asleep (sleep latency) is a major determinant of sleep quality. Chronic, long sleep latency is a major characteristic of sleep-onset insomnia and/or delayed sleep phase syndrome. In this study we aimed to discover common polymorphisms that contribute to the genetics of sleep latency. We performed a meta-analysis of genome-wide association studies (GWAS) including 2 572 737 single nucleotide polymorphisms (SNPs) established in seven European cohorts including 4242 individuals. We found a cluster of three highly correlated variants (rs9900428, rs9907432 and rs7211029) in the RNA-binding protein fox-1 homolog 3 gene (RBFOX3) associated with sleep latency (P-values=5.77 {\texttimes} 10(-08), 6.59 {\texttimes} 10(-)(08) and 9.17 {\texttimes} 10(-)(08)). These SNPs were replicated in up to 12 independent populations including 30 377 individuals (P-values=1.5 {\texttimes} 10(-)(02), 7.0 {\texttimes} 10(-)(03) and 2.5 {\texttimes} 10(-)(03); combined meta-analysis P-values=5.5 {\texttimes} 10(-07), 5.4 {\texttimes} 10(-07) and 1.0 {\texttimes} 10(-07)). A functional prediction of RBFOX3 based on co-expression with other genes shows that this gene is predominantly expressed in brain (P-value=1.4 {\texttimes} 10(-316)) and the central nervous system (P-value=7.5 {\texttimes} 10(-)(321)). The predicted function of RBFOX3 based on co-expression analysis with other genes shows that this gene is significantly involved in the release cycle of neurotransmitters including gamma-aminobutyric acid and various monoamines (P-values<2.9 {\texttimes} 10(-11)) that are crucial in triggering the onset of sleep. To conclude, in this first large-scale GWAS of sleep latency we report a novel association of variants in RBFOX3 gene. Further, a functional prediction of RBFOX3 supports the involvement of RBFOX3 with sleep latency.

}, issn = {1476-5438}, doi = {10.1038/ejhg.2016.31}, author = {Amin, Najaf and Allebrandt, Karla V and van der Spek, Ashley and M{\"u}ller-Myhsok, Bertram and Hek, Karin and Teder-Laving, Maris and Hayward, Caroline and Esko, T{\~o}nu and van Mill, Josine G and Mbarek, Hamdi and Watson, Nathaniel F and Melville, Scott A and Del Greco, Fabiola M and Byrne, Enda M and Oole, Edwin and Kolcic, Ivana and Chen, Ting-Hsu and Evans, Daniel S and Coresh, Josef and Vogelzangs, Nicole and Karjalainen, Juha and Willemsen, Gonneke and Gharib, Sina A and Zgaga, Lina and Mihailov, Evelin and Stone, Katie L and Campbell, Harry and Brouwer, Rutger Ww and Demirkan, Ayse and Isaacs, Aaron and Dogas, Zoran and Marciante, Kristin D and Campbell, Susan and Borovecki, Fran and Luik, Annemarie I and Li, Man and Hottenga, Jouke Jan and Huffman, Jennifer E and van den Hout, Mirjam Cgn and Cummings, Steven R and Aulchenko, Yurii S and Gehrman, Philip R and Uitterlinden, Andr{\'e} G and Wichmann, Heinz-Erich and M{\"u}ller-Nurasyid, Martina and Fehrmann, Rudolf Sn and Montgomery, Grant W and Hofman, Albert and Kao, Wen Hong Linda and Oostra, Ben A and Wright, Alan F and Vink, Jacqueline M and Wilson, James F and Pramstaller, Peter P and Hicks, Andrew A and Polasek, Ozren and Punjabi, Naresh M and Redline, Susan and Psaty, Bruce M and Heath, Andrew C and Merrow, Martha and Tranah, Gregory J and Gottlieb, Daniel J and Boomsma, Dorret I and Martin, Nicholas G and Rudan, Igor and Tiemeier, Henning and van IJcken, Wilfred Fj and Penninx, Brenda W and Metspalu, Andres and Meitinger, Thomas and Franke, Lude and Roenneberg, Till and van Duijn, Cornelia M} } @article {6936, title = {A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration.}, journal = {Hum Mol Genet}, volume = {25}, year = {2016}, month = {2016 Jan 15}, pages = {358-70}, abstract = {

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including \~{}120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3\% of the variance in plasma fibrinogen concentration.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddv454}, author = {de Vries, Paul S and Chasman, Daniel I and Sabater-Lleal, Maria and Chen, Ming-Huei and Huffman, Jennifer E and Steri, Maristella and Tang, Weihong and Teumer, Alexander and Marioni, Riccardo E and Grossmann, Vera and Hottenga, Jouke J and Trompet, Stella and M{\"u}ller-Nurasyid, Martina and Zhao, Jing Hua and Brody, Jennifer A and Kleber, Marcus E and Guo, Xiuqing and Wang, Jie Jin and Auer, Paul L and Attia, John R and Yanek, Lisa R and Ahluwalia, Tarunveer S and Lahti, Jari and Venturini, Cristina and Tanaka, Toshiko and Bielak, Lawrence F and Joshi, Peter K and Rocanin-Arjo, Ares and Kolcic, Ivana and Navarro, Pau and Rose, Lynda M and Oldmeadow, Christopher and Riess, Helene and Mazur, Johanna and Basu, Saonli and Goel, Anuj and Yang, Qiong and Ghanbari, Mohsen and Willemsen, Gonneke and Rumley, Ann and Fiorillo, Edoardo and de Craen, Anton J M and Grotevendt, Anne and Scott, Robert and Taylor, Kent D and Delgado, Graciela E and Yao, Jie and Kifley, Annette and Kooperberg, Charles and Qayyum, Rehan and Lopez, Lorna M and Berentzen, Tina L and R{\"a}ikk{\"o}nen, Katri and Mangino, Massimo and Bandinelli, Stefania and Peyser, Patricia A and Wild, Sarah and Tr{\'e}gou{\"e}t, David-Alexandre and Wright, Alan F and Marten, Jonathan and Zemunik, Tatijana and Morrison, Alanna C and Sennblad, Bengt and Tofler, Geoffrey and de Maat, Moniek P M and de Geus, Eco J C and Lowe, Gordon D and Zoledziewska, Magdalena and Sattar, Naveed and Binder, Harald and V{\"o}lker, Uwe and Waldenberger, Melanie and Khaw, Kay-Tee and McKnight, Barbara and Huang, Jie and Jenny, Nancy S and Holliday, Elizabeth G and Qi, Lihong and Mcevoy, Mark G and Becker, Diane M and Starr, John M and Sarin, Antti-Pekka and Hysi, Pirro G and Hernandez, Dena G and Jhun, Min A and Campbell, Harry and Hamsten, Anders and Rivadeneira, Fernando and McArdle, Wendy L and Slagboom, P Eline and Zeller, Tanja and Koenig, Wolfgang and Psaty, Bruce M and Haritunians, Talin and Liu, Jingmin and Palotie, Aarno and Uitterlinden, Andr{\'e} G and Stott, David J and Hofman, Albert and Franco, Oscar H and Polasek, Ozren and Rudan, Igor and Morange, Pierre-Emmanuel and Wilson, James F and Kardia, Sharon L R and Ferrucci, Luigi and Spector, Tim D and Eriksson, Johan G and Hansen, Torben and Deary, Ian J and Becker, Lewis C and Scott, Rodney J and Mitchell, Paul and M{\"a}rz, Winfried and Wareham, Nick J and Peters, Annette and Greinacher, Andreas and Wild, Philipp S and Jukema, J Wouter and Boomsma, Dorret I and Hayward, Caroline and Cucca, Francesco and Tracy, Russell and Watkins, Hugh and Reiner, Alex P and Folsom, Aaron R and Ridker, Paul M and O{\textquoteright}Donnell, Christopher J and Smith, Nicholas L and Strachan, David P and Dehghan, Abbas} } @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 {8570, title = {A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape.}, journal = {Nat Commun}, volume = {7}, year = {2016}, month = {2016 11 23}, pages = {13357}, abstract = {

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99\% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

}, keywords = {Anthropometry, Body Size, Genome-Wide Association Study, Genotype, Humans, Models, Genetic, Principal Component Analysis}, issn = {2041-1723}, doi = {10.1038/ncomms13357}, author = {Ried, Janina S and Jeff M, Janina and Chu, Audrey Y and Bragg-Gresham, Jennifer L and van Dongen, Jenny and Huffman, Jennifer E and Ahluwalia, Tarunveer S and Cadby, Gemma and Eklund, Niina and Eriksson, Joel and Esko, T{\~o}nu and Feitosa, Mary F and Goel, Anuj and Gorski, Mathias and Hayward, Caroline and Heard-Costa, Nancy L and Jackson, Anne U and Jokinen, Eero and Kanoni, Stavroula and Kristiansson, Kati and Kutalik, Zolt{\'a}n and Lahti, Jari and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Mahajan, Anubha and Mangino, Massimo and Medina-G{\'o}mez, Carolina and Monda, Keri L and Nolte, Ilja M and Perusse, Louis and Prokopenko, Inga and Qi, Lu and Rose, Lynda M and Salvi, Erika and Smith, Megan T and Snieder, Harold and Stan{\v c}{\'a}kov{\'a}, Alena and Ju Sung, Yun and Tachmazidou, Ioanna and Teumer, Alexander and Thorleifsson, Gudmar and van der Harst, Pim and Walker, Ryan W and Wang, Sophie R and Wild, Sarah H and Willems, Sara M and Wong, Andrew and Zhang, Weihua and Albrecht, Eva and Couto Alves, Alexessander and Bakker, Stephan J L and Barlassina, Cristina and Bartz, Traci M and Beilby, John and Bellis, Claire and Bergman, Richard N and Bergmann, Sven and Blangero, John and Bl{\"u}her, Matthias and Boerwinkle, Eric and Bonnycastle, Lori L and Bornstein, Stefan R and Bruinenberg, Marcel and Campbell, Harry and Chen, Yii-Der Ida and Chiang, Charleston W K and Chines, Peter S and Collins, Francis S and Cucca, Fracensco and Cupples, L Adrienne and D{\textquoteright}Avila, Francesca and de Geus, Eco J C and Dedoussis, George and Dimitriou, Maria and D{\"o}ring, Angela and Eriksson, Johan G and Farmaki, Aliki-Eleni and Farrall, Martin and Ferreira, Teresa and Fischer, Krista and Forouhi, Nita G and Friedrich, Nele and Gjesing, Anette Prior and Glorioso, Nicola and Graff, Mariaelisa and Grallert, Harald and Grarup, Niels and Gr{\"a}{\ss}ler, J{\"u}rgen and Grewal, Jagvir and Hamsten, Anders and Harder, Marie Neergaard and Hartman, Catharina A and Hassinen, Maija and Hastie, Nicholas and Hattersley, Andrew Tym and Havulinna, Aki S and Heli{\"o}vaara, Markku and Hillege, Hans and Hofman, Albert and Holmen, Oddgeir and Homuth, Georg and Hottenga, Jouke-Jan and Hui, Jennie and Husemoen, Lise Lotte and Hysi, Pirro G and Isaacs, Aaron and Ittermann, Till and Jalilzadeh, Shapour and James, Alan L and J{\o}rgensen, Torben and Jousilahti, Pekka and Jula, Antti and Marie Justesen, Johanne and Justice, Anne E and K{\"a}h{\"o}nen, Mika and Karaleftheri, Maria and Tee Khaw, Kay and Keinanen-Kiukaanniemi, Sirkka M and Kinnunen, Leena and Knekt, Paul B and Koistinen, Heikki A and Kolcic, Ivana and Kooner, Ishminder K and Koskinen, Seppo and Kovacs, Peter and Kyriakou, Theodosios and Laitinen, Tomi and Langenberg, Claudia and Lewin, Alexandra M and Lichtner, Peter and Lindgren, Cecilia M and Lindstr{\"o}m, Jaana and Linneberg, Allan and Lorbeer, Roberto and Lorentzon, Mattias and Luben, Robert and Lyssenko, Valeriya and M{\"a}nnist{\"o}, Satu and Manunta, Paolo and Leach, Irene Mateo and McArdle, Wendy L and McKnight, Barbara and Mohlke, Karen L and Mihailov, Evelin and Milani, Lili and Mills, Rebecca and Montasser, May E and Morris, Andrew P and M{\"u}ller, Gabriele and Musk, Arthur W and Narisu, Narisu and Ong, Ken K and Oostra, Ben A and Osmond, Clive and Palotie, Aarno and Pankow, James S and Paternoster, Lavinia and Penninx, Brenda W and Pichler, Irene and Pilia, Maria G and Polasek, Ozren and Pramstaller, Peter P and Raitakari, Olli T and Rankinen, Tuomo and Rao, D C and Rayner, Nigel W and Ribel-Madsen, Rasmus and Rice, Treva K and Richards, Marcus and Ridker, Paul M and Rivadeneira, Fernando and Ryan, Kathy A and Sanna, Serena and Sarzynski, Mark A and Scholtens, Salome and Scott, Robert A and Sebert, Sylvain and Southam, Lorraine and Spars{\o}, Thomas Hempel and Steinthorsdottir, Valgerdur and Stirrups, Kathleen and Stolk, Ronald P and Strauch, Konstantin and Stringham, Heather M and Swertz, Morris A and Swift, Amy J and T{\"o}njes, Anke and Tsafantakis, Emmanouil and van der Most, Peter J and van Vliet-Ostaptchouk, Jana V and Vandenput, Liesbeth and Vartiainen, Erkki and Venturini, Cristina and Verweij, Niek and Viikari, Jorma S and Vitart, Veronique and Vohl, Marie-Claude and Vonk, Judith M and Waeber, G{\'e}rard and Widen, Elisabeth and Willemsen, Gonneke and Wilsgaard, Tom and Winkler, Thomas W and Wright, Alan F and Yerges-Armstrong, Laura M and Hua Zhao, Jing and Zillikens, M Carola and Boomsma, Dorret I and Bouchard, Claude and Chambers, John C and Chasman, Daniel I and Cusi, Daniele and Gansevoort, Ron T and Gieger, Christian and Hansen, Torben and Hicks, Andrew A and Hu, Frank and Hveem, Kristian and Jarvelin, Marjo-Riitta and Kajantie, Eero and Kooner, Jaspal S and Kuh, Diana and Kuusisto, Johanna and Laakso, Markku and Lakka, Timo A and Lehtim{\"a}ki, Terho and Metspalu, Andres and Nj{\o}lstad, Inger and Ohlsson, Claes and Oldehinkel, Albertine J and Palmer, Lyle J and Pedersen, Oluf and Perola, Markus and Peters, Annette and Psaty, Bruce M and Puolijoki, Hannu and Rauramaa, Rainer and Rudan, Igor and Salomaa, Veikko and Schwarz, Peter E H and Shudiner, Alan R and Smit, Jan H and S{\o}rensen, Thorkild I A and Spector, Timothy D and Stefansson, Kari and Stumvoll, Michael and Tremblay, Angelo and Tuomilehto, Jaakko and Uitterlinden, Andr{\'e} G and Uusitupa, Matti and V{\"o}lker, Uwe and Vollenweider, Peter and Wareham, Nicholas J and Watkins, Hugh and Wilson, James F and Zeggini, Eleftheria and Abecasis, Goncalo R and Boehnke, Michael and Borecki, Ingrid B and Deloukas, Panos and van Duijn, Cornelia M and Fox, Caroline and Groop, Leif C and Heid, Iris M and Hunter, David J and Kaplan, Robert C and McCarthy, Mark I and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Schlessinger, David and Thorsteinsdottir, Unnur and Strachan, David P and Frayling, Timothy and Hirschhorn, Joel N and M{\"u}ller-Nurasyid, Martina and Loos, Ruth J F} } @article {7255, title = {SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.}, journal = {J Am Soc Nephrol}, year = {2016}, month = {2016 Dec 05}, abstract = {

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7{\texttimes}10(-7)), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4{\texttimes}10(-8) by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

}, issn = {1533-3450}, doi = {10.1681/ASN.2016020131}, author = {Li, Man and Li, Yong and Weeks, Olivia and Mijatovic, Vladan and Teumer, Alexander and Huffman, Jennifer E and Tromp, Gerard and Fuchsberger, Christian and Gorski, Mathias and Lyytik{\"a}inen, Leo-Pekka and Nutile, Teresa and Sedaghat, Sanaz and Sorice, Rossella and Tin, Adrienne and Yang, Qiong and Ahluwalia, Tarunveer S and Arking, Dan E and Bihlmeyer, Nathan A and B{\"o}ger, Carsten A and Carroll, Robert J and Chasman, Daniel I and Cornelis, Marilyn C and Dehghan, Abbas and Faul, Jessica D and Feitosa, Mary F and Gambaro, Giovanni and Gasparini, Paolo and Giulianini, Franco and Heid, Iris and Huang, Jinyan and Imboden, Medea and Jackson, Anne U and Jeff, Janina and Jhun, Min A and Katz, Ronit and Kifley, Annette and Kilpel{\"a}inen, Tuomas O and Kumar, Ashish and Laakso, Markku and Li-Gao, Ruifang and Lohman, Kurt and Lu, Yingchang and M{\"a}gi, Reedik and Malerba, Giovanni and Mihailov, Evelin and Mohlke, Karen L and Mook-Kanamori, Dennis O and Robino, Antonietta and Ruderfer, Douglas and Salvi, Erika and Schick, Ursula M and Schulz, Christina-Alexandra and Smith, Albert V and Smith, Jennifer A and Traglia, Michela and Yerges-Armstrong, Laura M and Zhao, Wei and Goodarzi, Mark O and Kraja, Aldi T and Liu, Chunyu and Wessel, Jennifer and Boerwinkle, Eric and Borecki, Ingrid B and Bork-Jensen, Jette and Bottinger, Erwin P and Braga, Daniele and Brandslund, Ivan and Brody, Jennifer A and Campbell, Archie and Carey, David J and Christensen, Cramer and Coresh, Josef and Crook, Errol and Curhan, Gary C and Cusi, Daniele and de Boer, Ian H and de Vries, Aiko P J and Denny, Joshua C and Devuyst, Olivier and Dreisbach, Albert W and Endlich, Karlhans and Esko, T{\~o}nu and Franco, Oscar H and Fulop, Tibor and Gerhard, Glenn S and Gl{\"u}mer, Charlotte and Gottesman, Omri and Grarup, Niels and Gudnason, Vilmundur and Harris, Tamara B and Hayward, Caroline and Hocking, Lynne and Hofman, Albert and Hu, Frank B and Husemoen, Lise Lotte N and Jackson, Rebecca D and J{\o}rgensen, Torben and J{\o}rgensen, Marit E and K{\"a}h{\"o}nen, Mika and Kardia, Sharon L R and K{\"o}nig, Wolfgang and Kooperberg, Charles and Kriebel, Jennifer and Launer, Lenore J and Lauritzen, Torsten and Lehtim{\"a}ki, Terho and Levy, Daniel and Linksted, Pamela and Linneberg, Allan and Liu, Yongmei and Loos, Ruth J F and Lupo, Antonio and Meisinger, Christine and Melander, Olle and Metspalu, Andres and Mitchell, Paul and Nauck, Matthias and N{\"u}rnberg, Peter and Orho-Melander, Marju and Parsa, Afshin and Pedersen, Oluf and Peters, Annette and Peters, Ulrike and Polasek, Ozren and Porteous, David and Probst-Hensch, Nicole M and Psaty, Bruce M and Qi, Lu and Raitakari, Olli T and Reiner, Alex P and Rettig, Rainer and Ridker, Paul M and Rivadeneira, Fernando and Rossouw, Jacques E and Schmidt, Frank and Siscovick, David and Soranzo, Nicole and Strauch, Konstantin and Toniolo, Daniela and Turner, Stephen T and Uitterlinden, Andr{\'e} G and Ulivi, Sheila and Velayutham, Dinesh and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Waldenberger, Melanie and Wang, Jie Jin and Weir, David R and Witte, Daniel and Kuivaniemi, Helena and Fox, Caroline S and Franceschini, Nora and Goessling, Wolfram and K{\"o}ttgen, Anna and Chu, Audrey Y} } @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 {7492, title = {Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.}, journal = {Hypertension}, year = {2017}, month = {2017 Jul 24}, abstract = {

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

}, issn = {1524-4563}, doi = {10.1161/HYPERTENSIONAHA.117.09438}, author = {Wain, Louise V and Vaez, Ahmad and Jansen, Rick and Joehanes, Roby and van der Most, Peter J and Erzurumluoglu, A Mesut and O{\textquoteright}Reilly, Paul F and Cabrera, Claudia P and Warren, Helen R and Rose, Lynda M and Verwoert, Germaine C and Hottenga, Jouke-Jan and Strawbridge, Rona J and Esko, T{\~o}nu and Arking, Dan E and Hwang, Shih-Jen and Guo, Xiuqing and Kutalik, Zolt{\'a}n and Trompet, Stella and Shrine, Nick and Teumer, Alexander and Ried, Janina S and Bis, Joshua C and Smith, Albert V and Amin, Najaf and Nolte, Ilja M and Lyytik{\"a}inen, Leo-Pekka and Mahajan, Anubha and Wareham, Nicholas J and Hofer, Edith and Joshi, Peter K and Kristiansson, Kati and Traglia, Michela and Havulinna, Aki S and Goel, Anuj and Nalls, Mike A and S{\~o}ber, Siim and Vuckovic, Dragana and Luan, Jian{\textquoteright}an and del Greco M, Fabiola and Ayers, Kristin L and Marrugat, Jaume and Ruggiero, Daniela and Lopez, Lorna M and Niiranen, Teemu and Enroth, Stefan and Jackson, Anne U and Nelson, Christopher P and Huffman, Jennifer E and Zhang, Weihua and Marten, Jonathan and Gandin, Ilaria and Harris, Sarah E and Zemunik, Tatijana and Lu, Yingchang and Evangelou, Evangelos and Shah, Nabi and de Borst, Martin H and Mangino, Massimo and Prins, Bram P and Campbell, Archie and Li-Gao, Ruifang and Chauhan, Ganesh and Oldmeadow, Christopher and Abecasis, Goncalo and Abedi, Maryam and Barbieri, Caterina M and Barnes, Michael R and Batini, Chiara and Beilby, John and Blake, Tineka and Boehnke, Michael and Bottinger, Erwin P and Braund, Peter S and Brown, Morris and Brumat, Marco and Campbell, Harry and Chambers, John C and Cocca, Massimiliano and Collins, Francis and Connell, John and Cordell, Heather J and Damman, Jeffrey J and Davies, Gail and de Geus, Eco J and de Mutsert, Ren{\'e}e and Deelen, Joris and Demirkale, Yusuf and Doney, Alex S F and D{\"o}rr, Marcus and Farrall, Martin and Ferreira, Teresa and Fr{\r a}nberg, Mattias and Gao, He and Giedraitis, Vilmantas and Gieger, Christian and Giulianini, Franco and Gow, Alan J and Hamsten, Anders and Harris, Tamara B and Hofman, Albert and Holliday, Elizabeth G and Hui, Jennie and Jarvelin, Marjo-Riitta and Johansson, Asa and Johnson, Andrew D and Jousilahti, Pekka and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kathiresan, Sekar and Khaw, Kay-Tee and Kolcic, Ivana and Koskinen, Seppo and Langenberg, Claudia and Larson, Marty and Launer, Lenore J and Lehne, Benjamin and Liewald, David C M and Lin, Li and Lind, Lars and Mach, Fran{\c c}ois and Mamasoula, Chrysovalanto and Menni, Cristina and Mifsud, Borbala and Milaneschi, Yuri and Morgan, Anna and Morris, Andrew D and Morrison, Alanna C and Munson, Peter J and Nandakumar, Priyanka and Nguyen, Quang Tri and Nutile, Teresa and Oldehinkel, Albertine J and Oostra, Ben A and Org, Elin and Padmanabhan, Sandosh and Palotie, Aarno and Par{\'e}, Guillaume and Pattie, Alison and Penninx, Brenda W J H and Poulter, Neil and Pramstaller, Peter P and Raitakari, Olli T and Ren, Meixia and Rice, Kenneth and Ridker, Paul M and Riese, Harri{\"e}tte and Ripatti, Samuli and Robino, Antonietta and Rotter, Jerome I and Rudan, Igor and Saba, Yasaman and Saint Pierre, Aude and Sala, Cinzia F and Sarin, Antti-Pekka and Schmidt, Reinhold and Scott, Rodney and Seelen, Marc A and Shields, Denis C and Siscovick, David and Sorice, Rossella and Stanton, Alice and Stott, David J and Sundstr{\"o}m, Johan and Swertz, Morris and Taylor, Kent D and Thom, Simon and Tzoulaki, Ioanna and Tzourio, Christophe and Uitterlinden, Andr{\'e} G and V{\"o}lker, Uwe and Vollenweider, Peter and Wild, Sarah and Willemsen, Gonneke and Wright, Alan F and Yao, Jie and Th{\'e}riault, S{\'e}bastien and Conen, David and Attia, John and Sever, Peter and Debette, Stephanie and Mook-Kanamori, Dennis O and Zeggini, Eleftheria and Spector, Tim D and van der Harst, Pim and Palmer, Colin N A and Vergnaud, Anne-Claire and Loos, Ruth J F and Polasek, Ozren and Starr, John M and Girotto, Giorgia and Hayward, Caroline and Kooner, Jaspal S and Lindgren, Cecila M and Vitart, Veronique and Samani, Nilesh J and Tuomilehto, Jaakko and Gyllensten, Ulf and Knekt, Paul and Deary, Ian J and Ciullo, Marina and Elosua, Roberto and Keavney, Bernard D and Hicks, Andrew A and Scott, Robert A and Gasparini, Paolo and Laan, Maris and Liu, Yongmei and Watkins, Hugh and Hartman, Catharina A and Salomaa, Veikko and Toniolo, Daniela and Perola, Markus and Wilson, James F and Schmidt, Helena and Zhao, Jing Hua and Lehtim{\"a}ki, Terho and van Duijn, Cornelia M and Gudnason, Vilmundur and Psaty, Bruce M and Peters, Annette and Rettig, Rainer and James, Alan and Jukema, J Wouter and Strachan, David P and Palmas, Walter and Metspalu, Andres and Ingelsson, Erik and Boomsma, Dorret I and Franco, Oscar H and Bochud, Murielle and Newton-Cheh, Christopher and Munroe, Patricia B and Elliott, Paul and Chasman, Daniel I and Chakravarti, Aravinda and Knight, Joanne and Morris, Andrew P and Levy, Daniel and Tobin, Martin D and Snieder, Harold and Caulfield, Mark J and Ehret, Georg B} } @article {7577, title = {Rare coding variants pinpoint genes that control human hematological traits.}, journal = {PLoS Genet}, volume = {13}, year = {2017}, month = {2017 Aug}, pages = {e1006925}, abstract = {

The identification of rare coding or splice site variants remains the most straightforward strategy to link genes with human phenotypes. Here, we analyzed the association between 137,086 rare (minor allele frequency (MAF) <1\%) coding or splice site variants and 15 hematological traits in up to 308,572 participants. We found 56 such rare coding or splice site variants at P<5x10-8, including 31 that are associated with a blood-cell phenotype for the first time. All but one of these 31 new independent variants map to loci previously implicated in hematopoiesis by genome-wide association studies (GWAS). This includes a rare splice acceptor variant (rs146597587, MAF = 0.5\%) in interleukin 33 (IL33) associated with reduced eosinophil count (P = 2.4x10-23), and lower risk of asthma (P = 2.6x10-7, odds ratio [95\% confidence interval] = 0.56 [0.45-0.70]) and allergic rhinitis (P = 4.2x10-4, odds ratio = 0.55 [0.39-0.76]). The single new locus identified in our study is defined by a rare p.Arg172Gly missense variant (rs145535174, MAF = 0.05\%) in plasminogen (PLG) associated with increased platelet count (P = 6.8x10-9), and decreased D-dimer concentration (P = 0.018) and platelet reactivity (P<0.03). Finally, our results indicate that searching for rare coding or splice site variants in very large sample sizes can help prioritize causal genes at many GWAS loci associated with complex human diseases and traits.

}, keywords = {Asthma, Databases, Genetic, Endometriosis, Female, Fibrin Fibrinogen Degradation Products, Gene Frequency, Genetic Loci, Genome, Human, Genome-Wide Association Study, Humans, Interleukin-33, Linear Models, Logistic Models, Male, Mutation, Missense, Phenotype, Plasminogen, Platelet Count, Polymorphism, Single Nucleotide, Principal Component Analysis, Protein Splicing, Rhinitis, Allergic, Sequence Analysis, DNA}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1006925}, author = {Mousas, Abdou and Ntritsos, Georgios and Chen, Ming-Huei and Song, Ci and Huffman, Jennifer E and Tzoulaki, Ioanna and Elliott, Paul and Psaty, Bruce M and Auer, Paul L and Johnson, Andrew D and Evangelou, Evangelos and Lettre, Guillaume and Reiner, Alexander P} } @article {7816, title = {DNA methylation age is associated with an altered hemostatic profile in a multi-ethnic meta-analysis.}, journal = {Blood}, year = {2018}, month = {2018 Jul 24}, abstract = {

Many hemostatic factors are associated with age and age-related diseases, however much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we used European and African-ancestry participants who were meta-analyzed separately and combined via a random effects meta-analysis. All other measures only included participants of European-ancestry. We found that 1-year higher extrinsic epigenetic age as compared to chronological age was associated with higher fibrinogen (0.004 g/L per year; 95\% CI: 0.001, 0.007; P = 0.01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL per year; 95\% CI: 0.07, 0.20; P = 6.6x10-5) concentrations as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the three fibrinogen subunit-encoding genes (FGA, FGG, and FGB), in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a pro-coagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

}, issn = {1528-0020}, doi = {10.1182/blood-2018-02-831347}, author = {Ward-Caviness, Cavin K and Huffman, Jennifer E and Evertt, Karl and Germain, Marine and van Dongen, Jenny and Hill, W David and Jhun, Min A and Brody, Jennifer A and Ghanbari, Mohsen and Du, Lei and Roetker, Nicholas S and de Vries, Paul S and Waldenberger, Melanie and Gieger, Christian and Wolf, Petra and Prokisch, Holger and Koenig, Wolfgang and O{\textquoteright}Donnell, Christopher J and Levy, Daniel and Liu, Chunyu and Truong, Vinh and Wells, Philip S and Tr{\'e}gou{\"e}t, David-Alexandre and Tang, Weihong and Morrison, Alanna C and Boerwinkle, Eric and Wiggins, Kerri L and McKnight, Barbara and Guo, Xiuqing and Psaty, Bruce M and Sotoodenia, Nona and Boomsa, Dorret I and Willemsen, Gonneke and Ligthart, Lannie and Deary, Ian J and Zhao, Wei and Ware, Erin B and Kardia, Sharon L R and van Meurs, Joyce B J and Uitterlinden, Andr{\'e} G and Franco, Oscar H and Eriksson, Per and Franco-Cereceda, Anders and Pankow, James S and Johnson, Andrew D and Gagnon, France and Morange, Pierre-Emmanuel and de Geus, Eco J C and Starr, John M and Smith, Jennifer A and Dehghan, Abbas and Bj{\"o}rck, Hanna M and Smith, Nicholas L and Peters, Annette} } @article {7784, title = {ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals.}, journal = {Circ Genom Precis Med}, volume = {11}, year = {2018}, month = {2018 Jan}, pages = {e001758}, abstract = {

BACKGROUND: QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest.

METHODS AND RESULTS: We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci.

CONCLUSIONS: Our analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.117.001758}, author = {Bihlmeyer, Nathan A and Brody, Jennifer A and Smith, Albert Vernon and Warren, Helen R and Lin, Honghuang and Isaacs, Aaron and Liu, Ching-Ti and Marten, Jonathan and Radmanesh, Farid and Hall, Leanne M and Grarup, Niels and Mei, Hao and M{\"u}ller-Nurasyid, Martina and Huffman, Jennifer E and Verweij, Niek and Guo, Xiuqing and Yao, Jie and Li-Gao, Ruifang and van den Berg, Marten and Weiss, Stefan and Prins, Bram P and van Setten, Jessica and Haessler, Jeffrey and Lyytik{\"a}inen, Leo-Pekka and Li, Man and Alonso, Alvaro and Soliman, Elsayed Z and Bis, Joshua C and Austin, Tom and Chen, Yii-Der Ida and Psaty, Bruce M and Harrris, Tamara B and Launer, Lenore J and Padmanabhan, Sandosh and Dominiczak, Anna and Huang, Paul L and Xie, Zhijun and Ellinor, Patrick T and Kors, Jan A and Campbell, Archie and Murray, Alison D and Nelson, Christopher P and Tobin, Martin D and Bork-Jensen, Jette and Hansen, Torben and Pedersen, Oluf and Linneberg, Allan and Sinner, Moritz F and Peters, Annette and Waldenberger, Melanie and Meitinger, Thomas and Perz, Siegfried and Kolcic, Ivana and Rudan, Igor and de Boer, Rudolf A and van der Meer, Peter and Lin, Henry J and Taylor, Kent D and de Mutsert, Ren{\'e}e and Trompet, Stella and Jukema, J Wouter and Maan, Arie C and Stricker, Bruno H C and Rivadeneira, Fernando and Uitterlinden, Andre and V{\"o}lker, Uwe and Homuth, Georg and V{\"o}lzke, Henry and Felix, Stephan B and Mangino, Massimo and Spector, Timothy D and Bots, Michiel L and Perez, Marco and Raitakari, Olli T and K{\"a}h{\"o}nen, Mika and Mononen, Nina and Gudnason, Vilmundur and Munroe, Patricia B and Lubitz, Steven A and van Duijn, Cornelia M and Newton-Cheh, Christopher H and Hayward, Caroline and Rosand, Jonathan and Samani, Nilesh J and Kanters, J{\o}rgen K and Wilson, James G and K{\"a}{\"a}b, Stefan and Polasek, Ozren and van der Harst, Pim and Heckbert, Susan R and Rotter, Jerome I and Mook-Kanamori, Dennis O and Eijgelsheim, Mark and D{\"o}rr, Marcus and Jamshidi, Yalda and Asselbergs, Folkert W and Kooperberg, Charles and Lehtim{\"a}ki, Terho and Arking, Dan E and Sotoodehnia, Nona} } @article {7845, title = {Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Oct}, pages = {1412-1425}, abstract = {

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0205-x}, author = {Evangelou, Evangelos and Warren, Helen R and Mosen-Ansorena, David and Mifsud, Borbala and Pazoki, Raha and Gao, He and Ntritsos, Georgios and Dimou, Niki and Cabrera, Claudia P and Karaman, Ibrahim and Ng, Fu Liang and Evangelou, Marina and Witkowska, Katarzyna and Tzanis, Evan and Hellwege, Jacklyn N and Giri, Ayush and Velez Edwards, Digna R and Sun, Yan V and Cho, Kelly and Gaziano, J Michael and Wilson, Peter W F and Tsao, Philip S and Kovesdy, Csaba P and Esko, T{\~o}nu and M{\"a}gi, Reedik and Milani, Lili and Almgren, Peter and Boutin, Thibaud and Debette, Stephanie and Ding, Jun and Giulianini, Franco and Holliday, Elizabeth G and Jackson, Anne U and Li-Gao, Ruifang and Lin, Wei-Yu and Luan, Jian{\textquoteright}an and Mangino, Massimo and Oldmeadow, Christopher and Prins, Bram Peter and Qian, Yong and Sargurupremraj, Muralidharan and Shah, Nabi and Surendran, Praveen and Th{\'e}riault, S{\'e}bastien and Verweij, Niek and Willems, Sara M and Zhao, Jing-Hua and Amouyel, Philippe and Connell, John and de Mutsert, Ren{\'e}e and Doney, Alex S F and Farrall, Martin and Menni, Cristina and Morris, Andrew D and Noordam, Raymond and Par{\'e}, Guillaume and Poulter, Neil R and Shields, Denis C and Stanton, Alice and Thom, Simon and Abecasis, Goncalo and Amin, Najaf and Arking, Dan E and Ayers, Kristin L and Barbieri, Caterina M and Batini, Chiara and Bis, Joshua C and Blake, Tineka and Bochud, Murielle and Boehnke, Michael and Boerwinkle, Eric and Boomsma, Dorret I and Bottinger, Erwin P and Braund, Peter S and Brumat, Marco and Campbell, Archie and Campbell, Harry and Chakravarti, Aravinda and Chambers, John C and Chauhan, Ganesh and Ciullo, Marina and Cocca, Massimiliano and Collins, Francis and Cordell, Heather J and Davies, Gail and Borst, Martin H de and Geus, Eco J de and Deary, Ian J and Deelen, Joris and del Greco M, Fabiola and Demirkale, Cumhur Yusuf and D{\"o}rr, Marcus and Ehret, Georg B and Elosua, Roberto and Enroth, Stefan and Erzurumluoglu, A Mesut and Ferreira, Teresa and Fr{\r a}nberg, Mattias and Franco, Oscar H and Gandin, Ilaria and Gasparini, Paolo and Giedraitis, Vilmantas and Gieger, Christian and Girotto, Giorgia and Goel, Anuj and Gow, Alan J and Gudnason, Vilmundur and Guo, Xiuqing and Gyllensten, Ulf and Hamsten, Anders and Harris, Tamara B and Harris, Sarah E and Hartman, Catharina A and Havulinna, Aki S and Hicks, Andrew A and Hofer, Edith and Hofman, Albert and Hottenga, Jouke-Jan and Huffman, Jennifer E and Hwang, Shih-Jen and Ingelsson, Erik and James, Alan and Jansen, Rick and Jarvelin, Marjo-Riitta and Joehanes, Roby and Johansson, Asa and Johnson, Andrew D and Joshi, Peter K and Jousilahti, Pekka and Jukema, J Wouter and Jula, Antti and K{\"a}h{\"o}nen, Mika and Kathiresan, Sekar and Keavney, Bernard D and Khaw, Kay-Tee and Knekt, Paul and Knight, Joanne and Kolcic, Ivana and Kooner, Jaspal S and Koskinen, Seppo and Kristiansson, Kati and Kutalik, Zolt{\'a}n and Laan, Maris and Larson, Marty and Launer, Lenore J and Lehne, Benjamin and Lehtim{\"a}ki, Terho and Liewald, David C M and Lin, Li and Lind, Lars and Lindgren, Cecilia M and Liu, Yongmei and Loos, Ruth J F and Lopez, Lorna M and Lu, Yingchang and Lyytik{\"a}inen, Leo-Pekka and Mahajan, Anubha and Mamasoula, Chrysovalanto and Marrugat, Jaume and Marten, Jonathan and Milaneschi, Yuri and Morgan, Anna and Morris, Andrew P and Morrison, Alanna C and Munson, Peter J and Nalls, Mike A and Nandakumar, Priyanka and Nelson, Christopher P and Niiranen, Teemu and Nolte, Ilja M and Nutile, Teresa and Oldehinkel, Albertine J and Oostra, Ben A and O{\textquoteright}Reilly, Paul F and Org, Elin and Padmanabhan, Sandosh and Palmas, Walter and Palotie, Aarno and Pattie, Alison and Penninx, Brenda W J H and Perola, Markus and Peters, Annette and Polasek, Ozren and Pramstaller, Peter P and Nguyen, Quang Tri and Raitakari, Olli T and Ren, Meixia and Rettig, Rainer and Rice, Kenneth and Ridker, Paul M and Ried, Janina S and Riese, Harri{\"e}tte and Ripatti, Samuli and Robino, Antonietta and Rose, Lynda M and Rotter, Jerome I and Rudan, Igor and Ruggiero, Daniela and Saba, Yasaman and Sala, Cinzia F and Salomaa, Veikko and Samani, Nilesh J and Sarin, Antti-Pekka and Schmidt, Reinhold and Schmidt, Helena and Shrine, Nick and Siscovick, David and Smith, Albert V and Snieder, Harold and S{\~o}ber, Siim and Sorice, Rossella and Starr, John M and Stott, David J and Strachan, David P and Strawbridge, Rona J and Sundstr{\"o}m, Johan and Swertz, Morris A and Taylor, Kent D and Teumer, Alexander and Tobin, Martin D and Tomaszewski, Maciej and Toniolo, Daniela and Traglia, Michela and Trompet, Stella and Tuomilehto, Jaakko and Tzourio, Christophe and Uitterlinden, Andr{\'e} G and Vaez, Ahmad and van der Most, Peter J and van Duijn, Cornelia M and Vergnaud, Anne-Claire and Verwoert, Germaine C and Vitart, Veronique and V{\"o}lker, Uwe and Vollenweider, Peter and Vuckovic, Dragana and Watkins, Hugh and Wild, Sarah H and Willemsen, Gonneke and Wilson, James F and Wright, Alan F and Yao, Jie and Zemunik, Tatijana and Zhang, Weihua and Attia, John R and Butterworth, Adam S and Chasman, Daniel I and Conen, David and Cucca, Francesco and Danesh, John and Hayward, Caroline and Howson, Joanna M M and Laakso, Markku and Lakatta, Edward G and Langenberg, Claudia and Melander, Olle and Mook-Kanamori, Dennis O and Palmer, Colin N A and Risch, Lorenz and Scott, Robert A and Scott, Rodney J and Sever, Peter and Spector, Tim D and van der Harst, Pim and Wareham, Nicholas J and Zeggini, Eleftheria and Levy, Daniel and Munroe, Patricia B and Newton-Cheh, Christopher and Brown, Morris J and Metspalu, Andres and Hung, Adriana M and O{\textquoteright}Donnell, Christopher J and Edwards, Todd L and Psaty, Bruce M and Tzoulaki, Ioanna and Barnes, Michael R and Wain, Louise V and Elliott, Paul and Caulfield, Mark J} } @article {7924, title = {Genome-Wide Association Trans-Ethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels.}, journal = {Circulation}, year = {2018}, month = {2018 Nov 20}, abstract = {

BACKGROUND: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.

METHODS: We meta-analyzed genome-wide association results from 46,354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated approximately 35 million imputed variants with natural-log transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization (MR) analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.

RESULTS: We identified 13 novel genome-wide significant (p<=2.5x10) associations; 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. MR suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.

CONCLUSIONS: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.

}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.118.034532}, author = {Sabater-Lleal, Maria and Huffman, Jennifer E and de Vries, Paul S and Marten, Jonathan and Mastrangelo, Michael A and Song, Ci and Pankratz, Nathan and Ward-Caviness, Cavin K and Yanek, Lisa R and Trompet, Stella and Delgado, Graciela E and Guo, Xiuqing and Bartz, Traci M and Martinez-Perez, Angel and Germain, Marine and de Haan, Hugoline G and Ozel, Ayse B and Polasek, Ozren and Smith, Albert V and Eicher, John D and Reiner, Alex P and Tang, Weihong and Davies, Neil M and Stott, David J and Rotter, Jerome I and Tofler, Geoffrey H and Boerwinkle, Eric and de Maat, Moniek P M and Kleber, Marcus E and Welsh, Paul and Brody, Jennifer A and Chen, Ming-Huei and Vaidya, Dhananjay and Soria, Jos{\'e} Manuel and Suchon, Pierre and van Hylckama Vlieg, Astrid and Desch, Karl C and Kolcic, Ivana and Joshi, Peter K and Launer, Lenore J and Harris, Tamara B and Campbell, Harry and Rudan, Igor and Becker, Diane M and Li, Jun Z and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Hofman, Albert and Franco, Oscar H and Cushman, Mary and Psaty, Bruce M and Morange, Pierre-Emmanuel and McKnight, Barbara and Chong, Michael R and Fernandez-Cadenas, Israel and Rosand, Jonathan and Lindgren, Arne and Gudnason, Vilmundur and Wilson, James F and Hayward, Caroline and Ginsburg, David and Fornage, Myriam and Rosendaal, Frits R and Souto, Juan Carlos and Becker, Lewis C and Jenny, Nancy S and M{\"a}rz, Winfried and Jukema, J Wouter and Dehghan, Abbas and Tr{\'e}gou{\"e}t, David-Alexandre and Morrison, Alanna C and Johnson, Andrew D and O{\textquoteright}Donnell, Christopher J and Strachan, David P and Lowenstein, Charles J and Smith, Nicholas L} } @article {7928, title = {Large-scale whole-exome sequencing association studies identify rare functional variants influencing serum urate levels.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 10 12}, pages = {4228}, abstract = {

Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among <=19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 {\texttimes} 10) and SLC2A9 (p = 4.5 {\texttimes} 10). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 {\texttimes} 10). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout.

}, keywords = {Exome, Genetic Predisposition to Disease, Glucose Transport Proteins, Facilitative, Humans, Kidney Function Tests, Meta-Analysis as Topic, Organic Anion Transporters, Organic Cation Transport Proteins, Protein Structure, Secondary, Uric Acid}, issn = {2041-1723}, doi = {10.1038/s41467-018-06620-4}, author = {Tin, Adrienne and Li, Yong and Brody, Jennifer A and Nutile, Teresa and Chu, Audrey Y and Huffman, Jennifer E and Yang, Qiong and Chen, Ming-Huei and Robinson-Cohen, Cassianne and Mace, Aurelien and Liu, Jun and Demirkan, Ayse and Sorice, Rossella and Sedaghat, Sanaz and Swen, Melody and Yu, Bing and Ghasemi, Sahar and Teumer, Alexanda and Vollenweider, Peter and Ciullo, Marina and Li, Meng and Uitterlinden, Andr{\'e} G and Kraaij, Robert and Amin, Najaf and van Rooij, Jeroen and Kutalik, Zolt{\'a}n and Dehghan, Abbas and McKnight, Barbara and van Duijn, Cornelia M and Morrison, Alanna and Psaty, Bruce M and Boerwinkle, Eric and Fox, Caroline S and Woodward, Owen M and K{\"o}ttgen, Anna} } @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 {7988, title = {A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology.}, journal = {Blood}, volume = {133}, year = {2019}, month = {2019 Feb 28}, pages = {967-977}, abstract = {

Factor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of 9 genome-wide association studies of plasma FVII levels (7 FVII activity and 2 FVII antigen) among 27 495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a -ancestry meta-analysis. Our primary analysis included the 7 studies that measured FVII activity, and a secondary analysis included all 9 studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using small-interfering RNA and then measuring messenger RNA and FVII protein expression. Lastly, we used meta-analysis results to perform Mendelian randomization analysis to estimate the causal effect of FVII activity on coronary artery disease, ischemic stroke (IS), and venous thromboembolism. We identified 2 novel ( and ) and 6 known loci associated with FVII activity, explaining 19.0\% of the phenotypic variance. Adding FVII antigen data to the meta-analysis did not result in the discovery of further loci. Silencing in HuH7 cells upregulated FVII, whereas silencing downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at and contribute to FVII activity by regulating expression levels. FVII activity appears to contribute to the etiology of IS in the general population.

}, issn = {1528-0020}, doi = {10.1182/blood-2018-05-849240}, author = {de Vries, Paul S and Sabater-Lleal, Maria and Huffman, Jennifer E and Marten, Jonathan and Song, Ci and Pankratz, Nathan and Bartz, Traci M and de Haan, Hugoline G and Delgado, Graciela E and Eicher, John D and Martinez-Perez, Angel and Ward-Caviness, Cavin K and Brody, Jennifer A and Chen, Ming-Huei and de Maat, Moniek P M and Fr{\r a}nberg, Mattias and Gill, Dipender and Kleber, Marcus E and Rivadeneira, Fernando and Soria, Jos{\'e} Manuel and Tang, Weihong and Tofler, Geoffrey H and Uitterlinden, Andr{\'e} G and van Hylckama Vlieg, Astrid and Seshadri, Sudha and Boerwinkle, Eric and Davies, Neil M and Giese, Anne-Katrin and Ikram, M Kamran and Kittner, Steven J and McKnight, Barbara and Psaty, Bruce M and Reiner, Alex P and Sargurupremraj, Muralidharan and Taylor, Kent D and Fornage, Myriam and Hamsten, Anders and M{\"a}rz, Winfried and Rosendaal, Frits R and Souto, Juan Carlos and Dehghan, Abbas and Johnson, Andrew D and Morrison, Alanna C and O{\textquoteright}Donnell, Christopher J and Smith, Nicholas L} } @article {8200, title = {Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism.}, journal = {Blood}, volume = {134}, year = {2019}, month = {2019 Nov 07}, pages = {1645-1657}, abstract = {

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

}, issn = {1528-0020}, doi = {10.1182/blood.2019000435}, author = {Lindstr{\"o}m, Sara and Wang, Lu and Smith, Erin N and Gordon, William and van Hylckama Vlieg, Astrid and de Andrade, Mariza and Brody, Jennifer A and Pattee, Jack W and Haessler, Jeffrey and Brumpton, Ben M and Chasman, Daniel I and Suchon, Pierre and Chen, Ming-Huei and Turman, Constance and Germain, Marine and Wiggins, Kerri L and MacDonald, James and Braekkan, Sigrid K and Armasu, Sebastian M and Pankratz, Nathan and Jackson, Rebecca D and Nielsen, Jonas B and Giulianini, Franco and Puurunen, Marja K and Ibrahim, Manal and Heckbert, Susan R and Damrauer, Scott M and Natarajan, Pradeep and Klarin, Derek and de Vries, Paul S and Sabater-Lleal, Maria and Huffman, Jennifer E and Bammler, Theo K and Frazer, Kelly A and McCauley, Bryan M and Taylor, Kent and Pankow, James S and Reiner, Alexander P and Gabrielsen, Maiken E and Deleuze, Jean-Francois and O{\textquoteright}Donnell, Chris J and Kim, Jihye and McKnight, Barbara and Kraft, Peter and Hansen, John-Bjarne and Rosendaal, Frits R and Heit, John A and Psaty, Bruce M and Tang, Weihong and Kooperberg, Charles and Hveem, Kristian and Ridker, Paul M and Morange, Pierre-Emmanuel and Johnson, Andrew D and Kabrhel, Christopher and Tr{\'e}gou{\"e}t, David-Alexandre and Smith, Nicholas L} } @article {8050, title = {Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease.}, journal = {PLoS One}, volume = {14}, year = {2019}, month = {2019}, pages = {e0216222}, abstract = {

BACKGROUND: Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.

METHODS AND FINDINGS: We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95\% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.

CONCLUSIONS: A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0216222}, author = {Ward-Caviness, Cavin K and de Vries, Paul S and Wiggins, Kerri L and Huffman, Jennifer E and Yanek, Lisa R and Bielak, Lawrence F and Giulianini, Franco and Guo, Xiuqing and Kleber, Marcus E and Kacprowski, Tim and Gro{\ss}, Stefan and Petersman, Astrid and Davey Smith, George and Hartwig, Fernando P and Bowden, Jack and Hemani, Gibran and M{\"u}ller-Nuraysid, Martina and Strauch, Konstantin and Koenig, Wolfgang and Waldenberger, Melanie and Meitinger, Thomas and Pankratz, Nathan and Boerwinkle, Eric and Tang, Weihong and Fu, Yi-Ping and Johnson, Andrew D and Song, Ci and de Maat, Moniek P M and Uitterlinden, Andr{\'e} G and Franco, Oscar H and Brody, Jennifer A and McKnight, Barbara and Chen, Yii-Der Ida and Psaty, Bruce M and Mathias, Rasika A and Becker, Diane M and Peyser, Patricia A and Smith, Jennifer A and Bielinski, Suzette J and Ridker, Paul M and Taylor, Kent D and Yao, Jie and Tracy, Russell and Delgado, Graciela and Trompet, Stella and Sattar, Naveed and Jukema, J Wouter and Becker, Lewis C and Kardia, Sharon L R and Rotter, Jerome I and M{\"a}rz, Winfried and D{\"o}rr, Marcus and Chasman, Daniel I and Dehghan, Abbas and O{\textquoteright}Donnell, Christopher J and Smith, Nicholas L and Peters, Annette and Morrison, Alanna C} } @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 {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 {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 {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 {9176, title = {Large-scale genome-wide association study of coronary artery disease in genetically diverse populations.}, journal = {Nat Med}, volume = {28}, year = {2022}, month = {2022 08}, pages = {1679-1692}, abstract = {

We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.

}, keywords = {Coronary Artery Disease, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1546-170X}, doi = {10.1038/s41591-022-01891-3}, author = {Tcheandjieu, Catherine and Zhu, Xiang and Hilliard, Austin T and Clarke, Shoa L and Napolioni, Valerio and Ma, Shining and Lee, Kyung Min and Fang, Huaying and Chen, Fei and Lu, Yingchang and Tsao, Noah L and Raghavan, Sridharan and Koyama, Satoshi and Gorman, Bryan R and Vujkovic, Marijana and Klarin, Derek and Levin, Michael G and Sinnott-Armstrong, Nasa and Wojcik, Genevieve L and Plomondon, Mary E and Maddox, Thomas M and Waldo, Stephen W and Bick, Alexander G and Pyarajan, Saiju and Huang, Jie and Song, Rebecca and Ho, Yuk-Lam and Buyske, Steven and Kooperberg, Charles and Haessler, Jeffrey and Loos, Ruth J F and Do, Ron and Verbanck, Marie and Chaudhary, Kumardeep and North, Kari E and Avery, Christy L and Graff, Mariaelisa and Haiman, Christopher A and Le Marchand, Lo{\"\i}c and Wilkens, Lynne R and Bis, Joshua C and Leonard, Hampton and Shen, Botong and Lange, Leslie A and Giri, Ayush and Dikilitas, Ozan and Kullo, Iftikhar J and Stanaway, Ian B and Jarvik, Gail P and Gordon, Adam S and Hebbring, Scott and Namjou, Bahram and Kaufman, Kenneth M and Ito, Kaoru and Ishigaki, Kazuyoshi and Kamatani, Yoichiro and Verma, Shefali S and Ritchie, Marylyn D and Kember, Rachel L and Baras, Aris and Lotta, Luca A and Kathiresan, Sekar and Hauser, Elizabeth R and Miller, Donald R and Lee, Jennifer S and Saleheen, Danish and Reaven, Peter D and Cho, Kelly and Gaziano, J Michael and Natarajan, Pradeep and Huffman, Jennifer E and Voight, Benjamin F and Rader, Daniel J and Chang, Kyong-Mi and Lynch, Julie A and Damrauer, Scott M and Wilson, Peter W F and Tang, Hua and Sun, Yan V and Tsao, Philip S and O{\textquoteright}Donnell, Christopher J and Assimes, Themistocles L} } @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 {9107, title = {Whole exome sequencing of 14 389 individuals from the ESP and CHARGE consortia identifies novel rare variation associated with hemostatic factors.}, journal = {Hum Mol Genet}, year = {2022}, month = {2022 May 12}, abstract = {

Plasma levels of fibrinogen, coagulation factors VII and VIII, and von Willebrand factor (vWF) are four intermediate phenotypes that are heritable and have been associated with the risk of clinical thrombotic events. To identify rare and low-frequency variants associated with these hemostatic factors, we conducted whole exome sequencing in 10 860 individuals of European ancestry (EA) and 3529 African Americans (AAs) from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium and the National Heart, Lung, and Blood Institute{\textquoteright}s Exome Sequencing Project (ESP). Gene-based tests demonstrated significant associations with rare variation (minor allele frequency < 5\%) in FGG (with fibrinogen, p = 9.1x10-13), F7 (with factor VII, p = 1.3x10-72; seven novel variants), and VWF (with factor VIII and vWF; p = 3.2x10-14; one novel variant). These eight novel rare variant associations were independent of the known common variants at these loci and tended to have much larger effect sizes. In addition, one of the rare novel variants in F7 was significantly associated with an increased risk of venous thromboembolism in AAs (Ile200Ser; rs141219108; p = 4.2x10-5). After restricting gene-based analyses to only loss-of-function variants, a novel significant association was detected and replicated between factor VIII levels and a stop-gain mutation exclusive to African Americans (rs3211938) in CD36. This variant has previously been linked to dyslipidemia but not with levels of a hemostatic factor. These efforts represent the largest integration of whole exome sequence data from two national projects to identify genetic variation associated with plasma hemostatic factors.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddac100}, author = {Pankratz, Nathan and Wei, Peng and Brody, Jennifer A and Chen, Ming-Huei and Vries, Paul S and Huffman, Jennifer E and Stimson, Mary Rachel and Auer, Paul L and Boerwinkle, Eric and Cushman, Mary and Maat, Moniek P M and Folsom, Aaron R and Franco, Oscar H and Gibbs, Richard A and Haagenson, Kelly K and Hofman, Albert and Johnsen, Jill M and Kovar, Christie L and Kraaij, Robert and McKnight, Barbara and Metcalf, Ginger A and Muzny, Donna and Psaty, Bruce M and Tang, Weihong and Uitterlinden, Andr{\'e} G and Rooij, Jeroen G J and Dehghan, Abbas and O{\textquoteright}Donnell, Christopher J and Reiner, Alex P and Morrison, Alanna C and Smith, Nicholas L} } @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 {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 {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} }