%0 Journal Article %J PLoS Genet %D 2009 %T NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium. %A Heard-Costa, Nancy L %A Zillikens, M Carola %A Monda, Keri L %A Johansson, Asa %A Harris, Tamara B %A Fu, Mao %A Haritunians, Talin %A Feitosa, Mary F %A Aspelund, Thor %A Eiriksdottir, Gudny %A Garcia, Melissa %A Launer, Lenore J %A Smith, Albert V %A Mitchell, Braxton D %A McArdle, Patrick F %A Shuldiner, Alan R %A Bielinski, Suzette J %A Boerwinkle, Eric %A Brancati, Fred %A Demerath, Ellen W %A Pankow, James S %A Arnold, Alice M %A Chen, Yii-Der Ida %A Glazer, Nicole L %A McKnight, Barbara %A Psaty, Bruce M %A Rotter, Jerome I %A Amin, Najaf %A Campbell, Harry %A Gyllensten, Ulf %A Pattaro, Cristian %A Pramstaller, Peter P %A Rudan, Igor %A Struchalin, Maksim %A Vitart, Veronique %A Gao, Xiaoyi %A Kraja, Aldi %A Province, Michael A %A Zhang, Qunyuan %A Atwood, Larry D %A Dupuis, Josée %A Hirschhorn, Joel N %A Jaquish, Cashell E %A O'Donnell, Christopher J %A Vasan, Ramachandran S %A White, Charles C %A Aulchenko, Yurii S %A Estrada, Karol %A Hofman, Albert %A Rivadeneira, Fernando %A Uitterlinden, André G %A Witteman, Jacqueline C M %A Oostra, Ben A %A Kaplan, Robert C %A Gudnason, Vilmundur %A O'Connell, Jeffrey R %A Borecki, Ingrid B %A van Duijn, Cornelia M %A Cupples, L Adrienne %A Fox, Caroline S %A North, Kari E %K Aged %K Body Mass Index %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Nerve Tissue Proteins %K Obesity %K Polymorphism, Single Nucleotide %K Waist Circumference %X

Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4x10(-7))]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3x10(-8) for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4x10(-6), 0.024 z-score units (0.10 kg/m(2)) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07-1.19; p = 3.2x10(-5) per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.

%B PLoS Genet %V 5 %P e1000539 %8 2009 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/19557197?dopt=Abstract %R 10.1371/journal.pgen.1000539 %0 Journal Article %J Nat Genet %D 2010 %T New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. %A Dupuis, Josée %A Langenberg, Claudia %A Prokopenko, Inga %A Saxena, Richa %A Soranzo, Nicole %A Jackson, Anne U %A Wheeler, Eleanor %A Glazer, Nicole L %A Bouatia-Naji, Nabila %A Gloyn, Anna L %A Lindgren, Cecilia M %A Mägi, Reedik %A Morris, Andrew P %A Randall, Joshua %A Johnson, Toby %A Elliott, Paul %A Rybin, Denis %A Thorleifsson, Gudmar %A Steinthorsdottir, Valgerdur %A Henneman, Peter %A Grallert, Harald %A Dehghan, Abbas %A Hottenga, Jouke Jan %A Franklin, Christopher S %A Navarro, Pau %A Song, Kijoung %A Goel, Anuj %A Perry, John R B %A Egan, Josephine M %A Lajunen, Taina %A Grarup, Niels %A Sparsø, Thomas %A Doney, Alex %A Voight, Benjamin F %A Stringham, Heather M %A Li, Man %A Kanoni, Stavroula %A Shrader, Peter %A Cavalcanti-Proença, Christine %A Kumari, Meena %A Qi, Lu %A Timpson, Nicholas J %A Gieger, Christian %A Zabena, Carina %A Rocheleau, Ghislain %A Ingelsson, Erik %A An, Ping %A O'Connell, Jeffrey %A Luan, Jian'an %A Elliott, Amanda %A McCarroll, Steven A %A Payne, Felicity %A Roccasecca, Rosa Maria %A Pattou, François %A Sethupathy, Praveen %A Ardlie, Kristin %A Ariyurek, Yavuz %A Balkau, Beverley %A Barter, Philip %A Beilby, John P %A Ben-Shlomo, Yoav %A Benediktsson, Rafn %A Bennett, Amanda J %A Bergmann, Sven %A Bochud, Murielle %A Boerwinkle, Eric %A Bonnefond, Amélie %A Bonnycastle, Lori L %A Borch-Johnsen, Knut %A Böttcher, Yvonne %A Brunner, Eric %A Bumpstead, Suzannah J %A Charpentier, Guillaume %A Chen, Yii-Der Ida %A Chines, Peter %A Clarke, Robert %A Coin, Lachlan J M %A Cooper, Matthew N %A Cornelis, Marilyn %A Crawford, Gabe %A Crisponi, Laura %A Day, Ian N M %A de Geus, Eco J C %A Delplanque, Jerome %A Dina, Christian %A Erdos, Michael R %A Fedson, Annette C %A Fischer-Rosinsky, Antje %A Forouhi, Nita G %A Fox, Caroline S %A Frants, Rune %A Franzosi, Maria Grazia %A Galan, Pilar %A Goodarzi, Mark O %A Graessler, Jürgen %A Groves, Christopher J %A Grundy, Scott %A Gwilliam, Rhian %A Gyllensten, Ulf %A Hadjadj, Samy %A Hallmans, Göran %A Hammond, Naomi %A Han, Xijing %A Hartikainen, Anna-Liisa %A Hassanali, Neelam %A Hayward, Caroline %A Heath, Simon C %A Hercberg, Serge %A Herder, Christian %A Hicks, Andrew A %A Hillman, David R %A Hingorani, Aroon D %A Hofman, Albert %A Hui, Jennie %A Hung, Joe %A Isomaa, Bo %A Johnson, Paul R V %A Jørgensen, Torben %A Jula, Antti %A Kaakinen, Marika %A Kaprio, Jaakko %A Kesaniemi, Y Antero %A Kivimaki, Mika %A Knight, Beatrice %A Koskinen, Seppo %A Kovacs, Peter %A Kyvik, Kirsten Ohm %A Lathrop, G Mark %A Lawlor, Debbie A %A Le Bacquer, Olivier %A Lecoeur, Cécile %A Li, Yun %A Lyssenko, Valeriya %A Mahley, Robert %A Mangino, Massimo %A Manning, Alisa K %A Martínez-Larrad, María Teresa %A McAteer, Jarred B %A McCulloch, Laura J %A McPherson, Ruth %A Meisinger, Christa %A Melzer, David %A Meyre, David %A Mitchell, Braxton D %A Morken, Mario A %A Mukherjee, Sutapa %A Naitza, Silvia %A Narisu, Narisu %A Neville, Matthew J %A Oostra, Ben A %A Orrù, Marco %A Pakyz, Ruth %A Palmer, Colin N A %A Paolisso, Giuseppe %A Pattaro, Cristian %A Pearson, Daniel %A Peden, John F %A Pedersen, Nancy L %A Perola, Markus %A Pfeiffer, Andreas F H %A Pichler, Irene %A Polasek, Ozren %A Posthuma, Danielle %A Potter, Simon C %A Pouta, Anneli %A Province, Michael A %A Psaty, Bruce M %A Rathmann, Wolfgang %A Rayner, Nigel W %A Rice, Kenneth %A Ripatti, Samuli %A Rivadeneira, Fernando %A Roden, Michael %A Rolandsson, Olov %A Sandbaek, Annelli %A Sandhu, Manjinder %A Sanna, Serena %A Sayer, Avan Aihie %A Scheet, Paul %A Scott, Laura J %A Seedorf, Udo %A Sharp, Stephen J %A Shields, Beverley %A Sigurethsson, Gunnar %A Sijbrands, Eric J G %A Silveira, Angela %A Simpson, Laila %A Singleton, Andrew %A Smith, Nicholas L %A Sovio, Ulla %A Swift, Amy %A Syddall, Holly %A Syvänen, Ann-Christine %A Tanaka, Toshiko %A Thorand, Barbara %A Tichet, Jean %A Tönjes, Anke %A Tuomi, Tiinamaija %A Uitterlinden, André G %A van Dijk, Ko Willems %A van Hoek, Mandy %A Varma, Dhiraj %A Visvikis-Siest, Sophie %A Vitart, Veronique %A Vogelzangs, Nicole %A Waeber, Gérard %A Wagner, Peter J %A Walley, Andrew %A Walters, G Bragi %A Ward, Kim L %A Watkins, Hugh %A Weedon, Michael N %A Wild, Sarah H %A Willemsen, Gonneke %A Witteman, Jaqueline C M %A Yarnell, John W G %A Zeggini, Eleftheria %A Zelenika, Diana %A Zethelius, Björn %A Zhai, Guangju %A Zhao, Jing Hua %A Zillikens, M Carola %A Borecki, Ingrid B %A Loos, Ruth J F %A Meneton, Pierre %A Magnusson, Patrik K E %A Nathan, David M %A Williams, Gordon H %A Hattersley, Andrew T %A Silander, Kaisa %A Salomaa, Veikko %A Smith, George Davey %A Bornstein, Stefan R %A Schwarz, Peter %A Spranger, Joachim %A Karpe, Fredrik %A Shuldiner, Alan R %A Cooper, Cyrus %A Dedoussis, George V %A Serrano-Ríos, Manuel %A Morris, Andrew D %A Lind, Lars %A Palmer, Lyle J %A Hu, Frank B %A Franks, Paul W %A Ebrahim, Shah %A Marmot, Michael %A Kao, W H Linda %A Pankow, James S %A Sampson, Michael J %A Kuusisto, Johanna %A Laakso, Markku %A Hansen, Torben %A Pedersen, Oluf %A Pramstaller, Peter Paul %A Wichmann, H Erich %A Illig, Thomas %A Rudan, Igor %A Wright, Alan F %A Stumvoll, Michael %A Campbell, Harry %A Wilson, James F %A Bergman, Richard N %A Buchanan, Thomas A %A Collins, Francis S %A Mohlke, Karen L %A Tuomilehto, Jaakko %A Valle, Timo T %A Altshuler, David %A Rotter, Jerome I %A Siscovick, David S %A Penninx, Brenda W J H %A Boomsma, Dorret I %A Deloukas, Panos %A Spector, Timothy D %A Frayling, Timothy M %A Ferrucci, Luigi %A Kong, Augustine %A Thorsteinsdottir, Unnur %A Stefansson, Kari %A van Duijn, Cornelia M %A Aulchenko, Yurii S %A Cao, Antonio %A Scuteri, Angelo %A Schlessinger, David %A Uda, Manuela %A Ruokonen, Aimo %A Jarvelin, Marjo-Riitta %A Waterworth, Dawn M %A Vollenweider, Peter %A Peltonen, Leena %A Mooser, Vincent %A Abecasis, Goncalo R %A Wareham, Nicholas J %A Sladek, Robert %A Froguel, Philippe %A Watanabe, Richard M %A Meigs, James B %A Groop, Leif %A Boehnke, Michael %A McCarthy, Mark I %A Florez, Jose C %A Barroso, Inês %K Adolescent %K Adult %K Alleles %K Blood Glucose %K Child %K Databases, Genetic %K Diabetes Mellitus, Type 2 %K DNA Copy Number Variations %K Fasting %K Gene Expression Regulation %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Homeostasis %K Humans %K Meta-Analysis as Topic %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Quantitative Trait, Heritable %K Reproducibility of Results %X

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

%B Nat Genet %V 42 %P 105-16 %8 2010 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/20081858?dopt=Abstract %R 10.1038/ng.520 %0 Journal Article %J Nat Genet %D 2010 %T New loci associated with kidney function and chronic kidney disease. %A Köttgen, Anna %A Pattaro, Cristian %A Böger, Carsten A %A Fuchsberger, Christian %A Olden, Matthias %A Glazer, Nicole L %A Parsa, Afshin %A Gao, Xiaoyi %A Yang, Qiong %A Smith, Albert V %A O'Connell, Jeffrey R %A Li, Man %A Schmidt, Helena %A Tanaka, Toshiko %A Isaacs, Aaron %A Ketkar, Shamika %A Hwang, Shih-Jen %A Johnson, Andrew D %A Dehghan, Abbas %A Teumer, Alexander %A Paré, Guillaume %A Atkinson, Elizabeth J %A Zeller, Tanja %A Lohman, Kurt %A Cornelis, Marilyn C %A Probst-Hensch, Nicole M %A Kronenberg, Florian %A Tönjes, Anke %A Hayward, Caroline %A Aspelund, Thor %A Eiriksdottir, Gudny %A Launer, Lenore J %A Harris, Tamara B %A Rampersaud, Evadnie %A Mitchell, Braxton D %A Arking, Dan E %A Boerwinkle, Eric %A Struchalin, Maksim %A Cavalieri, Margherita %A Singleton, Andrew %A Giallauria, Francesco %A Metter, Jeffrey %A de Boer, Ian H %A Haritunians, Talin %A Lumley, Thomas %A Siscovick, David %A Psaty, Bruce M %A Zillikens, M Carola %A Oostra, Ben A %A Feitosa, Mary %A Province, Michael %A de Andrade, Mariza %A Turner, Stephen T %A Schillert, Arne %A Ziegler, Andreas %A Wild, Philipp S %A Schnabel, Renate B %A Wilde, Sandra %A Munzel, Thomas F %A Leak, Tennille S %A Illig, Thomas %A Klopp, Norman %A Meisinger, Christa %A Wichmann, H-Erich %A Koenig, Wolfgang %A Zgaga, Lina %A Zemunik, Tatijana %A Kolcic, Ivana %A Minelli, Cosetta %A Hu, Frank B %A Johansson, Asa %A Igl, Wilmar %A Zaboli, Ghazal %A Wild, Sarah H %A Wright, Alan F %A Campbell, Harry %A Ellinghaus, David %A Schreiber, Stefan %A Aulchenko, Yurii S %A Felix, Janine F %A Rivadeneira, Fernando %A Uitterlinden, André G %A Hofman, Albert %A Imboden, Medea %A Nitsch, Dorothea %A Brandstätter, Anita %A Kollerits, Barbara %A Kedenko, Lyudmyla %A Mägi, Reedik %A Stumvoll, Michael %A Kovacs, Peter %A Boban, Mladen %A Campbell, Susan %A Endlich, Karlhans %A Völzke, Henry %A Kroemer, Heyo K %A Nauck, Matthias %A Völker, Uwe %A Polasek, Ozren %A Vitart, Veronique %A Badola, Sunita %A Parker, Alexander N %A Ridker, Paul M %A Kardia, Sharon L R %A Blankenberg, Stefan %A Liu, Yongmei %A Curhan, Gary C %A Franke, Andre %A Rochat, Thierry %A Paulweber, Bernhard %A Prokopenko, Inga %A Wang, Wei %A Gudnason, Vilmundur %A Shuldiner, Alan R %A Coresh, Josef %A Schmidt, Reinhold %A Ferrucci, Luigi %A Shlipak, Michael G %A van Duijn, Cornelia M %A Borecki, Ingrid %A Krämer, Bernhard K %A Rudan, Igor %A Gyllensten, Ulf %A Wilson, James F %A Witteman, Jacqueline C %A Pramstaller, Peter P %A Rettig, Rainer %A Hastie, Nick %A Chasman, Daniel I %A Kao, W H %A Heid, Iris M %A Fox, Caroline S %K Cohort Studies %K Creatinine %K Cystatin C %K Diet %K Europe %K Genetic Markers %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Kidney %K Kidney Failure, Chronic %K Models, Genetic %K Risk Factors %X

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.

%B Nat Genet %V 42 %P 376-84 %8 2010 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/20383146?dopt=Abstract %R 10.1038/ng.568 %0 Journal Article %J J Am Soc Nephrol %D 2011 %T CUBN is a gene locus for albuminuria. %A Böger, Carsten A %A Chen, Ming-Huei %A Tin, Adrienne %A Olden, Matthias %A Köttgen, Anna %A de Boer, Ian H %A Fuchsberger, Christian %A O'Seaghdha, Conall M %A Pattaro, Cristian %A Teumer, Alexander %A Liu, Ching-Ti %A Glazer, Nicole L %A Li, Man %A O'Connell, Jeffrey R %A Tanaka, Toshiko %A Peralta, Carmen A %A Kutalik, Zoltán %A Luan, Jian'an %A Zhao, Jing Hua %A Hwang, Shih-Jen %A Akylbekova, Ermeg %A Kramer, Holly %A van der Harst, Pim %A Smith, Albert V %A Lohman, Kurt %A de Andrade, Mariza %A Hayward, Caroline %A Kollerits, Barbara %A Tönjes, Anke %A Aspelund, Thor %A Ingelsson, Erik %A Eiriksdottir, Gudny %A Launer, Lenore J %A Harris, Tamara B %A Shuldiner, Alan R %A Mitchell, Braxton D %A Arking, Dan E %A Franceschini, Nora %A Boerwinkle, Eric %A Egan, Josephine %A Hernandez, Dena %A Reilly, Muredach %A Townsend, Raymond R %A Lumley, Thomas %A Siscovick, David S %A Psaty, Bruce M %A Kestenbaum, Bryan %A Haritunians, Talin %A Bergmann, Sven %A Vollenweider, Peter %A Waeber, Gérard %A Mooser, Vincent %A Waterworth, Dawn %A Johnson, Andrew D %A Florez, Jose C %A Meigs, James B %A Lu, Xiaoning %A Turner, Stephen T %A Atkinson, Elizabeth J %A Leak, Tennille S %A Aasarød, Knut %A Skorpen, Frank %A Syvänen, Ann-Christine %A Illig, Thomas %A Baumert, Jens %A Koenig, Wolfgang %A Krämer, Bernhard K %A Devuyst, Olivier %A Mychaleckyj, Josyf C %A Minelli, Cosetta %A Bakker, Stephan J L %A Kedenko, Lyudmyla %A Paulweber, Bernhard %A Coassin, Stefan %A Endlich, Karlhans %A Kroemer, Heyo K %A Biffar, Reiner %A Stracke, Sylvia %A Völzke, Henry %A Stumvoll, Michael %A Mägi, Reedik %A Campbell, Harry %A Vitart, Veronique %A Hastie, Nicholas D %A Gudnason, Vilmundur %A Kardia, Sharon L R %A Liu, Yongmei %A Polasek, Ozren %A Curhan, Gary %A Kronenberg, Florian %A Prokopenko, Inga %A Rudan, Igor %A Arnlöv, Johan %A Hallan, Stein %A Navis, Gerjan %A Parsa, Afshin %A Ferrucci, Luigi %A Coresh, Josef %A Shlipak, Michael G %A Bull, Shelley B %A Paterson, Nicholas J %A Wichmann, H-Erich %A Wareham, Nicholas J %A Loos, Ruth J F %A Rotter, Jerome I %A Pramstaller, Peter P %A Cupples, L Adrienne %A Beckmann, Jacques S %A Yang, Qiong %A Heid, Iris M %A Rettig, Rainer %A Dreisbach, Albert W %A Bochud, Murielle %A Fox, Caroline S %A Kao, W H L %K African Continental Ancestry Group %K Albuminuria %K European Continental Ancestry Group %K Genetic Loci %K Genetic Predisposition to Disease %K Humans %K Mutation, Missense %K Receptors, Cell Surface %X

Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.

%B J Am Soc Nephrol %V 22 %P 555-70 %8 2011 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21355061?dopt=Abstract %R 10.1681/ASN.2010060598 %0 Journal Article %J Nat Genet %D 2011 %T Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. %A Kilpeläinen, Tuomas O %A Zillikens, M Carola %A Stančáková, Alena %A Finucane, Francis M %A Ried, Janina S %A Langenberg, Claudia %A Zhang, Weihua %A Beckmann, Jacques S %A Luan, Jian'an %A Vandenput, Liesbeth %A Styrkarsdottir, Unnur %A Zhou, Yanhua %A Smith, Albert Vernon %A Zhao, Jing-Hua %A Amin, Najaf %A Vedantam, Sailaja %A Shin, So-Youn %A Haritunians, Talin %A Fu, Mao %A Feitosa, Mary F %A Kumari, Meena %A Halldorsson, Bjarni V %A Tikkanen, Emmi %A Mangino, Massimo %A Hayward, Caroline %A Song, Ci %A Arnold, Alice M %A Aulchenko, Yurii S %A Oostra, Ben A %A Campbell, Harry %A Cupples, L Adrienne %A Davis, Kathryn E %A Döring, Angela %A Eiriksdottir, Gudny %A Estrada, Karol %A Fernández-Real, José Manuel %A Garcia, Melissa %A Gieger, Christian %A Glazer, Nicole L %A Guiducci, Candace %A Hofman, Albert %A Humphries, Steve E %A Isomaa, Bo %A Jacobs, Leonie C %A Jula, Antti %A Karasik, David %A Karlsson, Magnus K %A Khaw, Kay-Tee %A Kim, Lauren J %A Kivimaki, Mika %A Klopp, Norman %A Kuhnel, Brigitte %A Kuusisto, Johanna %A Liu, Yongmei %A Ljunggren, Osten %A Lorentzon, Mattias %A Luben, Robert N %A McKnight, Barbara %A Mellström, Dan %A Mitchell, Braxton D %A Mooser, Vincent %A Moreno, José Maria %A Männistö, Satu %A O'Connell, Jeffery R %A Pascoe, Laura %A Peltonen, Leena %A Peral, Belén %A Perola, Markus %A Psaty, Bruce M %A Salomaa, Veikko %A Savage, David B %A Semple, Robert K %A Skaric-Juric, Tatjana %A Sigurdsson, Gunnar %A Song, Kijoung S %A Spector, Timothy D %A Syvänen, Ann-Christine %A Talmud, Philippa J %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Uitterlinden, André G %A van Duijn, Cornelia M %A Vidal-Puig, Antonio %A Wild, Sarah H %A Wright, Alan F %A Clegg, Deborah J %A Schadt, Eric %A Wilson, James F %A Rudan, Igor %A Ripatti, Samuli %A Borecki, Ingrid B %A Shuldiner, Alan R %A Ingelsson, Erik %A Jansson, John-Olov %A Kaplan, Robert C %A Gudnason, Vilmundur %A Harris, Tamara B %A Groop, Leif %A Kiel, Douglas P %A Rivadeneira, Fernando %A Walker, Mark %A Barroso, Inês %A Vollenweider, Peter %A Waeber, Gérard %A Chambers, John C %A Kooner, Jaspal S %A Soranzo, Nicole %A Hirschhorn, Joel N %A Stefansson, Kari %A Wichmann, H-Erich %A Ohlsson, Claes %A O'Rahilly, Stephen %A Wareham, Nicholas J %A Speliotes, Elizabeth K %A Fox, Caroline S %A Laakso, Markku %A Loos, Ruth J F %K Adiponectin %K Adiposity %K Alleles %K Body Fat Distribution %K Body Mass Index %K Body Weight %K Female %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Insulin Receptor Substrate Proteins %K Intracellular Signaling Peptides and Proteins %K Male %K Membrane Proteins %K Meta-Analysis as Topic %K Metabolome %K Obesity %K Polymorphism, Single Nucleotide %K Subcutaneous Fat %X

Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.

%B Nat Genet %V 43 %P 753-60 %8 2011 Jun 26 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/21706003?dopt=Abstract %R 10.1038/ng.866 %0 Journal Article %J Nat Genet %D 2011 %T Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque. %A Bis, Joshua C %A Kavousi, Maryam %A Franceschini, Nora %A Isaacs, Aaron %A Abecasis, Goncalo R %A Schminke, Ulf %A Post, Wendy S %A Smith, Albert V %A Cupples, L Adrienne %A Markus, Hugh S %A Schmidt, Reinhold %A Huffman, Jennifer E %A Lehtimäki, Terho %A Baumert, Jens %A Münzel, Thomas %A Heckbert, Susan R %A Dehghan, Abbas %A North, Kari %A Oostra, Ben %A Bevan, Steve %A Stoegerer, Eva-Maria %A Hayward, Caroline %A Raitakari, Olli %A Meisinger, Christa %A Schillert, Arne %A Sanna, Serena %A Völzke, Henry %A Cheng, Yu-Ching %A Thorsson, Bolli %A Fox, Caroline S %A Rice, Kenneth %A Rivadeneira, Fernando %A Nambi, Vijay %A Halperin, Eran %A Petrovic, Katja E %A Peltonen, Leena %A Wichmann, H Erich %A Schnabel, Renate B %A Dörr, Marcus %A Parsa, Afshin %A Aspelund, Thor %A Demissie, Serkalem %A Kathiresan, Sekar %A Reilly, Muredach P %A Taylor, Kent %A Uitterlinden, Andre %A Couper, David J %A Sitzer, Matthias %A Kähönen, Mika %A Illig, Thomas %A Wild, Philipp S %A Orrù, Marco %A Lüdemann, Jan %A Shuldiner, Alan R %A Eiriksdottir, Gudny %A White, Charles C %A Rotter, Jerome I %A Hofman, Albert %A Seissler, Jochen %A Zeller, Tanja %A Usala, Gianluca %A Ernst, Florian %A Launer, Lenore J %A D'Agostino, Ralph B %A O'Leary, Daniel H %A Ballantyne, Christie %A Thiery, Joachim %A Ziegler, Andreas %A Lakatta, Edward G %A Chilukoti, Ravi Kumar %A Harris, Tamara B %A Wolf, Philip A %A Psaty, Bruce M %A Polak, Joseph F %A Li, Xia %A Rathmann, Wolfgang %A Uda, Manuela %A Boerwinkle, Eric %A Klopp, Norman %A Schmidt, Helena %A Wilson, James F %A Viikari, Jorma %A Koenig, Wolfgang %A Blankenberg, Stefan %A Newman, Anne B %A Witteman, Jacqueline %A Heiss, Gerardo %A Duijn, Cornelia van %A Scuteri, Angelo %A Homuth, Georg %A Mitchell, Braxton D %A Gudnason, Vilmundur %A O'Donnell, Christopher J %K Adult %K Aged %K Aging %K Atherosclerosis %K Carotid Intima-Media Thickness %K Cohort Studies %K Coronary Artery Disease %K European Continental Ancestry Group %K Genetic Loci %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Genotype %K Heart %K Humans %K Middle Aged %K Phenotype %K Plaque, Atherosclerotic %K Polymorphism, Single Nucleotide %K Risk Factors %X

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 × 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.

%B Nat Genet %V 43 %P 940-7 %8 2011 Sep 11 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/21909108?dopt=Abstract %R 10.1038/ng.920 %0 Journal Article %J Nature %D 2011 %T New gene functions in megakaryopoiesis and platelet formation. %A Gieger, Christian %A Radhakrishnan, Aparna %A Cvejic, Ana %A Tang, Weihong %A Porcu, Eleonora %A Pistis, Giorgio %A Serbanovic-Canic, Jovana %A Elling, Ulrich %A Goodall, Alison H %A Labrune, Yann %A Lopez, Lorna M %A Mägi, Reedik %A Meacham, Stuart %A Okada, Yukinori %A Pirastu, Nicola %A Sorice, Rossella %A Teumer, Alexander %A Voss, Katrin %A Zhang, Weihua %A Ramirez-Solis, Ramiro %A Bis, Joshua C %A Ellinghaus, David %A Gögele, Martin %A Hottenga, Jouke-Jan %A Langenberg, Claudia %A Kovacs, Peter %A O'Reilly, Paul F %A Shin, So-Youn %A Esko, Tõnu %A Hartiala, Jaana %A Kanoni, Stavroula %A Murgia, Federico %A Parsa, Afshin %A Stephens, Jonathan %A van der Harst, Pim %A Ellen van der Schoot, C %A Allayee, Hooman %A Attwood, Antony %A Balkau, Beverley %A Bastardot, François %A Basu, Saonli %A Baumeister, Sebastian E %A Biino, Ginevra %A Bomba, Lorenzo %A Bonnefond, Amélie %A Cambien, Francois %A Chambers, John C %A Cucca, Francesco %A D'Adamo, Pio %A Davies, Gail %A de Boer, Rudolf A %A de Geus, Eco J C %A Döring, Angela %A Elliott, Paul %A Erdmann, Jeanette %A Evans, David M %A Falchi, Mario %A Feng, Wei %A Folsom, Aaron R %A Frazer, Ian H %A Gibson, Quince D %A Glazer, Nicole L %A Hammond, Chris %A Hartikainen, Anna-Liisa %A Heckbert, Susan R %A Hengstenberg, Christian %A Hersch, Micha %A Illig, Thomas %A Loos, Ruth J F %A Jolley, Jennifer %A Khaw, Kay Tee %A Kuhnel, Brigitte %A Kyrtsonis, Marie-Christine %A Lagou, Vasiliki %A Lloyd-Jones, Heather %A Lumley, Thomas %A Mangino, Massimo %A Maschio, Andrea %A Mateo Leach, Irene %A McKnight, Barbara %A Memari, Yasin %A Mitchell, Braxton D %A Montgomery, Grant W %A Nakamura, Yusuke %A Nauck, Matthias %A Navis, Gerjan %A Nöthlings, Ute %A Nolte, Ilja M %A Porteous, David J %A Pouta, Anneli %A Pramstaller, Peter P %A Pullat, Janne %A Ring, Susan M %A Rotter, Jerome I %A Ruggiero, Daniela %A Ruokonen, Aimo %A Sala, Cinzia %A Samani, Nilesh J %A Sambrook, Jennifer %A Schlessinger, David %A Schreiber, Stefan %A Schunkert, Heribert %A Scott, James %A Smith, Nicholas L %A Snieder, Harold %A Starr, John M %A Stumvoll, Michael %A Takahashi, Atsushi %A Tang, W H Wilson %A Taylor, Kent %A Tenesa, Albert %A Lay Thein, Swee %A Tönjes, Anke %A Uda, Manuela %A Ulivi, Sheila %A van Veldhuisen, Dirk J %A Visscher, Peter M %A Völker, Uwe %A Wichmann, H-Erich %A Wiggins, Kerri L %A Willemsen, Gonneke %A Yang, Tsun-Po %A Hua Zhao, Jing %A Zitting, Paavo %A Bradley, John R %A Dedoussis, George V %A Gasparini, Paolo %A Hazen, Stanley L %A Metspalu, Andres %A Pirastu, Mario %A Shuldiner, Alan R %A Joost van Pelt, L %A Zwaginga, Jaap-Jan %A Boomsma, Dorret I %A Deary, Ian J %A Franke, Andre %A Froguel, Philippe %A Ganesh, Santhi K %A Jarvelin, Marjo-Riitta %A Martin, Nicholas G %A Meisinger, Christa %A Psaty, Bruce M %A Spector, Timothy D %A Wareham, Nicholas J %A Akkerman, Jan-Willem N %A Ciullo, Marina %A Deloukas, Panos %A Greinacher, Andreas %A Jupe, Steve %A Kamatani, Naoyuki %A Khadake, Jyoti %A Kooner, Jaspal S %A Penninger, Josef %A Prokopenko, Inga %A Stemple, Derek %A Toniolo, Daniela %A Wernisch, Lorenz %A Sanna, Serena %A Hicks, Andrew A %A Rendon, Augusto %A Ferreira, Manuel A %A Ouwehand, Willem H %A Soranzo, Nicole %K Animals %K Blood Platelets %K Cell Size %K Drosophila melanogaster %K Drosophila Proteins %K Europe %K Gene Expression Profiling %K Gene Silencing %K Genome, Human %K Genome-Wide Association Study %K Hematopoiesis %K Humans %K Megakaryocytes %K Platelet Count %K Protein Interaction Maps %K Transcription, Genetic %K Zebrafish %K Zebrafish Proteins %X

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.

%B Nature %V 480 %P 201-8 %8 2011 Nov 30 %G eng %N 7376 %1 http://www.ncbi.nlm.nih.gov/pubmed/22139419?dopt=Abstract %R 10.1038/nature10659 %0 Journal Article %J J Bone Miner Res %D 2012 %T Assessment of gene-by-sex interaction effect on bone mineral density. %A Liu, Ching-Ti %A Estrada, Karol %A Yerges-Armstrong, Laura M %A Amin, Najaf %A Evangelou, Evangelos %A Li, Guo %A Minster, Ryan L %A Carless, Melanie A %A Kammerer, Candace M %A Oei, Ling %A Zhou, Yanhua %A Alonso, Nerea %A Dailiana, Zoe %A Eriksson, Joel %A García-Giralt, Natalia %A Giroux, Sylvie %A Husted, Lise Bjerre %A Khusainova, Rita I %A Koromila, Theodora %A Kung, Annie Waichee %A Lewis, Joshua R %A Masi, Laura %A Mencej-Bedrac, Simona %A Nogues, Xavier %A Patel, Millan S %A Prezelj, Janez %A Richards, J Brent %A Sham, Pak Chung %A Spector, Timothy %A Vandenput, Liesbeth %A Xiao, Su-Mei %A Zheng, Hou-Feng %A Zhu, Kun %A Balcells, Susana %A Brandi, Maria Luisa %A Frost, Morten %A Goltzman, David %A González-Macías, Jesús %A Karlsson, Magnus %A Khusnutdinova, Elza K %A Kollia, Panagoula %A Langdahl, Bente Lomholt %A Ljunggren, Osten %A Lorentzon, Mattias %A Marc, Janja %A Mellström, Dan %A Ohlsson, Claes %A Olmos, José M %A Ralston, Stuart H %A Riancho, José A %A Rousseau, François %A Urreizti, Roser %A Van Hul, Wim %A Zarrabeitia, María T %A Castano-Betancourt, Martha %A Demissie, Serkalem %A Grundberg, Elin %A Herrera, Lizbeth %A Kwan, Tony %A Medina-Gómez, Carolina %A Pastinen, Tomi %A Sigurdsson, Gunnar %A Thorleifsson, Gudmar %A Vanmeurs, Joyce Bj %A Blangero, John %A Hofman, Albert %A Liu, Yongmei %A Mitchell, Braxton D %A O'Connell, Jeffrey R %A Oostra, Ben A %A Rotter, Jerome I %A Stefansson, Kari %A Streeten, Elizabeth A %A Styrkarsdottir, Unnur %A Thorsteinsdottir, Unnur %A Tylavsky, Frances A %A Uitterlinden, Andre %A Cauley, Jane A %A Harris, Tamara B %A Ioannidis, John Pa %A Psaty, Bruce M %A Robbins, John A %A Zillikens, M Carola %A Vanduijn, Cornelia M %A Prince, Richard L %A Karasik, David %A Rivadeneira, Fernando %A Kiel, Douglas P %A Cupples, L Adrienne %A Hsu, Yi-Hsiang %K Bone Density %K Cohort Studies %K Female %K Genes %K Genome-Wide Association Study %K Humans %K Male %K Meta-Analysis as Topic %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Reproducibility of Results %K Sex Characteristics %X

Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10(-5) ; female effect = -0.007 and p = 3.3 × 10(-2) ), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP. © 2012 American Society for Bone and Mineral Research.

%B J Bone Miner Res %V 27 %P 2051-64 %8 2012 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/22692763?dopt=Abstract %R 10.1002/jbmr.1679 %0 Journal Article %J Circ Cardiovasc Genet %D 2012 %T Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies. %A Murabito, Joanne M %A White, Charles C %A Kavousi, Maryam %A Sun, Yan V %A Feitosa, Mary F %A Nambi, Vijay %A Lamina, Claudia %A Schillert, Arne %A Coassin, Stefan %A Bis, Joshua C %A Broer, Linda %A Crawford, Dana C %A Franceschini, Nora %A Frikke-Schmidt, Ruth %A Haun, Margot %A Holewijn, Suzanne %A Huffman, Jennifer E %A Hwang, Shih-Jen %A Kiechl, Stefan %A Kollerits, Barbara %A Montasser, May E %A Nolte, Ilja M %A Rudock, Megan E %A Senft, Andrea %A Teumer, Alexander %A van der Harst, Pim %A Vitart, Veronique %A Waite, Lindsay L %A Wood, Andrew R %A Wassel, Christina L %A Absher, Devin M %A Allison, Matthew A %A Amin, Najaf %A Arnold, Alice %A Asselbergs, Folkert W %A Aulchenko, Yurii %A Bandinelli, Stefania %A Barbalic, Maja %A Boban, Mladen %A Brown-Gentry, Kristin %A Couper, David J %A Criqui, Michael H %A Dehghan, Abbas %A den Heijer, Martin %A Dieplinger, Benjamin %A Ding, Jingzhong %A Dörr, Marcus %A Espinola-Klein, Christine %A Felix, Stephan B %A Ferrucci, Luigi %A Folsom, Aaron R %A Fraedrich, Gustav %A Gibson, Quince %A Goodloe, Robert %A Gunjaca, Grgo %A Haltmayer, Meinhard %A Heiss, Gerardo %A Hofman, Albert %A Kieback, Arne %A Kiemeney, Lambertus A %A Kolcic, Ivana %A Kullo, Iftikhar J %A Kritchevsky, Stephen B %A Lackner, Karl J %A Li, Xiaohui %A Lieb, Wolfgang %A Lohman, Kurt %A Meisinger, Christa %A Melzer, David %A Mohler, Emile R %A Mudnic, Ivana %A Mueller, Thomas %A Navis, Gerjan %A Oberhollenzer, Friedrich %A Olin, Jeffrey W %A O'Connell, Jeff %A O'Donnell, Christopher J %A Palmas, Walter %A Penninx, Brenda W %A Petersmann, Astrid %A Polasek, Ozren %A Psaty, Bruce M %A Rantner, Barbara %A Rice, Ken %A Rivadeneira, Fernando %A Rotter, Jerome I %A Seldenrijk, Adrie %A Stadler, Marietta %A Summerer, Monika %A Tanaka, Toshiko %A Tybjaerg-Hansen, Anne %A Uitterlinden, André G %A van Gilst, Wiek H %A Vermeulen, Sita H %A Wild, Sarah H %A Wild, Philipp S %A Willeit, Johann %A Zeller, Tanja %A Zemunik, Tatijana %A Zgaga, Lina %A Assimes, Themistocles L %A Blankenberg, Stefan %A Boerwinkle, Eric %A Campbell, Harry %A Cooke, John P %A de Graaf, Jacqueline %A Herrington, David %A Kardia, Sharon L R %A Mitchell, Braxton D %A Murray, Anna %A Münzel, Thomas %A Newman, Anne B %A Oostra, Ben A %A Rudan, Igor %A Shuldiner, Alan R %A Snieder, Harold %A van Duijn, Cornelia M %A Völker, Uwe %A Wright, Alan F %A Wichmann, H-Erich %A Wilson, James F %A Witteman, Jacqueline C M %A Liu, Yongmei %A Hayward, Caroline %A Borecki, Ingrid B %A Ziegler, Andreas %A North, Kari E %A Cupples, L Adrienne %A Kronenberg, Florian %K Adult %K Age Factors %K Aged %K Aged, 80 and over %K Alleles %K Ankle Brachial Index %K Chromosomes, Human, Pair 9 %K Cohort Studies %K Cyclin-Dependent Kinase Inhibitor p15 %K Female %K Genome-Wide Association Study %K Genotype %K HapMap Project %K Humans %K Logistic Models %K Male %K Middle Aged %K Peripheral Vascular Diseases %K Phenotype %K Polymorphism, Single Nucleotide %K Risk Factors %K Sex Factors %X

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=2.46×10(-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=2.65×10(-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=3.6×10(-5)), CYBA (rs3794624, P=6.3×10(-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.

%B Circ Cardiovasc Genet %V 5 %P 100-12 %8 2012 Feb 01 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/22199011?dopt=Abstract %R 10.1161/CIRCGENETICS.111.961292 %0 Journal Article %J Atherosclerosis %D 2012 %T Genetic determinants of the ankle-brachial index: a meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium. %A Wassel, Christina L %A Lamina, Claudia %A Nambi, Vijay %A Coassin, Stefan %A Mukamal, Kenneth J %A Ganesh, Santhi K %A Jacobs, David R %A Franceschini, Nora %A Papanicolaou, George J %A Gibson, Quince %A Yanek, Lisa R %A van der Harst, Pim %A Ferguson, Jane F %A Crawford, Dana C %A Waite, Lindsay L %A Allison, Matthew A %A Criqui, Michael H %A McDermott, Mary M %A Mehra, Reena %A Cupples, L Adrienne %A Hwang, Shih-Jen %A Redline, Susan %A Kaplan, Robert C %A Heiss, Gerardo %A Rotter, Jerome I %A Boerwinkle, Eric %A Taylor, Herman A %A Eraso, Luis H %A Haun, Margot %A Li, Mingyao %A Meisinger, Christa %A O'Connell, Jeffrey R %A Shuldiner, Alan R %A Tybjærg-Hansen, Anne %A Frikke-Schmidt, Ruth %A Kollerits, Barbara %A Rantner, Barbara %A Dieplinger, Benjamin %A Stadler, Marietta %A Mueller, Thomas %A Haltmayer, Meinhard %A Klein-Weigel, Peter %A Summerer, Monika %A Wichmann, H-Erich %A Asselbergs, Folkert W %A Navis, Gerjan %A Mateo Leach, Irene %A Brown-Gentry, Kristin %A Goodloe, Robert %A Assimes, Themistocles L %A Becker, Diane M %A Cooke, John P %A Absher, Devin M %A Olin, Jeffrey W %A Mitchell, Braxton D %A Reilly, Muredach P %A Mohler, Emile R %A North, Kari E %A Reiner, Alexander P %A Kronenberg, Florian %A Murabito, Joanne M %K Adult %K African Americans %K Aged %K Ankle Brachial Index %K Aryl Hydrocarbon Hydroxylases %K Cytochrome P-450 CYP2B6 %K European Continental Ancestry Group %K Female %K Humans %K Male %K Middle Aged %K Oxidoreductases, N-Demethylating %K Peripheral Arterial Disease %K Polymorphism, Single Nucleotide %K Risk Factors %K Transcription Factor 7-Like 2 Protein %X

BACKGROUND: Candidate gene association studies for peripheral artery disease (PAD), including subclinical disease assessed with the ankle-brachial index (ABI), have been limited by the modest number of genes examined. We conducted a two stage meta-analysis of ∼50,000 SNPs across ∼2100 candidate genes to identify genetic variants for ABI.

METHODS AND RESULTS: We studied subjects of European ancestry from 8 studies (n=21,547, 55% women, mean age 44-73 years) and African American ancestry from 5 studies (n=7267, 60% women, mean age 41-73 years) involved in the candidate gene association resource (CARe) consortium. In each ethnic group, additive genetic models were used (with each additional copy of the minor allele corresponding to the given beta) to test each SNP for association with continuous ABI (excluding ABI>1.40) and PAD (defined as ABI<0.90) using linear or logistic regression with adjustment for known PAD risk factors and population stratification. We then conducted a fixed-effects inverse-variance weighted meta-analyses considering a p<2×10(-6) to denote statistical significance.

RESULTS: In the European ancestry discovery meta-analyses, rs2171209 in SYTL3 (β=-0.007, p=6.02×10(-7)) and rs290481 in TCF7L2 (β=-0.008, p=7.01×10(-7)) were significantly associated with ABI. None of the SNP associations for PAD were significant, though a SNP in CYP2B6 (p=4.99×10(-5)) was among the strongest associations. These 3 genes are linked to key PAD risk factors (lipoprotein(a), type 2 diabetes, and smoking behavior, respectively). We sought replication in 6 population-based and 3 clinical samples (n=15,440) for rs290481 and rs2171209. However, in the replication stage (rs2171209, p=0.75; rs290481, p=0.19) and in the combined discovery and replication analysis the SNP-ABI associations were no longer significant (rs2171209, p=1.14×10(-3); rs290481, p=8.88×10(-5)). In African Americans, none of the SNP associations for ABI or PAD achieved an experiment-wide level of significance.

CONCLUSIONS: Genetic determinants of ABI and PAD remain elusive. Follow-up of these preliminary findings may uncover important biology given the known gene-risk factor associations. New and more powerful approaches to PAD gene discovery are warranted.

%B Atherosclerosis %V 222 %P 138-47 %8 2012 May %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/22361517?dopt=Abstract %R 10.1016/j.atherosclerosis.2012.01.039 %0 Journal Article %J Lancet Neurol %D 2012 %T Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies. %A Traylor, Matthew %A Farrall, Martin %A Holliday, Elizabeth G %A Sudlow, Cathie %A Hopewell, Jemma C %A Cheng, Yu-Ching %A Fornage, Myriam %A Ikram, M Arfan %A Malik, Rainer %A Bevan, Steve %A Thorsteinsdottir, Unnur %A Nalls, Mike A %A Longstreth, Wt %A Wiggins, Kerri L %A Yadav, Sunaina %A Parati, Eugenio A %A DeStefano, Anita L %A Worrall, Bradford B %A Kittner, Steven J %A Khan, Muhammad Saleem %A Reiner, Alex P %A Helgadottir, Anna %A Achterberg, Sefanja %A Fernandez-Cadenas, Israel %A Abboud, Sherine %A Schmidt, Reinhold %A Walters, Matthew %A Chen, Wei-Min %A Ringelstein, E Bernd %A O'Donnell, Martin %A Ho, Weang Kee %A Pera, Joanna %A Lemmens, Robin %A Norrving, Bo %A Higgins, Peter %A Benn, Marianne %A Sale, Michele %A Kuhlenbäumer, Gregor %A Doney, Alexander S F %A Vicente, Astrid M %A Delavaran, Hossein %A Algra, Ale %A Davies, Gail %A Oliveira, Sofia A %A Palmer, Colin N A %A Deary, Ian %A Schmidt, Helena %A Pandolfo, Massimo %A Montaner, Joan %A Carty, Cara %A de Bakker, Paul I W %A Kostulas, Konstantinos %A Ferro, Jose M %A van Zuydam, Natalie R %A Valdimarsson, Einar %A Nordestgaard, Børge G %A Lindgren, Arne %A Thijs, Vincent %A Slowik, Agnieszka %A Saleheen, Danish %A Paré, Guillaume %A Berger, Klaus %A Thorleifsson, Gudmar %A Hofman, Albert %A Mosley, Thomas H %A Mitchell, Braxton D %A Furie, Karen %A Clarke, Robert %A Levi, Christopher %A Seshadri, Sudha %A Gschwendtner, Andreas %A Boncoraglio, Giorgio B %A Sharma, Pankaj %A Bis, Joshua C %A Gretarsdottir, Solveig %A Psaty, Bruce M %A Rothwell, Peter M %A Rosand, Jonathan %A Meschia, James F %A Stefansson, Kari %A Dichgans, Martin %A Markus, Hugh S %K Brain Ischemia %K Databases, Genetic %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Risk Factors %K Stroke %X

BACKGROUND: Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.

METHODS: We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.

FINDINGS: We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10(-16)) and ZFHX3 (p=2·28×10(-8)), and for large-vessel stroke at a 9p21 locus (p=3·32×10(-5)) and HDAC9 (p=2·03×10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10(-6). However, we were unable to replicate any of these novel associations in the replication cohort.

INTERPRETATION: Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.

FUNDING: Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).

%B Lancet Neurol %V 11 %P 951-62 %8 2012 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/23041239?dopt=Abstract %R 10.1016/S1474-4422(12)70234-X %0 Journal Article %J PLoS Genet %D 2012 %T Genome-wide association and functional follow-up reveals new loci for kidney function. %A Pattaro, Cristian %A Köttgen, Anna %A Teumer, Alexander %A Garnaas, Maija %A Böger, Carsten A %A Fuchsberger, Christian %A Olden, Matthias %A Chen, Ming-Huei %A Tin, Adrienne %A Taliun, Daniel %A Li, Man %A Gao, Xiaoyi %A Gorski, Mathias %A Yang, Qiong %A Hundertmark, Claudia %A Foster, Meredith C %A O'Seaghdha, Conall M %A Glazer, Nicole %A Isaacs, Aaron %A Liu, Ching-Ti %A Smith, Albert V %A O'Connell, Jeffrey R %A Struchalin, Maksim %A Tanaka, Toshiko %A Li, Guo %A Johnson, Andrew D %A Gierman, Hinco J %A Feitosa, Mary %A Hwang, Shih-Jen %A Atkinson, Elizabeth J %A Lohman, Kurt %A Cornelis, Marilyn C %A Johansson, Asa %A Tönjes, Anke %A Dehghan, Abbas %A Chouraki, Vincent %A Holliday, Elizabeth G %A Sorice, Rossella %A Kutalik, Zoltán %A Lehtimäki, Terho %A Esko, Tõnu %A Deshmukh, Harshal %A Ulivi, Sheila %A Chu, Audrey Y %A Murgia, Federico %A Trompet, Stella %A Imboden, Medea %A Kollerits, Barbara %A Pistis, Giorgio %A Harris, Tamara B %A Launer, Lenore J %A Aspelund, Thor %A Eiriksdottir, Gudny %A Mitchell, Braxton D %A Boerwinkle, Eric %A Schmidt, Helena %A Cavalieri, Margherita %A Rao, Madhumathi %A Hu, Frank B %A Demirkan, Ayse %A Oostra, Ben A %A de Andrade, Mariza %A Turner, Stephen T %A Ding, Jingzhong %A Andrews, Jeanette S %A Freedman, Barry I %A Koenig, Wolfgang %A Illig, Thomas %A Döring, Angela %A Wichmann, H-Erich %A Kolcic, Ivana %A Zemunik, Tatijana %A Boban, Mladen %A Minelli, Cosetta %A Wheeler, Heather E %A Igl, Wilmar %A Zaboli, Ghazal %A Wild, Sarah H %A Wright, Alan F %A Campbell, Harry %A Ellinghaus, David %A Nöthlings, Ute %A Jacobs, Gunnar %A Biffar, Reiner %A Endlich, Karlhans %A Ernst, Florian %A Homuth, Georg %A Kroemer, Heyo K %A Nauck, Matthias %A Stracke, Sylvia %A Völker, Uwe %A Völzke, Henry %A Kovacs, Peter %A Stumvoll, Michael %A Mägi, Reedik %A Hofman, Albert %A Uitterlinden, André G %A Rivadeneira, Fernando %A Aulchenko, Yurii S %A Polasek, Ozren %A Hastie, Nick %A Vitart, Veronique %A Helmer, Catherine %A Wang, Jie Jin %A Ruggiero, Daniela %A Bergmann, Sven %A Kähönen, Mika %A Viikari, Jorma %A Nikopensius, Tiit %A Province, Michael %A Ketkar, Shamika %A Colhoun, Helen %A Doney, Alex %A Robino, Antonietta %A Giulianini, Franco %A Krämer, Bernhard K %A Portas, Laura %A Ford, Ian %A Buckley, Brendan M %A Adam, Martin %A Thun, Gian-Andri %A Paulweber, Bernhard %A Haun, Margot %A Sala, Cinzia %A Metzger, Marie %A Mitchell, Paul %A Ciullo, Marina %A Kim, Stuart K %A Vollenweider, Peter %A Raitakari, Olli %A Metspalu, Andres %A Palmer, Colin %A Gasparini, Paolo %A Pirastu, Mario %A Jukema, J Wouter %A Probst-Hensch, Nicole M %A Kronenberg, Florian %A Toniolo, Daniela %A Gudnason, Vilmundur %A Shuldiner, Alan R %A Coresh, Josef %A Schmidt, Reinhold %A Ferrucci, Luigi %A Siscovick, David S %A van Duijn, Cornelia M %A Borecki, Ingrid %A Kardia, Sharon L R %A Liu, Yongmei %A Curhan, Gary C %A Rudan, Igor %A Gyllensten, Ulf %A Wilson, James F %A Franke, Andre %A Pramstaller, Peter P %A Rettig, Rainer %A Prokopenko, Inga %A Witteman, Jacqueline C M %A Hayward, Caroline %A Ridker, Paul %A Parsa, Afshin %A Bochud, Murielle %A Heid, Iris M %A Goessling, Wolfram %A Chasman, Daniel I %A Kao, W H Linda %A Fox, Caroline S %K African Americans %K Aged %K Animals %K Caspase 9 %K Cyclin-Dependent Kinases %K DEAD-box RNA Helicases %K DNA Helicases %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Gene Knockdown Techniques %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Kidney %K Kidney Failure, Chronic %K Male %K Middle Aged %K Phosphoric Diester Hydrolases %K Zebrafish %X

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

%B PLoS Genet %V 8 %P e1002584 %8 2012 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22479191?dopt=Abstract %R 10.1371/journal.pgen.1002584 %0 Journal Article %J Nat Genet %D 2012 %T Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. %A Estrada, Karol %A Styrkarsdottir, Unnur %A Evangelou, Evangelos %A Hsu, Yi-Hsiang %A Duncan, Emma L %A Ntzani, Evangelia E %A Oei, Ling %A Albagha, Omar M E %A Amin, Najaf %A Kemp, John P %A Koller, Daniel L %A Li, Guo %A Liu, Ching-Ti %A Minster, Ryan L %A Moayyeri, Alireza %A Vandenput, Liesbeth %A Willner, Dana %A Xiao, Su-Mei %A Yerges-Armstrong, Laura M %A Zheng, Hou-Feng %A Alonso, Nerea %A Eriksson, Joel %A Kammerer, Candace M %A Kaptoge, Stephen K %A Leo, Paul J %A Thorleifsson, Gudmar %A Wilson, Scott G %A Wilson, James F %A Aalto, Ville %A Alen, Markku %A Aragaki, Aaron K %A Aspelund, Thor %A Center, Jacqueline R %A Dailiana, Zoe %A Duggan, David J %A Garcia, Melissa %A García-Giralt, Natalia %A Giroux, Sylvie %A Hallmans, Göran %A Hocking, Lynne J %A Husted, Lise Bjerre %A Jameson, Karen A %A Khusainova, Rita %A Kim, Ghi Su %A Kooperberg, Charles %A Koromila, Theodora %A Kruk, Marcin %A Laaksonen, Marika %A LaCroix, Andrea Z %A Lee, Seung Hun %A Leung, Ping C %A Lewis, Joshua R %A Masi, Laura %A Mencej-Bedrac, Simona %A Nguyen, Tuan V %A Nogues, Xavier %A Patel, Millan S %A Prezelj, Janez %A Rose, Lynda M %A Scollen, Serena %A Siggeirsdottir, Kristin %A Smith, Albert V %A Svensson, Olle %A Trompet, Stella %A Trummer, Olivia %A van Schoor, Natasja M %A Woo, Jean %A Zhu, Kun %A Balcells, Susana %A Brandi, Maria Luisa %A Buckley, Brendan M %A Cheng, Sulin %A Christiansen, Claus %A Cooper, Cyrus %A Dedoussis, George %A Ford, Ian %A Frost, Morten %A Goltzman, David %A González-Macías, Jesús %A Kähönen, Mika %A Karlsson, Magnus %A Khusnutdinova, Elza %A Koh, Jung-Min %A Kollia, Panagoula %A Langdahl, Bente Lomholt %A Leslie, William D %A Lips, Paul %A Ljunggren, Osten %A Lorenc, Roman S %A Marc, Janja %A Mellström, Dan %A Obermayer-Pietsch, Barbara %A Olmos, José M %A Pettersson-Kymmer, Ulrika %A Reid, David M %A Riancho, José A %A Ridker, Paul M %A Rousseau, François %A Slagboom, P Eline %A Tang, Nelson L S %A Urreizti, Roser %A Van Hul, Wim %A Viikari, Jorma %A Zarrabeitia, María T %A Aulchenko, Yurii S %A Castano-Betancourt, Martha %A Grundberg, Elin %A Herrera, Lizbeth %A Ingvarsson, Thorvaldur %A Johannsdottir, Hrefna %A Kwan, Tony %A Li, Rui %A Luben, Robert %A Medina-Gómez, Carolina %A Palsson, Stefan Th %A Reppe, Sjur %A Rotter, Jerome I %A Sigurdsson, Gunnar %A van Meurs, Joyce B J %A Verlaan, Dominique %A Williams, Frances M K %A Wood, Andrew R %A Zhou, Yanhua %A Gautvik, Kaare M %A Pastinen, Tomi %A Raychaudhuri, Soumya %A Cauley, Jane A %A Chasman, Daniel I %A Clark, Graeme R %A Cummings, Steven R %A Danoy, Patrick %A Dennison, Elaine M %A Eastell, Richard %A Eisman, John A %A Gudnason, Vilmundur %A Hofman, Albert %A Jackson, Rebecca D %A Jones, Graeme %A Jukema, J Wouter %A Khaw, Kay-Tee %A Lehtimäki, Terho %A Liu, Yongmei %A Lorentzon, Mattias %A McCloskey, Eugene %A Mitchell, Braxton D %A Nandakumar, Kannabiran %A Nicholson, Geoffrey C %A Oostra, Ben A %A Peacock, Munro %A Pols, Huibert A P %A Prince, Richard L %A Raitakari, Olli %A Reid, Ian R %A Robbins, John %A Sambrook, Philip N %A Sham, Pak Chung %A Shuldiner, Alan R %A Tylavsky, Frances A %A van Duijn, Cornelia M %A Wareham, Nick J %A Cupples, L Adrienne %A Econs, Michael J %A Evans, David M %A Harris, Tamara B %A Kung, Annie Wai Chee %A Psaty, Bruce M %A Reeve, Jonathan %A Spector, Timothy D %A Streeten, Elizabeth A %A Zillikens, M Carola %A Thorsteinsdottir, Unnur %A Ohlsson, Claes %A Karasik, David %A Richards, J Brent %A Brown, Matthew A %A Stefansson, Kari %A Uitterlinden, André G %A Ralston, Stuart H %A Ioannidis, John P A %A Kiel, Douglas P %A Rivadeneira, Fernando %K Bone Density %K Computational Biology %K European Continental Ancestry Group %K Extracellular Matrix Proteins %K Female %K Femur Neck %K Fractures, Bone %K Gene Expression Profiling %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Glycoproteins %K Humans %K Intercellular Signaling Peptides and Proteins %K Low Density Lipoprotein Receptor-Related Protein-5 %K Lumbar Vertebrae %K Male %K Mitochondrial Membrane Transport Proteins %K Osteoporosis %K Phosphoproteins %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Risk Factors %K Spectrin %X

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

%B Nat Genet %V 44 %P 491-501 %8 2012 Apr 15 %G eng %N 5 %R 10.1038/ng.2249 %0 Journal Article %J PLoS Genet %D 2012 %T Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals. %A Dastani, Zari %A Hivert, Marie-France %A Timpson, Nicholas %A Perry, John R B %A Yuan, Xin %A Scott, Robert A %A Henneman, Peter %A Heid, Iris M %A Kizer, Jorge R %A Lyytikäinen, Leo-Pekka %A Fuchsberger, Christian %A Tanaka, Toshiko %A Morris, Andrew P %A Small, Kerrin %A Isaacs, Aaron %A Beekman, Marian %A Coassin, Stefan %A Lohman, Kurt %A Qi, Lu %A Kanoni, Stavroula %A Pankow, James S %A Uh, Hae-Won %A Wu, Ying %A Bidulescu, Aurelian %A Rasmussen-Torvik, Laura J %A Greenwood, Celia M T %A Ladouceur, Martin %A Grimsby, Jonna %A Manning, Alisa K %A Liu, Ching-Ti %A Kooner, Jaspal %A Mooser, Vincent E %A Vollenweider, Peter %A Kapur, Karen A %A Chambers, John %A Wareham, Nicholas J %A Langenberg, Claudia %A Frants, Rune %A Willems-Vandijk, Ko %A Oostra, Ben A %A Willems, Sara M %A Lamina, Claudia %A Winkler, Thomas W %A Psaty, Bruce M %A Tracy, Russell P %A Brody, Jennifer %A Chen, Ida %A Viikari, Jorma %A Kähönen, Mika %A Pramstaller, Peter P %A Evans, David M %A St Pourcain, Beate %A Sattar, Naveed %A Wood, Andrew R %A Bandinelli, Stefania %A Carlson, Olga D %A Egan, Josephine M %A Böhringer, Stefan %A van Heemst, Diana %A Kedenko, Lyudmyla %A Kristiansson, Kati %A Nuotio, Marja-Liisa %A Loo, Britt-Marie %A Harris, Tamara %A Garcia, Melissa %A Kanaya, Alka %A Haun, Margot %A Klopp, Norman %A Wichmann, H-Erich %A Deloukas, Panos %A Katsareli, Efi %A Couper, David J %A Duncan, Bruce B %A Kloppenburg, Margreet %A Adair, Linda S %A Borja, Judith B %A Wilson, James G %A Musani, Solomon %A Guo, Xiuqing %A Johnson, Toby %A Semple, Robert %A Teslovich, Tanya M %A Allison, Matthew A %A Redline, Susan %A Buxbaum, Sarah G %A Mohlke, Karen L %A Meulenbelt, Ingrid %A Ballantyne, Christie M %A Dedoussis, George V %A Hu, Frank B %A Liu, Yongmei %A Paulweber, Bernhard %A Spector, Timothy D %A Slagboom, P Eline %A Ferrucci, Luigi %A Jula, Antti %A Perola, Markus %A Raitakari, Olli %A Florez, Jose C %A Salomaa, Veikko %A Eriksson, Johan G %A Frayling, Timothy M %A Hicks, Andrew A %A Lehtimäki, Terho %A Smith, George Davey %A Siscovick, David S %A Kronenberg, Florian %A van Duijn, Cornelia %A Loos, Ruth J F %A Waterworth, Dawn M %A Meigs, James B %A Dupuis, Josée %A Richards, J Brent %A Voight, Benjamin F %A Scott, Laura J %A Steinthorsdottir, Valgerdur %A Dina, Christian %A Welch, Ryan P %A Zeggini, Eleftheria %A Huth, Cornelia %A Aulchenko, Yurii S %A Thorleifsson, Gudmar %A McCulloch, Laura J %A Ferreira, Teresa %A Grallert, Harald %A Amin, Najaf %A Wu, Guanming %A Willer, Cristen J %A Raychaudhuri, Soumya %A McCarroll, Steve A %A Hofmann, Oliver M %A Segrè, Ayellet V %A van Hoek, Mandy %A Navarro, Pau %A Ardlie, Kristin %A Balkau, Beverley %A Benediktsson, Rafn %A Bennett, Amanda J %A Blagieva, Roza %A Boerwinkle, Eric %A Bonnycastle, Lori L %A Boström, Kristina Bengtsson %A Bravenboer, Bert %A Bumpstead, Suzannah %A Burtt, Noel P %A Charpentier, Guillaume %A Chines, Peter S %A Cornelis, Marilyn %A Crawford, Gabe %A Doney, Alex S F %A Elliott, Katherine S %A Elliott, Amanda L %A Erdos, Michael R %A Fox, Caroline S %A Franklin, Christopher S %A Ganser, Martha %A Gieger, Christian %A Grarup, Niels %A Green, Todd %A Griffin, Simon %A Groves, Christopher J %A Guiducci, Candace %A Hadjadj, Samy %A Hassanali, Neelam %A Herder, Christian %A Isomaa, Bo %A Jackson, Anne U %A Johnson, Paul R V %A Jørgensen, Torben %A Kao, Wen H L %A Kong, Augustine %A Kraft, Peter %A Kuusisto, Johanna %A Lauritzen, Torsten %A Li, Man %A Lieverse, Aloysius %A Lindgren, Cecilia M %A Lyssenko, Valeriya %A Marre, Michel %A Meitinger, Thomas %A Midthjell, Kristian %A Morken, Mario A %A Narisu, Narisu %A Nilsson, Peter %A Owen, Katharine R %A Payne, Felicity %A Petersen, Ann-Kristin %A Platou, Carl %A Proença, Christine %A Prokopenko, Inga %A Rathmann, Wolfgang %A Rayner, N William %A Robertson, Neil R %A Rocheleau, Ghislain %A Roden, Michael %A Sampson, Michael J %A Saxena, Richa %A Shields, Beverley M %A Shrader, Peter %A Sigurdsson, Gunnar %A Sparsø, Thomas %A Strassburger, Klaus %A Stringham, Heather M %A Sun, Qi %A Swift, Amy J %A Thorand, Barbara %A Tichet, Jean %A Tuomi, Tiinamaija %A van Dam, Rob M %A van Haeften, Timon W %A van Herpt, Thijs %A van Vliet-Ostaptchouk, Jana V %A Walters, G Bragi %A Weedon, Michael N %A Wijmenga, Cisca %A Witteman, Jacqueline %A Bergman, Richard N %A Cauchi, Stephane %A Collins, Francis S %A Gloyn, Anna L %A Gyllensten, Ulf %A Hansen, Torben %A Hide, Winston A %A Hitman, Graham A %A Hofman, Albert %A Hunter, David J %A Hveem, Kristian %A Laakso, Markku %A Morris, Andrew D %A Palmer, Colin N A %A Rudan, Igor %A Sijbrands, Eric %A Stein, Lincoln D %A Tuomilehto, Jaakko %A Uitterlinden, Andre %A Walker, Mark %A Watanabe, Richard M %A Abecasis, Goncalo R %A Boehm, Bernhard O %A Campbell, Harry %A Daly, Mark J %A Hattersley, Andrew T %A Pedersen, Oluf %A Barroso, Inês %A Groop, Leif %A Sladek, Rob %A Thorsteinsdottir, Unnur %A Wilson, James F %A Illig, Thomas %A Froguel, Philippe %A van Duijn, Cornelia M %A Stefansson, Kari %A Altshuler, David %A Boehnke, Michael %A McCarthy, Mark I %A Soranzo, Nicole %A Wheeler, Eleanor %A Glazer, Nicole L %A Bouatia-Naji, Nabila %A Mägi, Reedik %A Randall, Joshua %A Elliott, Paul %A Rybin, Denis %A Dehghan, Abbas %A Hottenga, Jouke Jan %A Song, Kijoung %A Goel, Anuj %A Lajunen, Taina %A Doney, Alex %A Cavalcanti-Proença, Christine %A Kumari, Meena %A Timpson, Nicholas J %A Zabena, Carina %A Ingelsson, Erik %A An, Ping %A O'Connell, Jeffrey %A Luan, Jian'an %A Elliott, Amanda %A McCarroll, Steven A %A Roccasecca, Rosa Maria %A Pattou, François %A Sethupathy, Praveen %A Ariyurek, Yavuz %A Barter, Philip %A Beilby, John P %A Ben-Shlomo, Yoav %A Bergmann, Sven %A Bochud, Murielle %A Bonnefond, Amélie %A Borch-Johnsen, Knut %A Böttcher, Yvonne %A Brunner, Eric %A Bumpstead, Suzannah J %A Chen, Yii-Der Ida %A Chines, Peter %A Clarke, Robert %A Coin, Lachlan J M %A Cooper, Matthew N %A Crisponi, Laura %A Day, Ian N M %A de Geus, Eco J C %A Delplanque, Jerome %A Fedson, Annette C %A Fischer-Rosinsky, Antje %A Forouhi, Nita G %A Franzosi, Maria Grazia %A Galan, Pilar %A Goodarzi, Mark O %A Graessler, Jürgen %A Grundy, Scott %A Gwilliam, Rhian %A Hallmans, Göran %A Hammond, Naomi %A Han, Xijing %A Hartikainen, Anna-Liisa %A Hayward, Caroline %A Heath, Simon C %A Hercberg, Serge %A Hillman, David R %A Hingorani, Aroon D %A Hui, Jennie %A Hung, Joe %A Kaakinen, Marika %A Kaprio, Jaakko %A Kesaniemi, Y Antero %A Kivimaki, Mika %A Knight, Beatrice %A Koskinen, Seppo %A Kovacs, Peter %A Kyvik, Kirsten Ohm %A Lathrop, G Mark %A Lawlor, Debbie A %A Le Bacquer, Olivier %A Lecoeur, Cécile %A Li, Yun %A Mahley, Robert %A Mangino, Massimo %A Martínez-Larrad, María Teresa %A McAteer, Jarred B %A McPherson, Ruth %A Meisinger, Christa %A Melzer, David %A Meyre, David %A Mitchell, Braxton D %A Mukherjee, Sutapa %A Naitza, Silvia %A Neville, Matthew J %A Orrù, Marco %A Pakyz, Ruth %A Paolisso, Giuseppe %A Pattaro, Cristian %A Pearson, Daniel %A Peden, John F %A Pedersen, Nancy L %A Pfeiffer, Andreas F H %A Pichler, Irene %A Polasek, Ozren %A Posthuma, Danielle %A Potter, Simon C %A Pouta, Anneli %A Province, Michael A %A Rayner, Nigel W %A Rice, Kenneth %A Ripatti, Samuli %A Rivadeneira, Fernando %A Rolandsson, Olov %A Sandbaek, Annelli %A Sandhu, Manjinder %A Sanna, Serena %A Sayer, Avan Aihie %A Scheet, Paul %A Seedorf, Udo %A Sharp, Stephen J %A Shields, Beverley %A Sigurðsson, Gunnar %A Sijbrands, Eric J G %A Silveira, Angela %A Simpson, Laila %A Singleton, Andrew %A Smith, Nicholas L %A Sovio, Ulla %A Swift, Amy %A Syddall, Holly %A Syvänen, Ann-Christine %A Tönjes, Anke %A Uitterlinden, André G %A van Dijk, Ko Willems %A Varma, Dhiraj %A Visvikis-Siest, Sophie %A Vitart, Veronique %A Vogelzangs, Nicole %A Waeber, Gérard %A Wagner, Peter J %A Walley, Andrew %A Ward, Kim L %A Watkins, Hugh %A Wild, Sarah H %A Willemsen, Gonneke %A Witteman, Jaqueline C M %A Yarnell, John W G %A Zelenika, Diana %A Zethelius, Björn %A Zhai, Guangju %A Zhao, Jing Hua %A Zillikens, M Carola %A Borecki, Ingrid B %A Meneton, Pierre %A Magnusson, Patrik K E %A Nathan, David M %A Williams, Gordon H %A Silander, Kaisa %A Bornstein, Stefan R %A Schwarz, Peter %A Spranger, Joachim %A Karpe, Fredrik %A Shuldiner, Alan R %A Cooper, Cyrus %A Serrano-Ríos, Manuel %A Lind, Lars %A Palmer, Lyle J %A Hu, Frank B %A Franks, Paul W %A Ebrahim, Shah %A Marmot, Michael %A Kao, W H Linda %A Pramstaller, Peter Paul %A Wright, Alan F %A Stumvoll, Michael %A Hamsten, Anders %A Buchanan, Thomas A %A Valle, Timo T %A Rotter, Jerome I %A Penninx, Brenda W J H %A Boomsma, Dorret I %A Cao, Antonio %A Scuteri, Angelo %A Schlessinger, David %A Uda, Manuela %A Ruokonen, Aimo %A Jarvelin, Marjo-Riitta %A Peltonen, Leena %A Mooser, Vincent %A Sladek, Robert %A Musunuru, Kiran %A Smith, Albert V %A Edmondson, Andrew C %A Stylianou, Ioannis M %A Koseki, Masahiro %A Pirruccello, James P %A Chasman, Daniel I %A Johansen, Christopher T %A Fouchier, Sigrid W %A Peloso, Gina M %A Barbalic, Maja %A Ricketts, Sally L %A Bis, Joshua C %A Feitosa, Mary F %A Orho-Melander, Marju %A Melander, Olle %A Li, Xiaohui %A Li, Mingyao %A Cho, Yoon Shin %A Go, Min Jin %A Kim, Young Jin %A Lee, Jong-Young %A Park, Taesung %A Kim, Kyunga %A Sim, Xueling %A Ong, Rick Twee-Hee %A Croteau-Chonka, Damien C %A Lange, Leslie A %A Smith, Joshua D %A Ziegler, Andreas %A Zhang, Weihua %A Zee, Robert Y L %A Whitfield, John B %A Thompson, John R %A Surakka, Ida %A Spector, Tim D %A Smit, Johannes H %A Sinisalo, Juha %A Scott, James %A Saharinen, Juha %A Sabatti, Chiara %A Rose, Lynda M %A Roberts, Robert %A Rieder, Mark %A Parker, Alex N %A Paré, Guillaume %A O'Donnell, Christopher J %A Nieminen, Markku S %A Nickerson, Deborah A %A Montgomery, Grant W %A McArdle, Wendy %A Masson, David %A Martin, Nicholas G %A Marroni, Fabio %A Lucas, Gavin %A Luben, Robert %A Lokki, Marja-Liisa %A Lettre, Guillaume %A Launer, Lenore J %A Lakatta, Edward G %A Laaksonen, Reijo %A Kyvik, Kirsten O %A König, Inke R %A Khaw, Kay-Tee %A Kaplan, Lee M %A Johansson, Asa %A Janssens, A Cecile J W %A Igl, Wilmar %A Hovingh, G Kees %A Hengstenberg, Christian %A Havulinna, Aki S %A Hastie, Nicholas D %A Harris, Tamara B %A Haritunians, Talin %A Hall, Alistair S %A Groop, Leif C %A Gonzalez, Elena %A Freimer, Nelson B %A Erdmann, Jeanette %A Ejebe, Kenechi G %A Döring, Angela %A Dominiczak, Anna F %A Demissie, Serkalem %A Deloukas, Panagiotis %A de Faire, Ulf %A Crawford, Gabriel %A Chen, Yii-der I %A Caulfield, Mark J %A Boekholdt, S Matthijs %A Assimes, Themistocles L %A Quertermous, Thomas %A Seielstad, Mark %A Wong, Tien Y %A Tai, E-Shyong %A Feranil, Alan B %A Kuzawa, Christopher W %A Taylor, Herman A %A Gabriel, Stacey B %A Holm, Hilma %A Gudnason, Vilmundur %A Krauss, Ronald M %A Ordovas, Jose M %A Munroe, Patricia B %A Kooner, Jaspal S %A Tall, Alan R %A Hegele, Robert A %A Kastelein, John J P %A Schadt, Eric E %A Strachan, David P %A Reilly, Muredach P %A Samani, Nilesh J %A Schunkert, Heribert %A Cupples, L Adrienne %A Sandhu, Manjinder S %A Ridker, Paul M %A Rader, Daniel J %A Kathiresan, Sekar %K Adiponectin %K African Americans %K Asian Continental Ancestry Group %K Cholesterol, HDL %K Diabetes Mellitus, Type 2 %K European Continental Ancestry Group %K Female %K Gene Expression %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Glucose Tolerance Test %K Humans %K Insulin Resistance %K Male %K Metabolic Networks and Pathways %K Polymorphism, Single Nucleotide %K Waist-Hip Ratio %X

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

%B PLoS Genet %V 8 %P e1002607 %8 2012 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22479202?dopt=Abstract %R 10.1371/journal.pgen.1002607 %0 Journal Article %J Nat Genet %D 2013 %T Common variants associated with plasma triglycerides and risk for coronary artery disease. %A Do, Ron %A Willer, Cristen J %A Schmidt, Ellen M %A Sengupta, Sebanti %A Gao, Chi %A Peloso, Gina M %A Gustafsson, Stefan %A Kanoni, Stavroula %A Ganna, Andrea %A Chen, Jin %A Buchkovich, Martin L %A Mora, Samia %A Beckmann, Jacques S %A Bragg-Gresham, Jennifer L %A Chang, Hsing-Yi %A Demirkan, Ayse %A Den Hertog, Heleen M %A Donnelly, Louise A %A Ehret, Georg B %A Esko, Tõnu %A Feitosa, Mary F %A Ferreira, Teresa %A Fischer, Krista %A Fontanillas, Pierre %A Fraser, Ross M %A Freitag, Daniel F %A Gurdasani, Deepti %A Heikkilä, Kauko %A Hyppönen, Elina %A Isaacs, Aaron %A Jackson, Anne U %A Johansson, Asa %A Johnson, Toby %A Kaakinen, Marika %A Kettunen, Johannes %A Kleber, Marcus E %A Li, Xiaohui %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A Magnusson, Patrik K E %A Mangino, Massimo %A Mihailov, Evelin %A Montasser, May E %A Müller-Nurasyid, Martina %A Nolte, Ilja M %A O'Connell, Jeffrey R %A Palmer, Cameron D %A Perola, Markus %A Petersen, Ann-Kristin %A Sanna, Serena %A Saxena, Richa %A Service, Susan K %A Shah, Sonia %A Shungin, Dmitry %A Sidore, Carlo %A Song, Ci %A Strawbridge, Rona J %A Surakka, Ida %A Tanaka, Toshiko %A Teslovich, Tanya M %A Thorleifsson, Gudmar %A van den Herik, Evita G %A Voight, Benjamin F %A Volcik, Kelly A %A Waite, Lindsay L %A Wong, Andrew %A Wu, Ying %A Zhang, Weihua %A Absher, Devin %A Asiki, Gershim %A Barroso, Inês %A Been, Latonya F %A Bolton, Jennifer L %A Bonnycastle, Lori L %A Brambilla, Paolo %A Burnett, Mary S %A Cesana, Giancarlo %A Dimitriou, Maria %A Doney, Alex S F %A Döring, Angela %A Elliott, Paul %A Epstein, Stephen E %A Eyjolfsson, Gudmundur Ingi %A Gigante, Bruna %A Goodarzi, Mark O %A Grallert, Harald %A Gravito, Martha L %A Groves, Christopher J %A Hallmans, Göran %A Hartikainen, Anna-Liisa %A Hayward, Caroline %A Hernandez, Dena %A Hicks, Andrew A %A Holm, Hilma %A Hung, Yi-Jen %A Illig, Thomas %A Jones, Michelle R %A Kaleebu, Pontiano %A Kastelein, John J P %A Khaw, Kay-Tee %A Kim, Eric %A Klopp, Norman %A Komulainen, Pirjo %A Kumari, Meena %A Langenberg, Claudia %A Lehtimäki, Terho %A Lin, Shih-Yi %A Lindström, Jaana %A Loos, Ruth J F %A Mach, François %A McArdle, Wendy L %A Meisinger, Christa %A Mitchell, Braxton D %A Müller, Gabrielle %A Nagaraja, Ramaiah %A Narisu, Narisu %A Nieminen, Tuomo V M %A Nsubuga, Rebecca N %A Olafsson, Isleifur %A Ong, Ken K %A Palotie, Aarno %A Papamarkou, Theodore %A Pomilla, Cristina %A Pouta, Anneli %A Rader, Daniel J %A Reilly, Muredach P %A Ridker, Paul M %A Rivadeneira, Fernando %A Rudan, Igor %A Ruokonen, Aimo %A Samani, Nilesh %A Scharnagl, Hubert %A Seeley, Janet %A Silander, Kaisa %A Stančáková, Alena %A Stirrups, Kathleen %A Swift, Amy J %A Tiret, Laurence %A Uitterlinden, André G %A van Pelt, L Joost %A Vedantam, Sailaja %A Wainwright, Nicholas %A Wijmenga, Cisca %A Wild, Sarah H %A Willemsen, Gonneke %A Wilsgaard, Tom %A Wilson, James F %A Young, Elizabeth H %A Zhao, Jing Hua %A Adair, Linda S %A Arveiler, Dominique %A Assimes, Themistocles L %A Bandinelli, Stefania %A Bennett, Franklyn %A Bochud, Murielle %A Boehm, Bernhard O %A Boomsma, Dorret I %A Borecki, Ingrid B %A Bornstein, Stefan R %A Bovet, Pascal %A Burnier, Michel %A Campbell, Harry %A Chakravarti, Aravinda %A Chambers, John C %A Chen, Yii-Der Ida %A Collins, Francis S %A Cooper, Richard S %A Danesh, John %A Dedoussis, George %A de Faire, Ulf %A Feranil, Alan B %A Ferrieres, Jean %A Ferrucci, Luigi %A Freimer, Nelson B %A Gieger, Christian %A Groop, Leif C %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Hamsten, Anders %A Harris, Tamara B %A Hingorani, Aroon %A Hirschhorn, Joel N %A Hofman, Albert %A Hovingh, G Kees %A Hsiung, Chao Agnes %A Humphries, Steve E %A Hunt, Steven C %A Hveem, Kristian %A Iribarren, Carlos %A Jarvelin, Marjo-Riitta %A Jula, Antti %A Kähönen, Mika %A Kaprio, Jaakko %A Kesäniemi, Antero %A Kivimaki, Mika %A Kooner, Jaspal S %A Koudstaal, Peter J %A Krauss, Ronald M %A Kuh, Diana %A Kuusisto, Johanna %A Kyvik, Kirsten O %A Laakso, Markku %A Lakka, Timo A %A Lind, Lars %A Lindgren, Cecilia M %A Martin, Nicholas G %A März, Winfried %A McCarthy, Mark I %A McKenzie, Colin A %A Meneton, Pierre %A Metspalu, Andres %A Moilanen, Leena %A Morris, Andrew D %A Munroe, Patricia B %A Njølstad, Inger %A Pedersen, Nancy L %A Power, Chris %A Pramstaller, Peter P %A Price, Jackie F %A Psaty, Bruce M %A Quertermous, Thomas %A Rauramaa, Rainer %A Saleheen, Danish %A Salomaa, Veikko %A Sanghera, Dharambir K %A Saramies, Jouko %A Schwarz, Peter E H %A Sheu, Wayne H-H %A Shuldiner, Alan R %A Siegbahn, Agneta %A Spector, Tim D %A Stefansson, Kari %A Strachan, David P %A Tayo, Bamidele O %A Tremoli, Elena %A Tuomilehto, Jaakko %A Uusitupa, Matti %A van Duijn, Cornelia M %A Vollenweider, Peter %A Wallentin, Lars %A Wareham, Nicholas J %A Whitfield, John B %A Wolffenbuttel, Bruce H R %A Altshuler, David %A Ordovas, Jose M %A Boerwinkle, Eric %A Palmer, Colin N A %A Thorsteinsdottir, Unnur %A Chasman, Daniel I %A Rotter, Jerome I %A Franks, Paul W %A Ripatti, Samuli %A Cupples, L Adrienne %A Sandhu, Manjinder S %A Rich, Stephen S %A Boehnke, Michael %A Deloukas, Panos %A Mohlke, Karen L %A Ingelsson, Erik %A Abecasis, Goncalo R %A Daly, Mark J %A Neale, Benjamin M %A Kathiresan, Sekar %K Biological Transport %K Cholesterol, HDL %K Cholesterol, LDL %K Coronary Artery Disease %K Humans %K Polymorphism, Single Nucleotide %K Risk Factors %K Triglycerides %X

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

%B Nat Genet %V 45 %P 1345-52 %8 2013 Nov %G eng %N 11 %R 10.1038/ng.2795 %0 Journal Article %J J Am Soc Nephrol %D 2013 %T Common variants in Mendelian kidney disease genes and their association with renal function. %A Parsa, Afshin %A Fuchsberger, Christian %A Köttgen, Anna %A O'Seaghdha, Conall M %A Pattaro, Cristian %A de Andrade, Mariza %A Chasman, Daniel I %A Teumer, Alexander %A Endlich, Karlhans %A Olden, Matthias %A Chen, Ming-Huei %A Tin, Adrienne %A Kim, Young J %A Taliun, Daniel %A Li, Man %A Feitosa, Mary %A Gorski, Mathias %A Yang, Qiong %A Hundertmark, Claudia %A Foster, Meredith C %A Glazer, Nicole %A Isaacs, Aaron %A Rao, Madhumathi %A Smith, Albert V %A O'Connell, Jeffrey R %A Struchalin, Maksim %A Tanaka, Toshiko %A Li, Guo %A Hwang, Shih-Jen %A Atkinson, Elizabeth J %A Lohman, Kurt %A Cornelis, Marilyn C %A Johansson, Asa %A Tönjes, Anke %A Dehghan, Abbas %A Couraki, Vincent %A Holliday, Elizabeth G %A Sorice, Rossella %A Kutalik, Zoltán %A Lehtimäki, Terho %A Esko, Tõnu %A Deshmukh, Harshal %A Ulivi, Sheila %A Chu, Audrey Y %A Murgia, Federico %A Trompet, Stella %A Imboden, Medea %A Kollerits, Barbara %A Pistis, Giorgio %A Harris, Tamara B %A Launer, Lenore J %A Aspelund, Thor %A Eiriksdottir, Gudny %A Mitchell, Braxton D %A Boerwinkle, Eric %A Schmidt, Helena %A Hofer, Edith %A Hu, Frank %A Demirkan, Ayse %A Oostra, Ben A %A Turner, Stephen T %A Ding, Jingzhong %A Andrews, Jeanette S %A Freedman, Barry I %A Giulianini, Franco %A Koenig, Wolfgang %A Illig, Thomas %A Döring, Angela %A Wichmann, H-Erich %A Zgaga, Lina %A Zemunik, Tatijana %A Boban, Mladen %A Minelli, Cosetta %A Wheeler, Heather E %A Igl, Wilmar %A Zaboli, Ghazal %A Wild, Sarah H %A Wright, Alan F %A Campbell, Harry %A Ellinghaus, David %A Nöthlings, Ute %A Jacobs, Gunnar %A Biffar, Reiner %A Ernst, Florian %A Homuth, Georg %A Kroemer, Heyo K %A Nauck, Matthias %A Stracke, Sylvia %A Völker, Uwe %A Völzke, Henry %A Kovacs, Peter %A Stumvoll, Michael %A Mägi, Reedik %A Hofman, Albert %A Uitterlinden, André G %A Rivadeneira, Fernando %A Aulchenko, Yurii S %A Polasek, Ozren %A Hastie, Nick %A Vitart, Veronique %A Helmer, Catherine %A Wang, Jie Jin %A Stengel, Bénédicte %A Ruggiero, Daniela %A Bergmann, Sven %A Kähönen, Mika %A Viikari, Jorma %A Nikopensius, Tiit %A Province, Michael %A Colhoun, Helen %A Doney, Alex %A Robino, Antonietta %A Krämer, Bernhard K %A Portas, Laura %A Ford, Ian %A Buckley, Brendan M %A Adam, Martin %A Thun, Gian-Andri %A Paulweber, Bernhard %A Haun, Margot %A Sala, Cinzia %A Mitchell, Paul %A Ciullo, Marina %A Vollenweider, Peter %A Raitakari, Olli %A Metspalu, Andres %A Palmer, Colin %A Gasparini, Paolo %A Pirastu, Mario %A Jukema, J Wouter %A Probst-Hensch, Nicole M %A Kronenberg, Florian %A Toniolo, Daniela %A Gudnason, Vilmundur %A Shuldiner, Alan R %A Coresh, Josef %A Schmidt, Reinhold %A Ferrucci, Luigi %A van Duijn, Cornelia M %A Borecki, Ingrid %A Kardia, Sharon L R %A Liu, Yongmei %A Curhan, Gary C %A Rudan, Igor %A Gyllensten, Ulf %A Wilson, James F %A Franke, Andre %A Pramstaller, Peter P %A Rettig, Rainer %A Prokopenko, Inga %A Witteman, Jacqueline %A Hayward, Caroline %A Ridker, Paul M %A Bochud, Murielle %A Heid, Iris M %A Siscovick, David S %A Fox, Caroline S %A Kao, W Linda %A Böger, Carsten A %K Databases, Genetic %K European Continental Ancestry Group %K Gene Frequency %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Kidney %K Mendelian Randomization Analysis %K Phenotype %K Polymorphism, Single Nucleotide %K Renal Insufficiency, Chronic %X

Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.

%B J Am Soc Nephrol %V 24 %P 2105-17 %8 2013 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/24029420?dopt=Abstract %R 10.1681/ASN.2012100983 %0 Journal Article %J Nat Genet %D 2013 %T Discovery and refinement of loci associated with lipid levels. %A Willer, Cristen J %A Schmidt, Ellen M %A Sengupta, Sebanti %A Peloso, Gina M %A Gustafsson, Stefan %A Kanoni, Stavroula %A Ganna, Andrea %A Chen, Jin %A Buchkovich, Martin L %A Mora, Samia %A Beckmann, Jacques S %A Bragg-Gresham, Jennifer L %A Chang, Hsing-Yi %A Demirkan, Ayse %A Den Hertog, Heleen M %A Do, Ron %A Donnelly, Louise A %A Ehret, Georg B %A Esko, Tõnu %A Feitosa, Mary F %A Ferreira, Teresa %A Fischer, Krista %A Fontanillas, Pierre %A Fraser, Ross M %A Freitag, Daniel F %A Gurdasani, Deepti %A Heikkilä, Kauko %A Hyppönen, Elina %A Isaacs, Aaron %A Jackson, Anne U %A Johansson, Asa %A Johnson, Toby %A Kaakinen, Marika %A Kettunen, Johannes %A Kleber, Marcus E %A Li, Xiaohui %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A Magnusson, Patrik K E %A Mangino, Massimo %A Mihailov, Evelin %A Montasser, May E %A Müller-Nurasyid, Martina %A Nolte, Ilja M %A O'Connell, Jeffrey R %A Palmer, Cameron D %A Perola, Markus %A Petersen, Ann-Kristin %A Sanna, Serena %A Saxena, Richa %A Service, Susan K %A Shah, Sonia %A Shungin, Dmitry %A Sidore, Carlo %A Song, Ci %A Strawbridge, Rona J %A Surakka, Ida %A Tanaka, Toshiko %A Teslovich, Tanya M %A Thorleifsson, Gudmar %A van den Herik, Evita G %A Voight, Benjamin F %A Volcik, Kelly A %A Waite, Lindsay L %A Wong, Andrew %A Wu, Ying %A Zhang, Weihua %A Absher, Devin %A Asiki, Gershim %A Barroso, Inês %A Been, Latonya F %A Bolton, Jennifer L %A Bonnycastle, Lori L %A Brambilla, Paolo %A Burnett, Mary S %A Cesana, Giancarlo %A Dimitriou, Maria %A Doney, Alex S F %A Döring, Angela %A Elliott, Paul %A Epstein, Stephen E %A Ingi Eyjolfsson, Gudmundur %A Gigante, Bruna %A Goodarzi, Mark O %A Grallert, Harald %A Gravito, Martha L %A Groves, Christopher J %A Hallmans, Göran %A Hartikainen, Anna-Liisa %A Hayward, Caroline %A Hernandez, Dena %A Hicks, Andrew A %A Holm, Hilma %A Hung, Yi-Jen %A Illig, Thomas %A Jones, Michelle R %A Kaleebu, Pontiano %A Kastelein, John J P %A Khaw, Kay-Tee %A Kim, Eric %A Klopp, Norman %A Komulainen, Pirjo %A Kumari, Meena %A Langenberg, Claudia %A Lehtimäki, Terho %A Lin, Shih-Yi %A Lindström, Jaana %A Loos, Ruth J F %A Mach, François %A McArdle, Wendy L %A Meisinger, Christa %A Mitchell, Braxton D %A Müller, Gabrielle %A Nagaraja, Ramaiah %A Narisu, Narisu %A Nieminen, Tuomo V M %A Nsubuga, Rebecca N %A Olafsson, Isleifur %A Ong, Ken K %A Palotie, Aarno %A Papamarkou, Theodore %A Pomilla, Cristina %A Pouta, Anneli %A Rader, Daniel J %A Reilly, Muredach P %A Ridker, Paul M %A Rivadeneira, Fernando %A Rudan, Igor %A Ruokonen, Aimo %A Samani, Nilesh %A Scharnagl, Hubert %A Seeley, Janet %A Silander, Kaisa %A Stančáková, Alena %A Stirrups, Kathleen %A Swift, Amy J %A Tiret, Laurence %A Uitterlinden, André G %A van Pelt, L Joost %A Vedantam, Sailaja %A Wainwright, Nicholas %A Wijmenga, Cisca %A Wild, Sarah H %A Willemsen, Gonneke %A Wilsgaard, Tom %A Wilson, James F %A Young, Elizabeth H %A Zhao, Jing Hua %A Adair, Linda S %A Arveiler, Dominique %A Assimes, Themistocles L %A Bandinelli, Stefania %A Bennett, Franklyn %A Bochud, Murielle %A Boehm, Bernhard O %A Boomsma, Dorret I %A Borecki, Ingrid B %A Bornstein, Stefan R %A Bovet, Pascal %A Burnier, Michel %A Campbell, Harry %A Chakravarti, Aravinda %A Chambers, John C %A Chen, Yii-Der Ida %A Collins, Francis S %A Cooper, Richard S %A Danesh, John %A Dedoussis, George %A de Faire, Ulf %A Feranil, Alan B %A Ferrieres, Jean %A Ferrucci, Luigi %A Freimer, Nelson B %A Gieger, Christian %A Groop, Leif C %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Hamsten, Anders %A Harris, Tamara B %A Hingorani, Aroon %A Hirschhorn, Joel N %A Hofman, Albert %A Hovingh, G Kees %A Hsiung, Chao Agnes %A Humphries, Steve E %A Hunt, Steven C %A Hveem, Kristian %A Iribarren, Carlos %A Jarvelin, Marjo-Riitta %A Jula, Antti %A Kähönen, Mika %A Kaprio, Jaakko %A Kesäniemi, Antero %A Kivimaki, Mika %A Kooner, Jaspal S %A Koudstaal, Peter J %A Krauss, Ronald M %A Kuh, Diana %A Kuusisto, Johanna %A Kyvik, Kirsten O %A Laakso, Markku %A Lakka, Timo A %A Lind, Lars %A Lindgren, Cecilia M %A Martin, Nicholas G %A März, Winfried %A McCarthy, Mark I %A McKenzie, Colin A %A Meneton, Pierre %A Metspalu, Andres %A Moilanen, Leena %A Morris, Andrew D %A Munroe, Patricia B %A Njølstad, Inger %A Pedersen, Nancy L %A Power, Chris %A Pramstaller, Peter P %A Price, Jackie F %A Psaty, Bruce M %A Quertermous, Thomas %A Rauramaa, Rainer %A Saleheen, Danish %A Salomaa, Veikko %A Sanghera, Dharambir K %A Saramies, Jouko %A Schwarz, Peter E H %A Sheu, Wayne H-H %A Shuldiner, Alan R %A Siegbahn, Agneta %A Spector, Tim D %A Stefansson, Kari %A Strachan, David P %A Tayo, Bamidele O %A Tremoli, Elena %A Tuomilehto, Jaakko %A Uusitupa, Matti %A van Duijn, Cornelia M %A Vollenweider, Peter %A Wallentin, Lars %A Wareham, Nicholas J %A Whitfield, John B %A Wolffenbuttel, Bruce H R %A Ordovas, Jose M %A Boerwinkle, Eric %A Palmer, Colin N A %A Thorsteinsdottir, Unnur %A Chasman, Daniel I %A Rotter, Jerome I %A Franks, Paul W %A Ripatti, Samuli %A Cupples, L Adrienne %A Sandhu, Manjinder S %A Rich, Stephen S %A Boehnke, Michael %A Deloukas, Panos %A Kathiresan, Sekar %A Mohlke, Karen L %A Ingelsson, Erik %A Abecasis, Goncalo R %K African Continental Ancestry Group %K Asian Continental Ancestry Group %K Cholesterol, HDL %K Cholesterol, LDL %K Coronary Artery Disease %K European Continental Ancestry Group %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Lipids %K Triglycerides %X

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

%B Nat Genet %V 45 %P 1274-1283 %8 2013 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/24097068?dopt=Abstract %R 10.1038/ng.2797 %0 Journal Article %J Nat Genet %D 2013 %T Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. %A den Hoed, Marcel %A Eijgelsheim, Mark %A Esko, Tõnu %A Brundel, Bianca J J M %A Peal, David S %A Evans, David M %A Nolte, Ilja M %A Segrè, Ayellet V %A Holm, Hilma %A Handsaker, Robert E %A Westra, Harm-Jan %A Johnson, Toby %A Isaacs, Aaron %A Yang, Jian %A Lundby, Alicia %A Zhao, Jing Hua %A Kim, Young Jin %A Go, Min Jin %A Almgren, Peter %A Bochud, Murielle %A Boucher, Gabrielle %A Cornelis, Marilyn C %A Gudbjartsson, Daniel %A Hadley, David %A van der Harst, Pim %A Hayward, Caroline %A den Heijer, Martin %A Igl, Wilmar %A Jackson, Anne U %A Kutalik, Zoltán %A Luan, Jian'an %A Kemp, John P %A Kristiansson, Kati %A Ladenvall, Claes %A Lorentzon, Mattias %A Montasser, May E %A Njajou, Omer T %A O'Reilly, Paul F %A Padmanabhan, Sandosh %A St Pourcain, Beate %A Rankinen, Tuomo %A Salo, Perttu %A Tanaka, Toshiko %A Timpson, Nicholas J %A Vitart, Veronique %A Waite, Lindsay %A Wheeler, William %A Zhang, Weihua %A Draisma, Harmen H M %A Feitosa, Mary F %A Kerr, Kathleen F %A Lind, Penelope A %A Mihailov, Evelin %A Onland-Moret, N Charlotte %A Song, Ci %A Weedon, Michael N %A Xie, Weijia %A Yengo, Loic %A Absher, Devin %A Albert, Christine M %A Alonso, Alvaro %A Arking, Dan E %A de Bakker, Paul I W %A Balkau, Beverley %A Barlassina, Cristina %A Benaglio, Paola %A Bis, Joshua C %A Bouatia-Naji, Nabila %A Brage, Søren %A Chanock, Stephen J %A Chines, Peter S %A Chung, Mina %A Darbar, Dawood %A Dina, Christian %A Dörr, Marcus %A Elliott, Paul %A Felix, Stephan B %A Fischer, Krista %A Fuchsberger, Christian %A de Geus, Eco J C %A Goyette, Philippe %A Gudnason, Vilmundur %A Harris, Tamara B %A Hartikainen, Anna-Liisa %A Havulinna, Aki S %A Heckbert, Susan R %A Hicks, Andrew A %A Hofman, Albert %A Holewijn, Suzanne %A Hoogstra-Berends, Femke %A Hottenga, Jouke-Jan %A Jensen, Majken K %A Johansson, Asa %A Junttila, Juhani %A Kääb, Stefan %A Kanon, Bart %A Ketkar, Shamika %A Khaw, Kay-Tee %A Knowles, Joshua W %A Kooner, Angrad S %A Kors, Jan A %A Kumari, Meena %A Milani, Lili %A Laiho, Päivi %A Lakatta, Edward G %A Langenberg, Claudia %A Leusink, Maarten %A Liu, Yongmei %A Luben, Robert N %A Lunetta, Kathryn L %A Lynch, Stacey N %A Markus, Marcello R P %A Marques-Vidal, Pedro %A Mateo Leach, Irene %A McArdle, Wendy L %A McCarroll, Steven A %A Medland, Sarah E %A Miller, Kathryn A %A Montgomery, Grant W %A Morrison, Alanna C %A Müller-Nurasyid, Martina %A Navarro, Pau %A Nelis, Mari %A O'Connell, Jeffrey R %A O'Donnell, Christopher J %A Ong, Ken K %A Newman, Anne B %A Peters, Annette %A Polasek, Ozren %A Pouta, Anneli %A Pramstaller, Peter P %A Psaty, Bruce M %A Rao, Dabeeru C %A Ring, Susan M %A Rossin, Elizabeth J %A Rudan, Diana %A Sanna, Serena %A Scott, Robert A %A Sehmi, Jaban S %A Sharp, Stephen %A Shin, Jordan T %A Singleton, Andrew B %A Smith, Albert V %A Soranzo, Nicole %A Spector, Tim D %A Stewart, Chip %A Stringham, Heather M %A Tarasov, Kirill V %A Uitterlinden, André G %A Vandenput, Liesbeth %A Hwang, Shih-Jen %A Whitfield, John B %A Wijmenga, Cisca %A Wild, Sarah H %A Willemsen, Gonneke %A Wilson, James F %A Witteman, Jacqueline C M %A Wong, Andrew %A Wong, Quenna %A Jamshidi, Yalda %A Zitting, Paavo %A Boer, Jolanda M A %A Boomsma, Dorret I %A Borecki, Ingrid B %A van Duijn, Cornelia M %A Ekelund, Ulf %A Forouhi, Nita G %A Froguel, Philippe %A Hingorani, Aroon %A Ingelsson, Erik %A Kivimaki, Mika %A Kronmal, Richard A %A Kuh, Diana %A Lind, Lars %A Martin, Nicholas G %A Oostra, Ben A %A Pedersen, Nancy L %A Quertermous, Thomas %A Rotter, Jerome I %A van der Schouw, Yvonne T %A Verschuren, W M Monique %A Walker, Mark %A Albanes, Demetrius %A Arnar, David O %A Assimes, Themistocles L %A Bandinelli, Stefania %A Boehnke, Michael %A de Boer, Rudolf A %A Bouchard, Claude %A Caulfield, W L Mark %A Chambers, John C %A Curhan, Gary %A Cusi, Daniele %A Eriksson, Johan %A Ferrucci, Luigi %A van Gilst, Wiek H %A Glorioso, Nicola %A de Graaf, Jacqueline %A Groop, Leif %A Gyllensten, Ulf %A Hsueh, Wen-Chi %A Hu, Frank B %A Huikuri, Heikki V %A Hunter, David J %A Iribarren, Carlos %A Isomaa, Bo %A Jarvelin, Marjo-Riitta %A Jula, Antti %A Kähönen, Mika %A Kiemeney, Lambertus A %A van der Klauw, Melanie M %A Kooner, Jaspal S %A Kraft, Peter %A Iacoviello, Licia %A Lehtimäki, Terho %A Lokki, Marja-Liisa L %A Mitchell, Braxton D %A Navis, Gerjan %A Nieminen, Markku S %A Ohlsson, Claes %A Poulter, Neil R %A Qi, Lu %A Raitakari, Olli T %A Rimm, Eric B %A Rioux, John D %A Rizzi, Federica %A Rudan, Igor %A Salomaa, Veikko %A Sever, Peter S %A Shields, Denis C %A Shuldiner, Alan R %A Sinisalo, Juha %A Stanton, Alice V %A Stolk, Ronald P %A Strachan, David P %A Tardif, Jean-Claude %A Thorsteinsdottir, Unnur %A Tuomilehto, Jaako %A van Veldhuisen, Dirk J %A Virtamo, Jarmo %A Viikari, Jorma %A Vollenweider, Peter %A Waeber, Gérard %A Widen, Elisabeth %A Cho, Yoon Shin %A Olsen, Jesper V %A Visscher, Peter M %A Willer, Cristen %A Franke, Lude %A Erdmann, Jeanette %A Thompson, John R %A Pfeufer, Arne %A Sotoodehnia, Nona %A Newton-Cheh, Christopher %A Ellinor, Patrick T %A Stricker, Bruno H Ch %A Metspalu, Andres %A Perola, Markus %A Beckmann, Jacques S %A Smith, George Davey %A Stefansson, Kari %A Wareham, Nicholas J %A Munroe, Patricia B %A Sibon, Ody C M %A Milan, David J %A Snieder, Harold %A Samani, Nilesh J %A Loos, Ruth J F %K Animals %K Arrhythmias, Cardiac %K Gene Frequency %K Genetic Loci %K Genome-Wide Association Study %K Heart Conduction System %K Heart Rate %K Humans %K Metabolic Networks and Pathways %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

%B Nat Genet %V 45 %P 621-31 %8 2013 Jun %G eng %N 6 %R 10.1038/ng.2610 %0 Journal Article %J Ann Neurol %D 2013 %T Ischemic stroke is associated with the ABO locus: the EuroCLOT study. %A Williams, Frances M K %A Carter, Angela M %A Hysi, Pirro G %A Surdulescu, Gabriela %A Hodgkiss, Dylan %A Soranzo, Nicole %A Traylor, Matthew %A Bevan, Steve %A Dichgans, Martin %A Rothwell, Peter M W %A Sudlow, Cathie %A Farrall, Martin %A Silander, Kaisa %A Kaunisto, Mari %A Wagner, Peter %A Saarela, Olli %A Kuulasmaa, Kari %A Virtamo, Jarmo %A Salomaa, Veikko %A Amouyel, Philippe %A Arveiler, Dominique %A Ferrieres, Jean %A Wiklund, Per-Gunnar %A Ikram, M Arfan %A Hofman, Albert %A Boncoraglio, Giorgio B %A Parati, Eugenio A %A Helgadottir, Anna %A Gretarsdottir, Solveig %A Thorsteinsdottir, Unnur %A Thorleifsson, Gudmar %A Stefansson, Kari %A Seshadri, Sudha %A DeStefano, Anita %A Gschwendtner, Andreas %A Psaty, Bruce %A Longstreth, Will %A Mitchell, Braxton D %A Cheng, Yu-Ching %A Clarke, Robert %A Ferrario, Marco %A Bis, Joshua C %A Levi, Christopher %A Attia, John %A Holliday, Elizabeth G %A Scott, Rodney J %A Fornage, Myriam %A Sharma, Pankaj %A Furie, Karen L %A Rosand, Jonathan %A Nalls, Mike %A Meschia, James %A Mosely, Thomas H %A Evans, Alun %A Palotie, Aarno %A Markus, Hugh S %A Grant, Peter J %A Spector, Tim D %K ABO Blood-Group System %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Blood Coagulation %K Brain Ischemia %K Cohort Studies %K Europe %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Stroke %K Young Adult %X

OBJECTIVE: End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.

METHODS: Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3).

RESULTS: Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 × 10(-8)) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 × 10(-186)), rs10665 with FVII (p = 2.4 × 10(-47)), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 × 10(-57)) and factor VIII (p = 1.2 × 10(-36)). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88-0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811).

INTERPRETATION: ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.

%B Ann Neurol %V 73 %P 16-31 %8 2013 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23381943?dopt=Abstract %R 10.1002/ana.23838 %0 Journal Article %J PLoS Genet %D 2013 %T A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. %A Porcu, Eleonora %A Medici, Marco %A Pistis, Giorgio %A Volpato, Claudia B %A Wilson, Scott G %A Cappola, Anne R %A Bos, Steffan D %A Deelen, Joris %A den Heijer, Martin %A Freathy, Rachel M %A Lahti, Jari %A Liu, Chunyu %A Lopez, Lorna M %A Nolte, Ilja M %A O'Connell, Jeffrey R %A Tanaka, Toshiko %A Trompet, Stella %A Arnold, Alice %A Bandinelli, Stefania %A Beekman, Marian %A Böhringer, Stefan %A Brown, Suzanne J %A Buckley, Brendan M %A Camaschella, Clara %A de Craen, Anton J M %A Davies, Gail %A de Visser, Marieke C H %A Ford, Ian %A Forsen, Tom %A Frayling, Timothy M %A Fugazzola, Laura %A Gögele, Martin %A Hattersley, Andrew T %A Hermus, Ad R %A Hofman, Albert %A Houwing-Duistermaat, Jeanine J %A Jensen, Richard A %A Kajantie, Eero %A Kloppenburg, Margreet %A Lim, Ee M %A Masciullo, Corrado %A Mariotti, Stefano %A Minelli, Cosetta %A Mitchell, Braxton D %A Nagaraja, Ramaiah %A Netea-Maier, Romana T %A Palotie, Aarno %A Persani, Luca %A Piras, Maria G %A Psaty, Bruce M %A Räikkönen, Katri %A Richards, J Brent %A Rivadeneira, Fernando %A Sala, Cinzia %A Sabra, Mona M %A Sattar, Naveed %A Shields, Beverley M %A Soranzo, Nicole %A Starr, John M %A Stott, David J %A Sweep, Fred C G J %A Usala, Gianluca %A van der Klauw, Melanie M %A van Heemst, Diana %A van Mullem, Alies %A Vermeulen, Sita H %A Visser, W Edward %A Walsh, John P %A Westendorp, Rudi G J %A Widen, Elisabeth %A Zhai, Guangju %A Cucca, Francesco %A Deary, Ian J %A Eriksson, Johan G %A Ferrucci, Luigi %A Fox, Caroline S %A Jukema, J Wouter %A Kiemeney, Lambertus A %A Pramstaller, Peter P %A Schlessinger, David %A Shuldiner, Alan R %A Slagboom, Eline P %A Uitterlinden, André G %A Vaidya, Bijay %A Visser, Theo J %A Wolffenbuttel, Bruce H R %A Meulenbelt, Ingrid %A Rotter, Jerome I %A Spector, Tim D %A Hicks, Andrew A %A Toniolo, Daniela %A Sanna, Serena %A Peeters, Robin P %A Naitza, Silvia %K Female %K Genome-Wide Association Study %K Humans %K Hyperthyroidism %K Hypothyroidism %K Male %K Phenotype %K Polymorphism, Genetic %K Polymorphism, Single Nucleotide %K Sex Characteristics %K Signal Transduction %K Thyroid Gland %K Thyrotropin %K Thyroxine %X

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.

%B PLoS Genet %V 9 %P e1003266 %8 2013 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23408906?dopt=Abstract %R 10.1371/journal.pgen.1003266 %0 Journal Article %J Stroke %D 2014 %T Effect of genetic variants associated with plasma homocysteine levels on stroke risk. %A Cotlarciuc, Ioana %A Malik, Rainer %A Holliday, Elizabeth G %A Ahmadi, Kourosh R %A Paré, Guillaume %A Psaty, Bruce M %A Fornage, Myriam %A Hasan, Nazeeha %A Rinne, Paul E %A Ikram, M Arfan %A Markus, Hugh S %A Rosand, Jonathan %A Mitchell, Braxton D %A Kittner, Steven J %A Meschia, James F %A van Meurs, Joyce B J %A Uitterlinden, André G %A Worrall, Bradford B %A Dichgans, Martin %A Sharma, Pankaj %K Brain Ischemia %K Cohort Studies %K Europe %K Genetic Association Studies %K Genetic Loci %K Genetic Predisposition to Disease %K Genetic Variation %K Genome %K Homocysteine %K Humans %K Polymorphism, Single Nucleotide %K Risk %K Stroke %X

BACKGROUND AND PURPOSE: Elevated total plasma homocysteine (tHcy) levels are known to be associated with increased risk of ischemic stroke (IS). Given that both tHcy and IS are heritable traits, we investigated a potential genetic relationship between homocysteine levels and stroke risk by assessing 18 polymorphisms previously associated with tHcy levels for their association with IS and its subtypes.

METHODS: Previous meta-analysis results from an international stroke collaborative network, METASTROKE, were used to assess association of the 18 tHcy-associated single-nucleotide polymorphisms (SNPs) in 12 389 IS cases and 62 004 controls. We also investigated the associations in regions located within 50 kb from the 18 tHcy-related SNPs and the association of a genetic risk score, including the 18 SNPs.

RESULTS: One SNP located in the RASIP1 gene and a cluster of 3 SNPs located at and near SLC17A3 were significantly associated with IS (P<0.0003) after correcting for multiple testing. For stroke subtypes, the sentinel SNP located upstream of MUT was significantly associated with small-vessel disease (P=0.0022), whereas 1 SNP located in MTHFR was significantly associated with large-vessel disease (P=0.00019). A genetic risk score, including the 18 SNPs, did not show significant association with IS or its subtypes.

CONCLUSIONS: This study found several potential associations with IS and its subtypes: an association of an MUT variant with small-vessel disease, an MTHFR variant with large-vessel disease, and associations of RASIP1 and SLC17A3 variants with overall IS.

%B Stroke %V 45 %P 1920-4 %8 2014 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/24846872?dopt=Abstract %R 10.1161/STROKEAHA.114.005208 %0 Journal Article %J Hum Mol Genet %D 2014 %T Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations. %A Yoneyama, Sachiko %A Guo, Yiran %A Lanktree, Matthew B %A Barnes, Michael R %A Elbers, Clara C %A Karczewski, Konrad J %A Padmanabhan, Sandosh %A Bauer, Florianne %A Baumert, Jens %A Beitelshees, Amber %A Berenson, Gerald S %A Boer, Jolanda M A %A Burke, Gregory %A Cade, Brian %A Chen, Wei %A Cooper-Dehoff, Rhonda M %A Gaunt, Tom R %A Gieger, Christian %A Gong, Yan %A Gorski, Mathias %A Heard-Costa, Nancy %A Johnson, Toby %A Lamonte, Michael J %A McDonough, Caitrin %A Monda, Keri L %A Onland-Moret, N Charlotte %A Nelson, Christopher P %A O'Connell, Jeffrey R %A Ordovas, Jose %A Peter, Inga %A Peters, Annette %A Shaffer, Jonathan %A Shen, Haiqinq %A Smith, Erin %A Speilotes, Liz %A Thomas, Fridtjof %A Thorand, Barbara %A Monique Verschuren, W M %A Anand, Sonia S %A Dominiczak, Anna %A Davidson, Karina W %A Hegele, Robert A %A Heid, Iris %A Hofker, Marten H %A Huggins, Gordon S %A Illig, Thomas %A Johnson, Julie A %A Kirkland, Susan %A König, Wolfgang %A Langaee, Taimour Y %A McCaffery, Jeanne %A Melander, Olle %A Mitchell, Braxton D %A Munroe, Patricia %A Murray, Sarah S %A Papanicolaou, George %A Redline, Susan %A Reilly, Muredach %A Samani, Nilesh J %A Schork, Nicholas J %A van der Schouw, Yvonne T %A Shimbo, Daichi %A Shuldiner, Alan R %A Tobin, Martin D %A Wijmenga, Cisca %A Yusuf, Salim %A Hakonarson, Hakon %A Lange, Leslie A %A Demerath, Ellen W %A Fox, Caroline S %A North, Kari E %A Reiner, Alex P %A Keating, Brendan %A Taylor, Kira C %K Adiposity %K Adult %K Aged %K Aged, 80 and over %K Body Mass Index %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Waist Circumference %K Waist-Hip Ratio %K Young Adult %X

Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20-80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10(-6)). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (β ± SE, 0.048 ± 0.008, P = 7.7 × 10(-9)) as was rs7302703-G in HOXC10 (β = 0.044 ± 0.008, P = 2.9 × 10(-7)) and rs936108-C in PEMT (β = 0.035 ± 0.007, P = 1.9 × 10(-6)). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (β = 0.10 ± 0.02, P = 1.9 × 10(-6)) and rs1037575-A in ATBDB4 (β = 0.046 ± 0.01, P = 2.2 × 10(-6)), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.

%B Hum Mol Genet %V 23 %P 2498-510 %8 2014 May 01 %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/24345515?dopt=Abstract %R 10.1093/hmg/ddt626 %0 Journal Article %J Neurology %D 2014 %T Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12. %A Kilarski, Laura L %A Achterberg, Sefanja %A Devan, William J %A Traylor, Matthew %A Malik, Rainer %A Lindgren, Arne %A Pare, Guillame %A Sharma, Pankaj %A Slowik, Agniesczka %A Thijs, Vincent %A Walters, Matthew %A Worrall, Bradford B %A Sale, Michèle M %A Algra, Ale %A Kappelle, L Jaap %A Wijmenga, Cisca %A Norrving, Bo %A Sandling, Johanna K %A Rönnblom, Lars %A Goris, An %A Franke, Andre %A Sudlow, Cathie %A Rothwell, Peter M %A Levi, Christopher %A Holliday, Elizabeth G %A Fornage, Myriam %A Psaty, Bruce %A Gretarsdottir, Solveig %A Thorsteinsdottir, Unnar %A Seshadri, Sudha %A Mitchell, Braxton D %A Kittner, Steven %A Clarke, Robert %A Hopewell, Jemma C %A Bis, Joshua C %A Boncoraglio, Giorgio B %A Meschia, James %A Ikram, M Arfan %A Hansen, Bjorn M %A Montaner, Joan %A Thorleifsson, Gudmar %A Stefanson, Kari %A Rosand, Jonathan %A de Bakker, Paul I W %A Farrall, Martin %A Dichgans, Martin %A Markus, Hugh S %A Bevan, Steve %K Brain Ischemia %K Cerebral Hemorrhage %K Chromosomes, Human, Pair 12 %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Polymorphism, Single Nucleotide %K Risk %K Stroke %X

OBJECTIVES: To perform a genome-wide association study (GWAS) using the Immunochip array in 3,420 cases of ischemic stroke and 6,821 controls, followed by a meta-analysis with data from more than 14,000 additional ischemic stroke cases.

METHODS: Using the Immunochip, we genotyped 3,420 ischemic stroke cases and 6,821 controls. After imputation we meta-analyzed the results with imputed GWAS data from 3,548 cases and 5,972 controls recruited from the ischemic stroke WTCCC2 study, and with summary statistics from a further 8,480 cases and 56,032 controls in the METASTROKE consortium. A final in silico "look-up" of 2 single nucleotide polymorphisms in 2,522 cases and 1,899 controls was performed. Associations were also examined in 1,088 cases with intracerebral hemorrhage and 1,102 controls.

RESULTS: In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07-1.13], p = 7.12 × 10(-11)) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90-1.17], p = 0.695).

CONCLUSION: Our results show, for the first time, a genetic risk locus associated with ischemic stroke as a whole, rather than in a subtype-specific manner. This finding was not associated with intracerebral hemorrhage.

%B Neurology %V 83 %P 678-85 %8 2014 Aug 19 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/25031287?dopt=Abstract %R 10.1212/WNL.0000000000000707 %0 Journal Article %J Stroke %D 2014 %T Multilocus genetic risk score associates with ischemic stroke in case-control and prospective cohort studies. %A Malik, Rainer %A Bevan, Steve %A Nalls, Michael A %A Holliday, Elizabeth G %A Devan, William J %A Cheng, Yu-Ching %A Ibrahim-Verbaas, Carla A %A Verhaaren, Benjamin F J %A Bis, Joshua C %A Joon, Aron Y %A de Stefano, Anita L %A Fornage, Myriam %A Psaty, Bruce M %A Ikram, M Arfan %A Launer, Lenore J %A van Duijn, Cornelia M %A Sharma, Pankaj %A Mitchell, Braxton D %A Rosand, Jonathan %A Meschia, James F %A Levi, Christopher %A Rothwell, Peter M %A Sudlow, Cathie %A Markus, Hugh S %A Seshadri, Sudha %A Dichgans, Martin %K Adult %K Aged %K Aged, 80 and over %K Atrial Fibrillation %K Blood Pressure %K Brain Ischemia %K Case-Control Studies %K Cohort Studies %K Coronary Artery Disease %K Female %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Hypertension %K Male %K Middle Aged %K Multilocus Sequence Typing %K Polymorphism, Single Nucleotide %K Population %K Prospective Studies %K Reproducibility of Results %K Risk Assessment %K Risk Factors %K Sex Factors %K Stroke %X

BACKGROUND AND PURPOSE: Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts.

METHODS: Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS.

RESULTS: A combined GRS for atrial fibrillation, coronary artery disease, hypertension, and systolic blood pressure significantly associated with IS both in the case-control samples and in the prospective population-based studies. Subjects in the top quintile of the combined GRS had >2-fold increased risk of IS compared with subjects in the lowest quintile. Addition of the combined GRS to a simple model based on sex significantly improved the prediction of IS in the combined clinic-based samples but not in the population-based studies, and there was no significant improvement in net reclassification.

CONCLUSIONS: A multilocus GRS based on common variants for established cardiovascular risk factors was significantly associated with IS both in clinic-based samples and in the general population. However, the improvement in clinical risk prediction was found to be small.

%B Stroke %V 45 %P 394-402 %8 2014 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24436234?dopt=Abstract %R 10.1161/STROKEAHA.113.002938 %0 Journal Article %J Stroke %D 2014 %T Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants. %A Dichgans, Martin %A Malik, Rainer %A König, Inke R %A Rosand, Jonathan %A Clarke, Robert %A Gretarsdottir, Solveig %A Thorleifsson, Gudmar %A Mitchell, Braxton D %A Assimes, Themistocles L %A Levi, Christopher %A O'Donnell, Christopher J %A Fornage, Myriam %A Thorsteinsdottir, Unnur %A Psaty, Bruce M %A Hengstenberg, Christian %A Seshadri, Sudha %A Erdmann, Jeanette %A Bis, Joshua C %A Peters, Annette %A Boncoraglio, Giorgio B %A März, Winfried %A Meschia, James F %A Kathiresan, Sekar %A Ikram, M Arfan %A McPherson, Ruth %A Stefansson, Kari %A Sudlow, Cathie %A Reilly, Muredach P %A Thompson, John R %A Sharma, Pankaj %A Hopewell, Jemma C %A Chambers, John C %A Watkins, Hugh %A Rothwell, Peter M %A Roberts, Robert %A Markus, Hugh S %A Samani, Nilesh J %A Farrall, Martin %A Schunkert, Heribert %K Brain Ischemia %K Coronary Artery Disease %K Data Interpretation, Statistical %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Phenotype %K Polymorphism, Single Nucleotide %K Reproducibility of Results %K Risk Factors %K Stroke %X

BACKGROUND AND PURPOSE: Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases.

METHODS: Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype.

RESULTS: Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5×10(-8)) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (PIS=1.62×10(-7)) and ABO (PIS=2.6×10(-4)), as well as at HDAC9 (PLAS=2.32×10(-12)), 9p21 (PLAS=3.70×10(-6)), RAI1-PEMT-RASD1 (PLAS=2.69×10(-5)), EDNRA (PLAS=7.29×10(-4)), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9×10(-4)).

CONCLUSIONS: Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.

%B Stroke %V 45 %P 24-36 %8 2014 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24262325?dopt=Abstract %R 10.1161/STROKEAHA.113.002707 %0 Journal Article %J Neurology %D 2015 %T Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease. %A Rannikmae, Kristiina %A Davies, Gail %A Thomson, Pippa A %A Bevan, Steve %A Devan, William J %A Falcone, Guido J %A Traylor, Matthew %A Anderson, Christopher D %A Battey, Thomas W K %A Radmanesh, Farid %A Deka, Ranjan %A Woo, Jessica G %A Martin, Lisa J %A Jimenez-Conde, Jordi %A Selim, Magdy %A Brown, Devin L %A Silliman, Scott L %A Kidwell, Chelsea S %A Montaner, Joan %A Langefeld, Carl D %A Slowik, Agnieszka %A Hansen, Bjorn M %A Lindgren, Arne G %A Meschia, James F %A Fornage, Myriam %A Bis, Joshua C %A Debette, Stephanie %A Ikram, Mohammad A %A Longstreth, Will T %A Schmidt, Reinhold %A Zhang, Cathy R %A Yang, Qiong %A Sharma, Pankaj %A Kittner, Steven J %A Mitchell, Braxton D %A Holliday, Elizabeth G %A Levi, Christopher R %A Attia, John %A Rothwell, Peter M %A Poole, Deborah L %A Boncoraglio, Giorgio B %A Psaty, Bruce M %A Malik, Rainer %A Rost, Natalia %A Worrall, Bradford B %A Dichgans, Martin %A Van Agtmael, Tom %A Woo, Daniel %A Markus, Hugh S %A Seshadri, Sudha %A Rosand, Jonathan %A Sudlow, Cathie L M %K Cerebral Small Vessel Diseases %K Collagen Type IV %K Genetic Association Studies %K Genetic Variation %K Humans %K Polymorphism, Single Nucleotide %X

OBJECTIVES: We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease.

METHODS: We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084).

RESULTS: Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r(2) > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes.

CONCLUSIONS: Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry.

%B Neurology %V 84 %P 918-26 %8 2015 Mar 3 %G ENG %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/25653287?dopt=Abstract %R 10.1212/WNL.0000000000001309 %0 Journal Article %J Stroke %D 2015 %T Genetic overlap between diagnostic subtypes of ischemic stroke. %A Holliday, Elizabeth G %A Traylor, Matthew %A Malik, Rainer %A Bevan, Steve %A Falcone, Guido %A Hopewell, Jemma C %A Cheng, Yu-Ching %A Cotlarciuc, Ioana %A Bis, Joshua C %A Boerwinkle, Eric %A Boncoraglio, Giorgio B %A Clarke, Robert %A Cole, John W %A Fornage, Myriam %A Furie, Karen L %A Ikram, M Arfan %A Jannes, Jim %A Kittner, Steven J %A Lincz, Lisa F %A Maguire, Jane M %A Meschia, James F %A Mosley, Thomas H %A Nalls, Mike A %A Oldmeadow, Christopher %A Parati, Eugenio A %A Psaty, Bruce M %A Rothwell, Peter M %A Seshadri, Sudha %A Scott, Rodney J %A Sharma, Pankaj %A Sudlow, Cathie %A Wiggins, Kerri L %A Worrall, Bradford B %A Rosand, Jonathan %A Mitchell, Braxton D %A Dichgans, Martin %A Markus, Hugh S %A Levi, Christopher %A Attia, John %A Wray, Naomi R %K Alleles %K Atherosclerosis %K Cerebral Small Vessel Diseases %K Cohort Studies %K Data Interpretation, Statistical %K Embolism %K Genome-Wide Association Study %K Genotype %K Humans %K Ischemia %K Linear Models %K Meta-Analysis as Topic %K Phenotype %K Polymorphism, Single Nucleotide %K Stroke %X

BACKGROUND AND PURPOSE: Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample sizes. We assessed evidence for a shared genetic basis among the 3 major subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses.

METHODS: Analyses used genome-wide summary data for 12 389 ischemic stroke cases (including 2167 LAA, 2405 cardioembolism, and 1854 SVD) and 62 004 controls from the Metastroke consortium. For 4561 cases and 7094 controls, individual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models and polygenic profile scores. Meta-analysis of a combined LAA-SVD phenotype (4021 cases and 51 976 controls) was performed to identify shared risk alleles.

RESULTS: High genetic correlation was identified between LAA and SVD using linear mixed models (rg=0.96, SE=0.47, P=9×10(-4)) and profile scores (rg=0.72; 95% confidence interval, 0.52-0.93). Between LAA and cardioembolism and SVD and cardioembolism, correlation was moderate using linear mixed models but not significantly different from zero for profile scoring. Joint meta-analysis of LAA and SVD identified strong association (P=1×10(-7)) for single nucleotide polymorphisms near the opioid receptor μ1 (OPRM1) gene.

CONCLUSIONS: Our results suggest that LAA and SVD, which have been hitherto treated as genetically distinct, may share a substantial genetic component. Combined analyses of LAA and SVD may increase power to identify small-effect alleles influencing shared pathophysiological processes.

%B Stroke %V 46 %P 615-9 %8 2015 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/25613305?dopt=Abstract %R 10.1161/STROKEAHA.114.007930 %0 Journal Article %J Stroke %D 2015 %T Meta-Analysis of Genome-Wide Association Studies Identifies Genetic Risk Factors for Stroke in African Americans. %A Carty, Cara L %A Keene, Keith L %A Cheng, Yu-Ching %A Meschia, James F %A Chen, Wei-Min %A Nalls, Mike %A Bis, Joshua C %A Kittner, Steven J %A Rich, Stephen S %A Tajuddin, Salman %A Zonderman, Alan B %A Evans, Michele K %A Langefeld, Carl D %A Gottesman, Rebecca %A Mosley, Thomas H %A Shahar, Eyal %A Woo, Daniel %A Yaffe, Kristine %A Liu, Yongmei %A Sale, Michèle M %A Dichgans, Martin %A Malik, Rainer %A Longstreth, W T %A Mitchell, Braxton D %A Psaty, Bruce M %A Kooperberg, Charles %A Reiner, Alexander %A Worrall, Bradford B %A Fornage, Myriam %K African Americans %K Case-Control Studies %K Cohort Studies %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Polymorphism, Single Nucleotide %K Risk Factors %K Stroke %X

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

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

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

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

%B Stroke %V 46 %P 2063-8 %8 2015 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/26089329?dopt=Abstract %R 10.1161/STROKEAHA.115.009044 %0 Journal Article %J Neurology %D 2015 %T Shared genetic basis for migraine and ischemic stroke: A genome-wide analysis of common variants. %A Malik, Rainer %A Freilinger, Tobias %A Winsvold, Bendik S %A Anttila, Verneri %A Vander Heiden, Jason %A Traylor, Matthew %A de Vries, Boukje %A Holliday, Elizabeth G %A Terwindt, Gisela M %A Sturm, Jonathan %A Bis, Joshua C %A Hopewell, Jemma C %A Ferrari, Michel D %A Rannikmae, Kristiina %A Wessman, Maija %A Kallela, Mikko %A Kubisch, Christian %A Fornage, Myriam %A Meschia, James F %A Lehtimäki, Terho %A Sudlow, Cathie %A Clarke, Robert %A Chasman, Daniel I %A Mitchell, Braxton D %A Maguire, Jane %A Kaprio, Jaakko %A Farrall, Martin %A Raitakari, Olli T %A Kurth, Tobias %A Ikram, M Arfan %A Reiner, Alex P %A Longstreth, W T %A Rothwell, Peter M %A Strachan, David P %A Sharma, Pankaj %A Seshadri, Sudha %A Quaye, Lydia %A Cherkas, Lynn %A Schürks, Markus %A Rosand, Jonathan %A Ligthart, Lannie %A Boncoraglio, Giorgio B %A Davey Smith, George %A van Duijn, Cornelia M %A Stefansson, Kari %A Worrall, Bradford B %A Nyholt, Dale R %A Markus, Hugh S %A van den Maagdenberg, Arn M J M %A Cotsapas, Chris %A Zwart, John A %A Palotie, Aarno %A Dichgans, Martin %K Brain Ischemia %K Genome-Wide Association Study %K Humans %K Migraine with Aura %K Migraine without Aura %K Stroke %X

OBJECTIVE: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation.

METHODS: We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping.

RESULTS: We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p = 6.4 × 10(-28) for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p = 2.7 × 10(-20) for the CE score in MO).

CONCLUSIONS: Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype.

%B Neurology %V 84 %P 2132-45 %8 2015 May 26 %G eng %N 21 %1 http://www.ncbi.nlm.nih.gov/pubmed/25934857?dopt=Abstract %R 10.1212/WNL.0000000000001606 %0 Journal Article %J J Am Soc Nephrol %D 2016 %T Genetic Variants Associated with Circulating Parathyroid Hormone. %A Robinson-Cohen, Cassianne %A Lutsey, Pamela L %A Kleber, Marcus E %A Nielson, Carrie M %A Mitchell, Braxton D %A Bis, Joshua C %A Eny, Karen M %A Portas, Laura %A Eriksson, Joel %A Lorentzon, Mattias %A Koller, Daniel L %A Milaneschi, Yuri %A Teumer, Alexander %A Pilz, Stefan %A Nethander, Maria %A Selvin, Elizabeth %A Tang, Weihong %A Weng, Lu-Chen %A Wong, Hoi Suen %A Lai, Dongbing %A Peacock, Munro %A Hannemann, Anke %A Völker, Uwe %A Homuth, Georg %A Nauk, Matthias %A Murgia, Federico %A Pattee, Jack W %A Orwoll, Eric %A Zmuda, Joseph M %A Riancho, Jose Antonio %A Wolf, Myles %A Williams, Frances %A Penninx, Brenda %A Econs, Michael J %A Ryan, Kathleen A %A Ohlsson, Claes %A Paterson, Andrew D %A Psaty, Bruce M %A Siscovick, David S %A Rotter, Jerome I %A Pirastu, Mario %A Streeten, Elizabeth %A März, Winfried %A Fox, Caroline %A Coresh, Josef %A Wallaschofski, Henri %A Pankow, James S %A de Boer, Ian H %A Kestenbaum, Bryan %X

Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry. We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2 × 10(-53)), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within RGS14 (P=6.6 × 10(-17)), rs219779 adjacent to CLDN14 (P=3.5 × 10(-16)), rs4443100 near RTDR1 (P=8.7 × 10(-9)), and rs73186030 near CASR (P=4.8 × 10(-8)). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.

%B J Am Soc Nephrol %8 2016 Dec 07 %G eng %R 10.1681/ASN.2016010069 %0 Journal Article %J Stroke %D 2016 %T Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2. %A Cheng, Yu-Ching %A Stanne, Tara M %A Giese, Anne-Katrin %A Ho, Weang Kee %A Traylor, Matthew %A Amouyel, Philippe %A Holliday, Elizabeth G %A Malik, Rainer %A Xu, Huichun %A Kittner, Steven J %A Cole, John W %A O'Connell, Jeffrey R %A Danesh, John %A Rasheed, Asif %A Zhao, Wei %A Engelter, Stefan %A Grond-Ginsbach, Caspar %A Kamatani, Yoichiro %A Lathrop, Mark %A Leys, Didier %A Thijs, Vincent %A Metso, Tiina M %A Tatlisumak, Turgut %A Pezzini, Alessandro %A Parati, Eugenio A %A Norrving, Bo %A Bevan, Steve %A Rothwell, Peter M %A Sudlow, Cathie %A Slowik, Agnieszka %A Lindgren, Arne %A Walters, Matthew R %A Jannes, Jim %A Shen, Jess %A Crosslin, David %A Doheny, Kimberly %A Laurie, Cathy C %A Kanse, Sandip M %A Bis, Joshua C %A Fornage, Myriam %A Mosley, Thomas H %A Hopewell, Jemma C %A Strauch, Konstantin %A Müller-Nurasyid, Martina %A Gieger, Christian %A Waldenberger, Melanie %A Peters, Annette %A Meisinger, Christine %A Ikram, M Arfan %A Longstreth, W T %A Meschia, James F %A Seshadri, Sudha %A Sharma, Pankaj %A Worrall, Bradford %A Jern, Christina %A Levi, Christopher %A Dichgans, Martin %A Boncoraglio, Giorgio B %A Markus, Hugh S %A Debette, Stephanie %A Rolfs, Arndt %A Saleheen, Danish %A Mitchell, Braxton D %K Adult %K African Continental Ancestry Group %K Age of Onset %K Aged %K Asian Continental Ancestry Group %K Brain Ischemia %K Chromosomes, Human, Pair 10 %K Computer Simulation %K DNA, Intergenic %K European Continental Ancestry Group %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Odds Ratio %K Polymorphism, Single Nucleotide %K Serine Endopeptidases %K Stroke %X

BACKGROUND AND PURPOSE: Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset <60 years.

METHODS: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10(-6) and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls.

RESULTS: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2.

CONCLUSIONS: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.

%B Stroke %V 47 %P 307-16 %8 2016 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26732560?dopt=Abstract %R 10.1161/STROKEAHA.115.011328 %0 Journal Article %J Circ Cardiovasc Genet %D 2016 %T Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis. %A Natarajan, Pradeep %A Bis, Joshua C %A Bielak, Lawrence F %A Cox, Amanda J %A Dörr, Marcus %A Feitosa, Mary F %A Franceschini, Nora %A Guo, Xiuqing %A Hwang, Shih-Jen %A Isaacs, Aaron %A Jhun, Min A %A Kavousi, Maryam %A Li-Gao, Ruifang %A Lyytikäinen, Leo-Pekka %A Marioni, Riccardo E %A Schminke, Ulf %A Stitziel, Nathan O %A Tada, Hayato %A van Setten, Jessica %A Smith, Albert V %A Vojinovic, Dina %A Yanek, Lisa R %A Yao, Jie %A Yerges-Armstrong, Laura M %A Amin, Najaf %A Baber, Usman %A Borecki, Ingrid B %A Carr, J Jeffrey %A Chen, Yii-Der Ida %A Cupples, L Adrienne %A de Jong, Pim A %A de Koning, Harry %A de Vos, Bob D %A Demirkan, Ayse %A Fuster, Valentin %A Franco, Oscar H %A Goodarzi, Mark O %A Harris, Tamara B %A Heckbert, Susan R %A Heiss, Gerardo %A Hoffmann, Udo %A Hofman, Albert %A Išgum, Ivana %A Jukema, J Wouter %A Kähönen, Mika %A Kardia, Sharon L R %A Kral, Brian G %A Launer, Lenore J %A Massaro, Joseph %A Mehran, Roxana %A Mitchell, Braxton D %A Mosley, Thomas H %A de Mutsert, Renée %A Newman, Anne B %A Nguyen, Khanh-Dung %A North, Kari E %A O'Connell, Jeffrey R %A Oudkerk, Matthijs %A Pankow, James S %A Peloso, Gina M %A Post, Wendy %A Province, Michael A %A Raffield, Laura M %A Raitakari, Olli T %A Reilly, Dermot F %A Rivadeneira, Fernando %A Rosendaal, Frits %A Sartori, Samantha %A Taylor, Kent D %A Teumer, Alexander %A Trompet, Stella %A Turner, Stephen T %A Uitterlinden, André G %A Vaidya, Dhananjay %A van der Lugt, Aad %A Völker, Uwe %A Wardlaw, Joanna M %A Wassel, Christina L %A Weiss, Stefan %A Wojczynski, Mary K %A Becker, Diane M %A Becker, Lewis C %A Boerwinkle, Eric %A Bowden, Donald W %A Deary, Ian J %A Dehghan, Abbas %A Felix, Stephan B %A Gudnason, Vilmundur %A Lehtimäki, Terho %A Mathias, Rasika %A Mook-Kanamori, Dennis O %A Psaty, Bruce M %A Rader, Daniel J %A Rotter, Jerome I %A Wilson, James G %A van Duijn, Cornelia M %A Völzke, Henry %A Kathiresan, Sekar %A Peyser, Patricia A %A O'Donnell, Christopher J %X

BACKGROUND: -The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease (CHD). We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent CHD.

METHODS AND RESULTS: -We studied a total of 25,109 European ancestry and African-American participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52,869 with common carotid intima media thickness (CIMT) measured by ultrasonography within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Participants were genotyped for 247,870 DNA sequence variants (231,539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and CIMT. APOB p.Arg3527Gln was associated with four-fold excess CAC (P = 3×10(-10)). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P = 1×10(-12)) and 1.4% reduced CIMT (P = 4×10(-14)) in carriers compared with non-carriers. In secondary analyses conditioning on LDL cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for CHD (OR 0.77; P = 1×10(-11)).

CONCLUSIONS: -Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities as well as clinical CHD.

%B Circ Cardiovasc Genet %8 2016 Nov 21 %G eng %R 10.1161/CIRCGENETICS.116.001572 %0 Journal Article %J Nat Genet %D 2017 %T Analysis commons, a team approach to discovery in a big-data environment for genetic epidemiology. %A Brody, Jennifer A %A Morrison, Alanna C %A Bis, Joshua C %A O'Connell, Jeffrey R %A Brown, Michael R %A Huffman, Jennifer E %A Ames, Darren C %A Carroll, Andrew %A Conomos, Matthew P %A Gabriel, Stacey %A Gibbs, Richard A %A Gogarten, Stephanie M %A Gupta, Namrata %A Jaquish, Cashell E %A Johnson, Andrew D %A Lewis, Joshua P %A Liu, Xiaoming %A Manning, Alisa K %A Papanicolaou, George J %A Pitsillides, Achilleas N %A Rice, Kenneth M %A Salerno, William %A Sitlani, Colleen M %A Smith, Nicholas L %A Heckbert, Susan R %A Laurie, Cathy C %A Mitchell, Braxton D %A Vasan, Ramachandran S %A Rich, Stephen S %A Rotter, Jerome I %A Wilson, James G %A Boerwinkle, Eric %A Psaty, Bruce M %A Cupples, L Adrienne %B Nat Genet %V 49 %P 1560-1563 %8 2017 Oct 27 %G eng %N 11 %R 10.1038/ng.3968 %0 Journal Article %J Nat Commun %D 2017 %T Large meta-analysis of genome-wide association studies identifies five loci for lean body mass. %A Zillikens, M Carola %A Demissie, Serkalem %A Hsu, Yi-Hsiang %A Yerges-Armstrong, Laura M %A Chou, Wen-Chi %A Stolk, Lisette %A Livshits, Gregory %A Broer, Linda %A Johnson, Toby %A Koller, Daniel L %A Kutalik, Zoltán %A Luan, Jian'an %A Malkin, Ida %A Ried, Janina S %A Smith, Albert V %A Thorleifsson, Gudmar %A Vandenput, Liesbeth %A Hua Zhao, Jing %A Zhang, Weihua %A Aghdassi, Ali %A Åkesson, Kristina %A Amin, Najaf %A Baier, Leslie J %A Barroso, Inês %A Bennett, David A %A Bertram, Lars %A Biffar, Rainer %A Bochud, Murielle %A Boehnke, Michael %A Borecki, Ingrid B %A Buchman, Aron S %A Byberg, Liisa %A Campbell, Harry %A Campos Obanda, Natalia %A Cauley, Jane A %A Cawthon, Peggy M %A Cederberg, Henna %A Chen, Zhao %A Cho, Nam H %A Jin Choi, Hyung %A Claussnitzer, Melina %A Collins, Francis %A Cummings, Steven R %A De Jager, Philip L %A Demuth, Ilja %A Dhonukshe-Rutten, Rosalie A M %A Diatchenko, Luda %A Eiriksdottir, Gudny %A Enneman, Anke W %A Erdos, Mike %A Eriksson, Johan G %A Eriksson, Joel %A Estrada, Karol %A Evans, Daniel S %A Feitosa, Mary F %A Fu, Mao %A Garcia, Melissa %A Gieger, Christian %A Girke, Thomas %A Glazer, Nicole L %A Grallert, Harald %A Grewal, Jagvir %A Han, Bok-Ghee %A Hanson, Robert L %A Hayward, Caroline %A Hofman, Albert %A Hoffman, Eric P %A Homuth, Georg %A Hsueh, Wen-Chi %A Hubal, Monica J %A Hubbard, Alan %A Huffman, Kim M %A Husted, Lise B %A Illig, Thomas %A Ingelsson, Erik %A Ittermann, Till %A Jansson, John-Olov %A Jordan, Joanne M %A Jula, Antti %A Karlsson, Magnus %A Khaw, Kay-Tee %A Kilpeläinen, Tuomas O %A Klopp, Norman %A Kloth, Jacqueline S L %A Koistinen, Heikki A %A Kraus, William E %A Kritchevsky, Stephen %A Kuulasmaa, Teemu %A Kuusisto, Johanna %A Laakso, Markku %A Lahti, Jari %A Lang, Thomas %A Langdahl, Bente L %A Launer, Lenore J %A Lee, Jong-Young %A Lerch, Markus M %A Lewis, Joshua R %A Lind, Lars %A Lindgren, Cecilia %A Liu, Yongmei %A Liu, Tian %A Liu, Youfang %A Ljunggren, Osten %A Lorentzon, Mattias %A Luben, Robert N %A Maixner, William %A McGuigan, Fiona E %A Medina-Gómez, Carolina %A Meitinger, Thomas %A Melhus, Håkan %A Mellström, Dan %A Melov, Simon %A Michaëlsson, Karl %A Mitchell, Braxton D %A Morris, Andrew P %A Mosekilde, Leif %A Newman, Anne %A Nielson, Carrie M %A O'Connell, Jeffrey R %A Oostra, Ben A %A Orwoll, Eric S %A Palotie, Aarno %A Parker, Stephen C J %A Peacock, Munro %A Perola, Markus %A Peters, Annette %A Polasek, Ozren %A Prince, Richard L %A Räikkönen, Katri %A Ralston, Stuart H %A Ripatti, Samuli %A Robbins, John A %A Rotter, Jerome I %A Rudan, Igor %A Salomaa, Veikko %A Satterfield, Suzanne %A Schadt, Eric E %A Schipf, Sabine %A Scott, Laura %A Sehmi, Joban %A Shen, Jian %A Soo Shin, Chan %A Sigurdsson, Gunnar %A Smith, Shad %A Soranzo, Nicole %A Stančáková, Alena %A Steinhagen-Thiessen, Elisabeth %A Streeten, Elizabeth A %A Styrkarsdottir, Unnur %A Swart, Karin M A %A Tan, Sian-Tsung %A Tarnopolsky, Mark A %A Thompson, Patricia %A Thomson, Cynthia A %A Thorsteinsdottir, Unnur %A Tikkanen, Emmi %A Tranah, Gregory J %A Tuomilehto, Jaakko %A van Schoor, Natasja M %A Verma, Arjun %A Vollenweider, Peter %A Völzke, Henry %A Wactawski-Wende, Jean %A Walker, Mark %A Weedon, Michael N %A Welch, Ryan %A Wichmann, H-Erich %A Widen, Elisabeth %A Williams, Frances M K %A Wilson, James F %A Wright, Nicole C %A Xie, Weijia %A Yu, Lei %A Zhou, Yanhua %A Chambers, John C %A Döring, Angela %A van Duijn, Cornelia M %A Econs, Michael J %A Gudnason, Vilmundur %A Kooner, Jaspal S %A Psaty, Bruce M %A Spector, Timothy D %A Stefansson, Kari %A Rivadeneira, Fernando %A Uitterlinden, André G %A Wareham, Nicholas J %A Ossowski, Vicky %A Waterworth, Dawn %A Loos, Ruth J F %A Karasik, David %A Harris, Tamara B %A Ohlsson, Claes %A Kiel, Douglas P %X

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10-8) or suggestively genome wide (p < 2.3 × 10-6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.

%B Nat Commun %V 8 %P 80 %8 2017 Jul 19 %G eng %N 1 %R 10.1038/s41467-017-00031-7 %0 Journal Article %J Nat Commun %D 2017 %T Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness. %A Willems, Sara M %A Wright, Daniel J %A Day, Felix R %A Trajanoska, Katerina %A Joshi, Peter K %A Morris, John A %A Matteini, Amy M %A Garton, Fleur C %A Grarup, Niels %A Oskolkov, Nikolay %A Thalamuthu, Anbupalam %A Mangino, Massimo %A Liu, Jun %A Demirkan, Ayse %A Lek, Monkol %A Xu, Liwen %A Wang, Guan %A Oldmeadow, Christopher %A Gaulton, Kyle J %A Lotta, Luca A %A Miyamoto-Mikami, Eri %A Rivas, Manuel A %A White, Tom %A Loh, Po-Ru %A Aadahl, Mette %A Amin, Najaf %A Attia, John R %A Austin, Krista %A Benyamin, Beben %A Brage, Søren %A Cheng, Yu-Ching %A Cięszczyk, Paweł %A Derave, Wim %A Eriksson, Karl-Fredrik %A Eynon, Nir %A Linneberg, Allan %A Lucia, Alejandro %A Massidda, Myosotis %A Mitchell, Braxton D %A Miyachi, Motohiko %A Murakami, Haruka %A Padmanabhan, Sandosh %A Pandey, Ashutosh %A Papadimitriou, Ioannis %A Rajpal, Deepak K %A Sale, Craig %A Schnurr, Theresia M %A Sessa, Francesco %A Shrine, Nick %A Tobin, Martin D %A Varley, Ian %A Wain, Louise V %A Wray, Naomi R %A Lindgren, Cecilia M %A MacArthur, Daniel G %A Waterworth, Dawn M %A McCarthy, Mark I %A Pedersen, Oluf %A Khaw, Kay-Tee %A Kiel, Douglas P %A Pitsiladis, Yannis %A Fuku, Noriyuki %A Franks, Paul W %A North, Kathryn N %A van Duijn, Cornelia M %A Mather, Karen A %A Hansen, Torben %A Hansson, Ola %A Spector, Tim %A Murabito, Joanne M %A Richards, J Brent %A Rivadeneira, Fernando %A Langenberg, Claudia %A Perry, John R B %A Wareham, Nick J %A Scott, Robert A %X

Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.

%B Nat Commun %V 8 %P 16015 %8 2017 Jul 12 %G eng %R 10.1038/ncomms16015 %0 Journal Article %J J Clin Lipidol %D 2017 %T Novel polymorphisms associated with hyperalphalipoproteinemia and apparent cardioprotection. %A Oates, Connor P %A Koenig, Darya %A Rhyne, Jeffrey %A Bogush, Nikolay %A O'Connell, Jeffrey %A Mitchell, Braxton D %A Miller, Michael %X

BACKGROUND: Hyperalphalipoproteinemia (HALP) is inversely correlated with coronary heart disease (CHD) although genetic variants associated with high serum levels of high-density lipoprotein cholesterol (HDL-C) have not been shown to be cardioprotective.

OBJECTIVE: The objective of the study was to uncover novel genetic variants associated with HALP and possibly with reduced risk of CHD.

METHODS: Exome sequencing data, HDL-C, and triglyceride levels were analyzed in 1645 subjects. They included the University of Maryland outpatients with high HDL-C (n = 12), Cardiovascular Health Study (n = 210), Jackson Heart Study (n = 402), Multi-Ethnic Study of Atherosclerosis (n = 404), Framingham Heart Study (n = 463), and Old Order Amish (n = 154).

RESULTS: Novel nonsynonymous single-nucleotide polymorphisms (nsSNPs) were identified in men and women with primary HALP (mean HDL-C, 145 ± 30 mg/dL). Using PolyPhen-2 and Combined Annotation Dependent Depletion to estimate the predictive effect of each nsSNP on the gene product, rare, deleterious polymorphisms in UGT1A3, PLLP, PLEKHH1, ANK2, DIS3L, ACACB, and LRP4 were identified in 16 subjects with HALP but not in any tested subject with low HDL-C (<40 mg/dL). In addition, a single novel polymorphism, rs376849274, was found in OSBPL1A. The majority of these candidate genes have been implicated in fat and lipid metabolism, and none of these subjects has a history of CHD despite 75% of subjects having risk factors for CHD. Overall, the probability of finding these nsSNPs in a non-high HDL-C population ranges from 1 × 10-17 to 1 × 10-25.

CONCLUSION: Novel functional polymorphisms in 8 candidate genes are associated with HALP in the absence of CHD. Future study is required to examine the extent to which these genes may affect HDL function and serve as potential therapeutic targets for CHD risk reduction.

%B J Clin Lipidol %8 2017 Nov 21 %G eng %R 10.1016/j.jacl.2017.10.021 %0 Journal Article %J PLoS Genet %D 2018 %T Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain. %A Suri, Pradeep %A Palmer, Melody R %A Tsepilov, Yakov A %A Freidin, Maxim B %A Boer, Cindy G %A Yau, Michelle S %A Evans, Daniel S %A Gelemanovic, Andrea %A Bartz, Traci M %A Nethander, Maria %A Arbeeva, Liubov %A Karssen, Lennart %A Neogi, Tuhina %A Campbell, Archie %A Mellström, Dan %A Ohlsson, Claes %A Marshall, Lynn M %A Orwoll, Eric %A Uitterlinden, Andre %A Rotter, Jerome I %A Lauc, Gordan %A Psaty, Bruce M %A Karlsson, Magnus K %A Lane, Nancy E %A Jarvik, Gail P %A Polasek, Ozren %A Hochberg, Marc %A Jordan, Joanne M %A van Meurs, Joyce B J %A Jackson, Rebecca %A Nielson, Carrie M %A Mitchell, Braxton D %A Smith, Blair H %A Hayward, Caroline %A Smith, Nicholas L %A Aulchenko, Yurii S %A Williams, Frances M K %X

Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3-6 months; non-cases were included as comparisons ("controls"). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10-8. Suggestive (p<5×10-7) and genome-wide significant (p<5×10-8) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2×10-10). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p = 5.3×10-11), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p = 4.5×10-19). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4×10-13), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4×10-10). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).

%B PLoS Genet %V 14 %P e1007601 %8 2018 Sep %G eng %N 9 %R 10.1371/journal.pgen.1007601 %0 Journal Article %J Nat Genet %D 2018 %T Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. %A Malik, Rainer %A Chauhan, Ganesh %A Traylor, Matthew %A Sargurupremraj, Muralidharan %A Okada, Yukinori %A Mishra, Aniket %A Rutten-Jacobs, Loes %A Giese, Anne-Katrin %A van der Laan, Sander W %A Gretarsdottir, Solveig %A Anderson, Christopher D %A Chong, Michael %A Adams, Hieab H H %A Ago, Tetsuro %A Almgren, Peter %A Amouyel, Philippe %A Ay, Hakan %A Bartz, Traci M %A Benavente, Oscar R %A Bevan, Steve %A Boncoraglio, Giorgio B %A Brown, Robert D %A Butterworth, Adam S %A Carrera, Caty %A Carty, Cara L %A Chasman, Daniel I %A Chen, Wei-Min %A Cole, John W %A Correa, Adolfo %A Cotlarciuc, Ioana %A Cruchaga, Carlos %A Danesh, John %A de Bakker, Paul I W %A DeStefano, Anita L %A den Hoed, Marcel %A Duan, Qing %A Engelter, Stefan T %A Falcone, Guido J %A Gottesman, Rebecca F %A Grewal, Raji P %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Haessler, Jeffrey %A Harris, Tamara B %A Hassan, Ahamad %A Havulinna, Aki S %A Heckbert, Susan R %A Holliday, Elizabeth G %A Howard, George %A Hsu, Fang-Chi %A Hyacinth, Hyacinth I %A Ikram, M Arfan %A Ingelsson, Erik %A Irvin, Marguerite R %A Jian, Xueqiu %A Jimenez-Conde, Jordi %A Johnson, Julie A %A Jukema, J Wouter %A Kanai, Masahiro %A Keene, Keith L %A Kissela, Brett M %A Kleindorfer, Dawn O %A Kooperberg, Charles %A Kubo, Michiaki %A Lange, Leslie A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lee, Jin-Moo %A Lemmens, Robin %A Leys, Didier %A Lewis, Cathryn M %A Lin, Wei-Yu %A Lindgren, Arne G %A Lorentzen, Erik %A Magnusson, Patrik K %A Maguire, Jane %A Manichaikul, Ani %A McArdle, Patrick F %A Meschia, James F %A Mitchell, Braxton D %A Mosley, Thomas H %A Nalls, Michael A %A Ninomiya, Toshiharu %A O'Donnell, Martin J %A Psaty, Bruce M %A Pulit, Sara L %A Rannikmae, Kristiina %A Reiner, Alexander P %A Rexrode, Kathryn M %A Rice, Kenneth %A Rich, Stephen S %A Ridker, Paul M %A Rost, Natalia S %A Rothwell, Peter M %A Rotter, Jerome I %A Rundek, Tatjana %A Sacco, Ralph L %A Sakaue, Saori %A Sale, Michèle M %A Salomaa, Veikko %A Sapkota, Bishwa R %A Schmidt, Reinhold %A Schmidt, Carsten O %A Schminke, Ulf %A Sharma, Pankaj %A Slowik, Agnieszka %A Sudlow, Cathie L M %A Tanislav, Christian %A Tatlisumak, Turgut %A Taylor, Kent D %A Thijs, Vincent N S %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tiedt, Steffen %A Trompet, Stella %A Tzourio, Christophe %A van Duijn, Cornelia M %A Walters, Matthew %A Wareham, Nicholas J %A Wassertheil-Smoller, Sylvia %A Wilson, James G %A Wiggins, Kerri L %A Yang, Qiong %A Yusuf, Salim %A Bis, Joshua C %A Pastinen, Tomi %A Ruusalepp, Arno %A Schadt, Eric E %A Koplev, Simon %A Björkegren, Johan L M %A Codoni, Veronica %A Civelek, Mete %A Smith, Nicholas L %A Trégouët, David A %A Christophersen, Ingrid E %A Roselli, Carolina %A Lubitz, Steven A %A Ellinor, Patrick T %A Tai, E Shyong %A Kooner, Jaspal S %A Kato, Norihiro %A He, Jiang %A van der Harst, Pim %A Elliott, Paul %A Chambers, John C %A Takeuchi, Fumihiko %A Johnson, Andrew D %A Sanghera, Dharambir K %A Melander, Olle %A Jern, Christina %A Strbian, Daniel %A Fernandez-Cadenas, Israel %A Longstreth, W T %A Rolfs, Arndt %A Hata, Jun %A Woo, Daniel %A Rosand, Jonathan %A Paré, Guillaume %A Hopewell, Jemma C %A Saleheen, Danish %A Stefansson, Kari %A Worrall, Bradford B %A Kittner, Steven J %A Seshadri, Sudha %A Fornage, Myriam %A Markus, Hugh S %A Howson, Joanna M M %A Kamatani, Yoichiro %A Debette, Stephanie %A Dichgans, Martin %A Malik, Rainer %A Chauhan, Ganesh %A Traylor, Matthew %A Sargurupremraj, Muralidharan %A Okada, Yukinori %A Mishra, Aniket %A Rutten-Jacobs, Loes %A Giese, Anne-Katrin %A van der Laan, Sander W %A Gretarsdottir, Solveig %A Anderson, Christopher D %A Chong, Michael %A Adams, Hieab H H %A Ago, Tetsuro %A Almgren, Peter %A Amouyel, Philippe %A Ay, Hakan %A Bartz, Traci M %A Benavente, Oscar R %A Bevan, Steve %A Boncoraglio, Giorgio B %A Brown, Robert D %A Butterworth, Adam S %A Carrera, Caty %A Carty, Cara L %A Chasman, Daniel I %A Chen, Wei-Min %A Cole, John W %A Correa, Adolfo %A Cotlarciuc, Ioana %A Cruchaga, Carlos %A Danesh, John %A de Bakker, Paul I W %A DeStefano, Anita L %A Hoed, Marcel den %A Duan, Qing %A Engelter, Stefan T %A Falcone, Guido J %A Gottesman, Rebecca F %A Grewal, Raji P %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Haessler, Jeffrey %A Harris, Tamara B %A Hassan, Ahamad %A Havulinna, Aki S %A Heckbert, Susan R %A Holliday, Elizabeth G %A Howard, George %A Hsu, Fang-Chi %A Hyacinth, Hyacinth I %A Ikram, M Arfan %A Ingelsson, Erik %A Irvin, Marguerite R %A Jian, Xueqiu %A Jimenez-Conde, Jordi %A Johnson, Julie A %A Jukema, J Wouter %A Kanai, Masahiro %A Keene, Keith L %A Kissela, Brett M %A Kleindorfer, Dawn O %A Kooperberg, Charles %A Kubo, Michiaki %A Lange, Leslie A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lee, Jin-Moo %A Lemmens, Robin %A Leys, Didier %A Lewis, Cathryn M %A Lin, Wei-Yu %A Lindgren, Arne G %A Lorentzen, Erik %A Magnusson, Patrik K %A Maguire, Jane %A Manichaikul, Ani %A McArdle, Patrick F %A Meschia, James F %A Mitchell, Braxton D %A Mosley, Thomas H %A Nalls, Michael A %A Ninomiya, Toshiharu %A O'Donnell, Martin J %A Psaty, Bruce M %A Pulit, Sara L %A Rannikmae, Kristiina %A Reiner, Alexander P %A Rexrode, Kathryn M %A Rice, Kenneth %A Rich, Stephen S %A Ridker, Paul M %A Rost, Natalia S %A Rothwell, Peter M %A Rotter, Jerome I %A Rundek, Tatjana %A Sacco, Ralph L %A Sakaue, Saori %A Sale, Michèle M %A Salomaa, Veikko %A Sapkota, Bishwa R %A Schmidt, Reinhold %A Schmidt, Carsten O %A Schminke, Ulf %A Sharma, Pankaj %A Slowik, Agnieszka %A Sudlow, Cathie L M %A Tanislav, Christian %A Tatlisumak, Turgut %A Taylor, Kent D %A Thijs, Vincent N S %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tiedt, Steffen %A Trompet, Stella %A Tzourio, Christophe %A van Duijn, Cornelia M %A Walters, Matthew %A Wareham, Nicholas J %A Wassertheil-Smoller, Sylvia %A Wilson, James G %A Wiggins, Kerri L %A Yang, Qiong %A Yusuf, Salim %A Amin, Najaf %A Aparicio, Hugo S %A Arnett, Donna K %A Attia, John %A Beiser, Alexa S %A Berr, Claudine %A Buring, Julie E %A Bustamante, Mariana %A Caso, Valeria %A Cheng, Yu-Ching %A Choi, Seung Hoan %A Chowhan, Ayesha %A Cullell, Natalia %A Dartigues, Jean-François %A Delavaran, Hossein %A Delgado, Pilar %A Dörr, Marcus %A Engström, Gunnar %A Ford, Ian %A Gurpreet, Wander S %A Hamsten, Anders %A Heitsch, Laura %A Hozawa, Atsushi %A Ibanez, Laura %A Ilinca, Andreea %A Ingelsson, Martin %A Iwasaki, Motoki %A Jackson, Rebecca D %A Jood, Katarina %A Jousilahti, Pekka %A Kaffashian, Sara %A Kalra, Lalit %A Kamouchi, Masahiro %A Kitazono, Takanari %A Kjartansson, Olafur %A Kloss, Manja %A Koudstaal, Peter J %A Krupinski, Jerzy %A Labovitz, Daniel L %A Laurie, Cathy C %A Levi, Christopher R %A Li, Linxin %A Lind, Lars %A Lindgren, Cecilia M %A Lioutas, Vasileios %A Liu, Yong Mei %A Lopez, Oscar L %A Makoto, Hirata %A Martinez-Majander, Nicolas %A Matsuda, Koichi %A Minegishi, Naoko %A Montaner, Joan %A Morris, Andrew P %A Muiño, Elena %A Müller-Nurasyid, Martina %A Norrving, Bo %A Ogishima, Soichi %A Parati, Eugenio A %A Peddareddygari, Leema Reddy %A Pedersen, Nancy L %A Pera, Joanna %A Perola, Markus %A Pezzini, Alessandro %A Pileggi, Silvana %A Rabionet, Raquel %A Riba-Llena, Iolanda %A Ribasés, Marta %A Romero, Jose R %A Roquer, Jaume %A Rudd, Anthony G %A Sarin, Antti-Pekka %A Sarju, Ralhan %A Sarnowski, Chloe %A Sasaki, Makoto %A Satizabal, Claudia L %A Satoh, Mamoru %A Sattar, Naveed %A Sawada, Norie %A Sibolt, Gerli %A Sigurdsson, Ásgeir %A Smith, Albert %A Sobue, Kenji %A Soriano-Tárraga, Carolina %A Stanne, Tara %A Stine, O Colin %A Stott, David J %A Strauch, Konstantin %A Takai, Takako %A Tanaka, Hideo %A Tanno, Kozo %A Teumer, Alexander %A Tomppo, Liisa %A Torres-Aguila, Nuria P %A Touze, Emmanuel %A Tsugane, Shoichiro %A Uitterlinden, André G %A Valdimarsson, Einar M %A van der Lee, Sven J %A Völzke, Henry %A Wakai, Kenji %A Weir, David %A Williams, Stephen R %A Wolfe, Charles D A %A Wong, Quenna %A Xu, Huichun %A Yamaji, Taiki %A Sanghera, Dharambir K %A Melander, Olle %A Jern, Christina %A Strbian, Daniel %A Fernandez-Cadenas, Israel %A Longstreth, W T %A Rolfs, Arndt %A Hata, Jun %A Woo, Daniel %A Rosand, Jonathan %A Paré, Guillaume %A Hopewell, Jemma C %A Saleheen, Danish %A Stefansson, Kari %A Worrall, Bradford B %A Kittner, Steven J %A Seshadri, Sudha %A Fornage, Myriam %A Markus, Hugh S %A Howson, Joanna M M %A Kamatani, Yoichiro %A Debette, Stephanie %A Dichgans, Martin %X

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

%B Nat Genet %V 50 %P 524-537 %8 2018 Apr %G eng %N 4 %R 10.1038/s41588-018-0058-3 %0 Journal Article %J Nat Commun %D 2018 %T PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity. %A van Setten, Jessica %A Brody, Jennifer A %A Jamshidi, Yalda %A Swenson, Brenton R %A Butler, Anne M %A Campbell, Harry %A Del Greco, Fabiola M %A Evans, Daniel S %A Gibson, Quince %A Gudbjartsson, Daniel F %A Kerr, Kathleen F %A Krijthe, Bouwe P %A Lyytikäinen, Leo-Pekka %A Müller, Christian %A Müller-Nurasyid, Martina %A Nolte, Ilja M %A Padmanabhan, Sandosh %A Ritchie, Marylyn D %A Robino, Antonietta %A Smith, Albert V %A Steri, Maristella %A Tanaka, Toshiko %A Teumer, Alexander %A Trompet, Stella %A Ulivi, Sheila %A Verweij, Niek %A Yin, Xiaoyan %A Arnar, David O %A Asselbergs, Folkert W %A Bader, Joel S %A Barnard, John %A Bis, Josh %A Blankenberg, Stefan %A Boerwinkle, Eric %A Bradford, Yuki %A Buckley, Brendan M %A Chung, Mina K %A Crawford, Dana %A den Hoed, Marcel %A Denny, Josh C %A Dominiczak, Anna F %A Ehret, Georg B %A Eijgelsheim, Mark %A Ellinor, Patrick T %A Felix, Stephan B %A Franco, Oscar H %A Franke, Lude %A Harris, Tamara B %A Holm, Hilma %A Ilaria, Gandin %A Iorio, Annamaria %A Kähönen, Mika %A Kolcic, Ivana %A Kors, Jan A %A Lakatta, Edward G %A Launer, Lenore J %A Lin, Honghuang %A Lin, Henry J %A Loos, Ruth J F %A Lubitz, Steven A %A Macfarlane, Peter W %A Magnani, Jared W %A Leach, Irene Mateo %A Meitinger, Thomas %A Mitchell, Braxton D %A Münzel, Thomas %A Papanicolaou, George J %A Peters, Annette %A Pfeufer, Arne %A Pramstaller, Peter P %A Raitakari, Olli T %A Rotter, Jerome I %A Rudan, Igor %A Samani, Nilesh J %A Schlessinger, David %A Silva Aldana, Claudia T %A Sinner, Moritz F %A Smith, Jonathan D %A Snieder, Harold %A Soliman, Elsayed Z %A Spector, Timothy D %A Stott, David J %A Strauch, Konstantin %A Tarasov, Kirill V %A Thorsteinsdottir, Unnur %A Uitterlinden, André G %A Van Wagoner, David R %A Völker, Uwe %A Völzke, Henry %A Waldenberger, Melanie %A Jan Westra, Harm %A Wild, Philipp S %A Zeller, Tanja %A Alonso, Alvaro %A Avery, Christy L %A Bandinelli, Stefania %A Benjamin, Emelia J %A Cucca, Francesco %A Dörr, Marcus %A Ferrucci, Luigi %A Gasparini, Paolo %A Gudnason, Vilmundur %A Hayward, Caroline %A Heckbert, Susan R %A Hicks, Andrew A %A Jukema, J Wouter %A Kääb, Stefan %A Lehtimäki, Terho %A Liu, Yongmei %A Munroe, Patricia B %A Parsa, Afshin %A Polasek, Ozren %A Psaty, Bruce M %A Roden, Dan M %A Schnabel, Renate B %A Sinagra, Gianfranco %A Stefansson, Kari %A Stricker, Bruno H %A van der Harst, Pim %A van Duijn, Cornelia M %A Wilson, James F %A Gharib, Sina A %A de Bakker, Paul I W %A Isaacs, Aaron %A Arking, Dan E %A Sotoodehnia, Nona %X

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

%B Nat Commun %V 9 %P 2904 %8 2018 Jul 25 %G eng %N 1 %R 10.1038/s41467-018-04766-9 %0 Journal Article %J Am J Clin Nutr %D 2019 %T Disentangling the genetics of lean mass. %A Karasik, David %A Zillikens, M Carola %A Hsu, Yi-Hsiang %A Aghdassi, Ali %A Åkesson, Kristina %A Amin, Najaf %A Barroso, Inês %A Bennett, David A %A Bertram, Lars %A Bochud, Murielle %A Borecki, Ingrid B %A Broer, Linda %A Buchman, Aron S %A Byberg, Liisa %A Campbell, Harry %A Campos-Obando, Natalia %A Cauley, Jane A %A Cawthon, Peggy M %A Chambers, John C %A Chen, Zhao %A Cho, Nam H %A Choi, Hyung Jin %A Chou, Wen-Chi %A Cummings, Steven R %A de Groot, Lisette C P G M %A De Jager, Phillip L %A Demuth, Ilja %A Diatchenko, Luda %A Econs, Michael J %A Eiriksdottir, Gudny %A Enneman, Anke W %A Eriksson, Joel %A Eriksson, Johan G %A Estrada, Karol %A Evans, Daniel S %A Feitosa, Mary F %A Fu, Mao %A Gieger, Christian %A Grallert, Harald %A Gudnason, Vilmundur %A Lenore, Launer J %A Hayward, Caroline %A Hofman, Albert %A Homuth, Georg %A Huffman, Kim M %A Husted, Lise B %A Illig, Thomas %A Ingelsson, Erik %A Ittermann, Till %A Jansson, John-Olov %A Johnson, Toby %A Biffar, Reiner %A Jordan, Joanne M %A Jula, Antti %A Karlsson, Magnus %A Khaw, Kay-Tee %A Kilpeläinen, Tuomas O %A Klopp, Norman %A Kloth, Jacqueline S L %A Koller, Daniel L %A Kooner, Jaspal S %A Kraus, William E %A Kritchevsky, Stephen %A Kutalik, Zoltán %A Kuulasmaa, Teemu %A Kuusisto, Johanna %A Laakso, Markku %A Lahti, Jari %A Lang, Thomas %A Langdahl, Bente L %A Lerch, Markus M %A Lewis, Joshua R %A Lill, Christina %A Lind, Lars %A Lindgren, Cecilia %A Liu, Yongmei %A Livshits, Gregory %A Ljunggren, Osten %A Loos, Ruth J F %A Lorentzon, Mattias %A Luan, Jian'an %A Luben, Robert N %A Malkin, Ida %A McGuigan, Fiona E %A Medina-Gómez, Carolina %A Meitinger, Thomas %A Melhus, Håkan %A Mellström, Dan %A Michaëlsson, Karl %A Mitchell, Braxton D %A Morris, Andrew P %A Mosekilde, Leif %A Nethander, Maria %A Newman, Anne B %A O'Connell, Jeffery R %A Oostra, Ben A %A Orwoll, Eric S %A Palotie, Aarno %A Peacock, Munro %A Perola, Markus %A Peters, Annette %A Prince, Richard L %A Psaty, Bruce M %A Räikkönen, Katri %A Ralston, Stuart H %A Ripatti, Samuli %A Rivadeneira, Fernando %A Robbins, John A %A Rotter, Jerome I %A Rudan, Igor %A Salomaa, Veikko %A Satterfield, Suzanne %A Schipf, Sabine %A Shin, Chan Soo %A Smith, Albert V %A Smith, Shad B %A Soranzo, Nicole %A Spector, Timothy D %A Stančáková, Alena %A Stefansson, Kari %A Steinhagen-Thiessen, Elisabeth %A Stolk, Lisette %A Streeten, Elizabeth A %A Styrkarsdottir, Unnur %A Swart, Karin M A %A Thompson, Patricia %A Thomson, Cynthia A %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tikkanen, Emmi %A Tranah, Gregory J %A Uitterlinden, André G %A van Duijn, Cornelia M %A van Schoor, Natasja M %A Vandenput, Liesbeth %A Vollenweider, Peter %A Völzke, Henry %A Wactawski-Wende, Jean %A Walker, Mark %A J Wareham, Nicholas %A Waterworth, Dawn %A Weedon, Michael N %A Wichmann, H-Erich %A Widen, Elisabeth %A Williams, Frances M K %A Wilson, James F %A Wright, Nicole C %A Yerges-Armstrong, Laura M %A Yu, Lei %A Zhang, Weihua %A Zhao, Jing Hua %A Zhou, Yanhua %A Nielson, Carrie M %A Harris, Tamara B %A Demissie, Serkalem %A Kiel, Douglas P %A Ohlsson, Claes %X

Background: Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass.

Objectives: To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci.

Methods: We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms).

Results: Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection.

Conclusions: In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass.

%B Am J Clin Nutr %V 109 %P 276-287 %8 2019 Feb 01 %G eng %N 2 %R 10.1093/ajcn/nqy272 %0 Journal Article %J Am J Hum Genet %D 2019 %T Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program. %A Sarnowski, Chloe %A Leong, Aaron %A Raffield, Laura M %A Wu, Peitao %A de Vries, Paul S %A DiCorpo, Daniel %A Guo, Xiuqing %A Xu, Huichun %A Liu, Yongmei %A Zheng, Xiuwen %A Hu, Yao %A Brody, Jennifer A %A Goodarzi, Mark O %A Hidalgo, Bertha A %A Highland, Heather M %A Jain, Deepti %A Liu, Ching-Ti %A Naik, Rakhi P %A O'Connell, Jeffrey R %A Perry, James A %A Porneala, Bianca C %A Selvin, Elizabeth %A Wessel, Jennifer %A Psaty, Bruce M %A Curran, Joanne E %A Peralta, Juan M %A Blangero, John %A Kooperberg, Charles %A Mathias, Rasika %A Johnson, Andrew D %A Reiner, Alexander P %A Mitchell, Braxton D %A Cupples, L Adrienne %A Vasan, Ramachandran S %A Correa, Adolfo %A Morrison, Alanna C %A Boerwinkle, Eric %A Rotter, Jerome I %A Rich, Stephen S %A Manning, Alisa K %A Dupuis, Josée %A Meigs, James B %X

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

%B Am J Hum Genet %V 105 %P 706-718 %8 2019 Oct 03 %G eng %N 4 %R 10.1016/j.ajhg.2019.08.010 %0 Journal Article %J Nature %D 2020 %T Inherited causes of clonal haematopoiesis in 97,691 whole genomes. %A Bick, Alexander G %A Weinstock, Joshua S %A Nandakumar, Satish K %A Fulco, Charles P %A Bao, Erik L %A Zekavat, Seyedeh M %A Szeto, Mindy D %A Liao, Xiaotian %A Leventhal, Matthew J %A Nasser, Joseph %A Chang, Kyle %A Laurie, Cecelia %A Burugula, Bala Bharathi %A Gibson, Christopher J %A Lin, Amy E %A Taub, Margaret A %A Aguet, Francois %A Ardlie, Kristin %A Mitchell, Braxton D %A Barnes, Kathleen C %A Moscati, Arden %A Fornage, Myriam %A Redline, Susan %A Psaty, Bruce M %A Silverman, Edwin K %A Weiss, Scott T %A Palmer, Nicholette D %A Vasan, Ramachandran S %A Burchard, Esteban G %A Kardia, Sharon L R %A He, Jiang %A Kaplan, Robert C %A Smith, Nicholas L %A Arnett, Donna K %A Schwartz, David A %A Correa, Adolfo %A de Andrade, Mariza %A Guo, Xiuqing %A Konkle, Barbara A %A Custer, Brian %A Peralta, Juan M %A Gui, Hongsheng %A Meyers, Deborah A %A McGarvey, Stephen T %A Chen, Ida Yii-Der %A Shoemaker, M Benjamin %A Peyser, Patricia A %A Broome, Jai G %A Gogarten, Stephanie M %A Wang, Fei Fei %A Wong, Quenna %A Montasser, May E %A Daya, Michelle %A Kenny, Eimear E %A North, Kari E %A Launer, Lenore J %A Cade, Brian E %A Bis, Joshua C %A Cho, Michael H %A Lasky-Su, Jessica %A Bowden, Donald W %A Cupples, L Adrienne %A Mak, Angel C Y %A Becker, Lewis C %A Smith, Jennifer A %A Kelly, Tanika N %A Aslibekyan, Stella %A Heckbert, Susan R %A Tiwari, Hemant K %A Yang, Ivana V %A Heit, John A %A Lubitz, Steven A %A Johnsen, Jill M %A Curran, Joanne E %A Wenzel, Sally E %A Weeks, Daniel E %A Rao, Dabeeru C %A Darbar, Dawood %A Moon, Jee-Young %A Tracy, Russell P %A Buth, Erin J %A Rafaels, Nicholas %A Loos, Ruth J F %A Durda, Peter %A Liu, Yongmei %A Hou, Lifang %A Lee, Jiwon %A Kachroo, Priyadarshini %A Freedman, Barry I %A Levy, Daniel %A Bielak, Lawrence F %A Hixson, James E %A Floyd, James S %A Whitsel, Eric A %A Ellinor, Patrick T %A Irvin, Marguerite R %A Fingerlin, Tasha E %A Raffield, Laura M %A Armasu, Sebastian M %A Wheeler, Marsha M %A Sabino, Ester C %A Blangero, John %A Williams, L Keoki %A Levy, Bruce D %A Sheu, Wayne Huey-Herng %A Roden, Dan M %A Boerwinkle, Eric %A Manson, JoAnn E %A Mathias, Rasika A %A Desai, Pinkal %A Taylor, Kent D %A Johnson, Andrew D %A Auer, Paul L %A Kooperberg, Charles %A Laurie, Cathy C %A Blackwell, Thomas W %A Smith, Albert V %A Zhao, Hongyu %A Lange, Ethan %A Lange, Leslie %A Rich, Stephen S %A Rotter, Jerome I %A Wilson, James G %A Scheet, Paul %A Kitzman, Jacob O %A Lander, Eric S %A Engreitz, Jesse M %A Ebert, Benjamin L %A Reiner, Alexander P %A Jaiswal, Siddhartha %A Abecasis, Goncalo %A Sankaran, Vijay G %A Kathiresan, Sekar %A Natarajan, Pradeep %X

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

%B Nature %V 586 %P 763-768 %8 2020 10 %G eng %N 7831 %R 10.1038/s41586-020-2819-2 %0 Journal Article %J Nat Commun %D 2021 %T Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices. %A Natarajan, Pradeep %A Pampana, Akhil %A Graham, Sarah E %A Ruotsalainen, Sanni E %A Perry, James A %A de Vries, Paul S %A Broome, Jai G %A Pirruccello, James P %A Honigberg, Michael C %A Aragam, Krishna %A Wolford, Brooke %A Brody, Jennifer A %A Antonacci-Fulton, Lucinda %A Arden, Moscati %A Aslibekyan, Stella %A Assimes, Themistocles L %A Ballantyne, Christie M %A Bielak, Lawrence F %A Bis, Joshua C %A Cade, Brian E %A Do, Ron %A Doddapaneni, Harsha %A Emery, Leslie S %A Hung, Yi-Jen %A Irvin, Marguerite R %A Khan, Alyna T %A Lange, Leslie %A Lee, Jiwon %A Lemaitre, Rozenn N %A Martin, Lisa W %A Metcalf, Ginger %A Montasser, May E %A Moon, Jee-Young %A Muzny, Donna %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Peralta, Juan M %A Peyser, Patricia A %A Stilp, Adrienne M %A Tsai, Michael %A Wang, Fei Fei %A Weeks, Daniel E %A Yanek, Lisa R %A Wilson, James G %A Abecasis, Goncalo %A Arnett, Donna K %A Becker, Lewis C %A Blangero, John %A Boerwinkle, Eric %A Bowden, Donald W %A Chang, Yi-Cheng %A Chen, Yii-der I %A Choi, Won Jung %A Correa, Adolfo %A Curran, Joanne E %A Daly, Mark J %A Dutcher, Susan K %A Ellinor, Patrick T %A Fornage, Myriam %A Freedman, Barry I %A Gabriel, Stacey %A Germer, Soren %A Gibbs, Richard A %A He, Jiang %A Hveem, Kristian %A Jarvik, Gail P %A Kaplan, Robert C %A Kardia, Sharon L R %A Kenny, Eimear %A Kim, Ryan W %A Kooperberg, Charles %A Laurie, Cathy C %A Lee, Seonwook %A Lloyd-Jones, Don M %A Loos, Ruth J F %A Lubitz, Steven A %A Mathias, Rasika A %A Martinez, Karine A Viaud %A McGarvey, Stephen T %A Mitchell, Braxton D %A Nickerson, Deborah A %A North, Kari E %A Palotie, Aarno %A Park, Cheol Joo %A Psaty, Bruce M %A Rao, D C %A Redline, Susan %A Reiner, Alexander P %A Seo, Daekwan %A Seo, Jeong-Sun %A Smith, Albert V %A Tracy, Russell P %A Vasan, Ramachandran S %A Kathiresan, Sekar %A Cupples, L Adrienne %A Rotter, Jerome I %A Morrison, Alanna C %A Rich, Stephen S %A Ripatti, Samuli %A Willer, Cristen %A Peloso, Gina M %X

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

%B Nat Commun %V 12 %P 2182 %8 2021 04 12 %G eng %N 1 %R 10.1038/s41467-021-22339-1 %0 Journal Article %J PLoS One %D 2021 %T Identification of novel and rare variants associated with handgrip strength using whole genome sequence data from the NHLBI Trans-Omics in Precision Medicine (TOPMed) Program. %A Sarnowski, Chloe %A Chen, Han %A Biggs, Mary L %A Wassertheil-Smoller, Sylvia %A Bressler, Jan %A Irvin, Marguerite R %A Ryan, Kathleen A %A Karasik, David %A Arnett, Donna K %A Cupples, L Adrienne %A Fardo, David W %A Gogarten, Stephanie M %A Heavner, Benjamin D %A Jain, Deepti %A Kang, Hyun Min %A Kooperberg, Charles %A Mainous, Arch G %A Mitchell, Braxton D %A Morrison, Alanna C %A O'Connell, Jeffrey R %A Psaty, Bruce M %A Rice, Kenneth %A Smith, Albert V %A Vasan, Ramachandran S %A Windham, B Gwen %A Kiel, Douglas P %A Murabito, Joanne M %A Lunetta, Kathryn L %X

Handgrip strength is a widely used measure of muscle strength and a predictor of a range of morbidities including cardiovascular diseases and all-cause mortality. Previous genome-wide association studies of handgrip strength have focused on common variants primarily in persons of European descent. We aimed to identify rare and ancestry-specific genetic variants associated with handgrip strength by conducting whole-genome sequence association analyses using 13,552 participants from six studies representing diverse population groups from the Trans-Omics in Precision Medicine (TOPMed) Program. By leveraging multiple handgrip strength measures performed in study participants over time, we increased our effective sample size by 7-12%. Single-variant analyses identified ten handgrip strength loci among African-Americans: four rare variants, five low-frequency variants, and one common variant. One significant and four suggestive genes were identified associated with handgrip strength when aggregating rare and functional variants; all associations were ancestry-specific. We additionally leveraged the different ancestries available in the UK Biobank to further explore the ancestry-specific association signals from the single-variant association analyses. In conclusion, our study identified 11 new loci associated with handgrip strength with rare and/or ancestry-specific genetic variations, highlighting the added value of whole-genome sequencing in diverse samples. Several of the associations identified using single-variant or aggregate analyses lie in genes with a function relevant to the brain or muscle or were reported to be associated with muscle or age-related traits. Further studies in samples with sequence data and diverse ancestries are needed to confirm these findings.

%B PLoS One %V 16 %P e0253611 %8 2021 %G eng %N 7 %R 10.1371/journal.pone.0253611 %0 Journal Article %J Nature %D 2021 %T Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. %A Taliun, Daniel %A Harris, Daniel N %A Kessler, Michael D %A Carlson, Jedidiah %A Szpiech, Zachary A %A Torres, Raul %A Taliun, Sarah A Gagliano %A Corvelo, André %A Gogarten, Stephanie M %A Kang, Hyun Min %A Pitsillides, Achilleas N %A LeFaive, Jonathon %A Lee, Seung-Been %A Tian, Xiaowen %A Browning, Brian L %A Das, Sayantan %A Emde, Anne-Katrin %A Clarke, Wayne E %A Loesch, Douglas P %A Shetty, Amol C %A Blackwell, Thomas W %A Smith, Albert V %A Wong, Quenna %A Liu, Xiaoming %A Conomos, Matthew P %A Bobo, Dean M %A Aguet, Francois %A Albert, Christine %A Alonso, Alvaro %A Ardlie, Kristin G %A Arking, Dan E %A Aslibekyan, Stella %A Auer, Paul L %A Barnard, John %A Barr, R Graham %A Barwick, Lucas %A Becker, Lewis C %A Beer, Rebecca L %A Benjamin, Emelia J %A Bielak, Lawrence F %A Blangero, John %A Boehnke, Michael %A Bowden, Donald W %A Brody, Jennifer A %A Burchard, Esteban G %A Cade, Brian E %A Casella, James F %A Chalazan, Brandon %A Chasman, Daniel I %A Chen, Yii-Der Ida %A Cho, Michael H %A Choi, Seung Hoan %A Chung, Mina K %A Clish, Clary B %A Correa, Adolfo %A Curran, Joanne E %A Custer, Brian %A Darbar, Dawood %A Daya, Michelle %A de Andrade, Mariza %A DeMeo, Dawn L %A Dutcher, Susan K %A Ellinor, Patrick T %A Emery, Leslie S %A Eng, Celeste %A Fatkin, Diane %A Fingerlin, Tasha %A Forer, Lukas %A Fornage, Myriam %A Franceschini, Nora %A Fuchsberger, Christian %A Fullerton, Stephanie M %A Germer, Soren %A Gladwin, Mark T %A Gottlieb, Daniel J %A Guo, Xiuqing %A Hall, Michael E %A He, Jiang %A Heard-Costa, Nancy L %A Heckbert, Susan R %A Irvin, Marguerite R %A Johnsen, Jill M %A Johnson, Andrew D %A Kaplan, Robert %A Kardia, Sharon L R %A Kelly, Tanika %A Kelly, Shannon %A Kenny, Eimear E %A Kiel, Douglas P %A Klemmer, Robert %A Konkle, Barbara A %A Kooperberg, Charles %A Köttgen, Anna %A Lange, Leslie A %A Lasky-Su, Jessica %A Levy, Daniel %A Lin, Xihong %A Lin, Keng-Han %A Liu, Chunyu %A Loos, Ruth J F %A Garman, Lori %A Gerszten, Robert %A Lubitz, Steven A %A Lunetta, Kathryn L %A Mak, Angel C Y %A Manichaikul, Ani %A Manning, Alisa K %A Mathias, Rasika A %A McManus, David D %A McGarvey, Stephen T %A Meigs, James B %A Meyers, Deborah A %A Mikulla, Julie L %A Minear, Mollie A %A Mitchell, Braxton D %A Mohanty, Sanghamitra %A Montasser, May E %A Montgomery, Courtney %A Morrison, Alanna C %A Murabito, Joanne M %A Natale, Andrea %A Natarajan, Pradeep %A Nelson, Sarah C %A North, Kari E %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Pankratz, Nathan %A Peloso, Gina M %A Peyser, Patricia A %A Pleiness, Jacob %A Post, Wendy S %A Psaty, Bruce M %A Rao, D C %A Redline, Susan %A Reiner, Alexander P %A Roden, Dan %A Rotter, Jerome I %A Ruczinski, Ingo %A Sarnowski, Chloe %A Schoenherr, Sebastian %A Schwartz, David A %A Seo, Jeong-Sun %A Seshadri, Sudha %A Sheehan, Vivien A %A Sheu, Wayne H %A Shoemaker, M Benjamin %A Smith, Nicholas L %A Smith, Jennifer A %A Sotoodehnia, Nona %A Stilp, Adrienne M %A Tang, Weihong %A Taylor, Kent D %A Telen, Marilyn %A Thornton, Timothy A %A Tracy, Russell P %A Van Den Berg, David J %A Vasan, Ramachandran S %A Viaud-Martinez, Karine A %A Vrieze, Scott %A Weeks, Daniel E %A Weir, Bruce S %A Weiss, Scott T %A Weng, Lu-Chen %A Willer, Cristen J %A Zhang, Yingze %A Zhao, Xutong %A Arnett, Donna K %A Ashley-Koch, Allison E %A Barnes, Kathleen C %A Boerwinkle, Eric %A Gabriel, Stacey %A Gibbs, Richard %A Rice, Kenneth M %A Rich, Stephen S %A Silverman, Edwin K %A Qasba, Pankaj %A Gan, Weiniu %A Papanicolaou, George J %A Nickerson, Deborah A %A Browning, Sharon R %A Zody, Michael C %A Zöllner, Sebastian %A Wilson, James G %A Cupples, L Adrienne %A Laurie, Cathy C %A Jaquish, Cashell E %A Hernandez, Ryan D %A O'Connor, Timothy D %A Abecasis, Goncalo R %X

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

%B Nature %V 590 %P 290-299 %8 2021 02 %G eng %N 7845 %R 10.1038/s41586-021-03205-y %0 Journal Article %J Am J Epidemiol %D 2021 %T A System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. %A Stilp, Adrienne M %A Emery, Leslie S %A Broome, Jai G %A Buth, Erin J %A Khan, Alyna T %A Laurie, Cecelia A %A Wang, Fei Fei %A Wong, Quenna %A Chen, Dongquan %A D'Augustine, Catherine M %A Heard-Costa, Nancy L %A Hohensee, Chancellor R %A Johnson, William Craig %A Juarez, Lucia D %A Liu, Jingmin %A Mutalik, Karen M %A Raffield, Laura M %A Wiggins, Kerri L %A de Vries, Paul S %A Kelly, Tanika N %A Kooperberg, Charles %A Natarajan, Pradeep %A Peloso, Gina M %A Peyser, Patricia A %A Reiner, Alex P %A Arnett, Donna K %A Aslibekyan, Stella %A Barnes, Kathleen C %A Bielak, Lawrence F %A Bis, Joshua C %A Cade, Brian E %A Chen, Ming-Huei %A Correa, Adolfo %A Cupples, L Adrienne %A de Andrade, Mariza %A Ellinor, Patrick T %A Fornage, Myriam %A Franceschini, Nora %A Gan, Weiniu %A Ganesh, Santhi K %A Graffelman, Jan %A Grove, Megan L %A Guo, Xiuqing %A Hawley, Nicola L %A Hsu, Wan-Ling %A Jackson, Rebecca D %A Jaquish, Cashell E %A Johnson, Andrew D %A Kardia, Sharon L R %A Kelly, Shannon %A Lee, Jiwon %A Mathias, Rasika A %A McGarvey, Stephen T %A Mitchell, Braxton D %A Montasser, May E %A Morrison, Alanna C %A North, Kari E %A Nouraie, Seyed Mehdi %A Oelsner, Elizabeth C %A Pankratz, Nathan %A Rich, Stephen S %A Rotter, Jerome I %A Smith, Jennifer A %A Taylor, Kent D %A Vasan, Ramachandran S %A Weeks, Daniel E %A Weiss, Scott T %A Wilson, Carla G %A Yanek, Lisa R %A Psaty, Bruce M %A Heckbert, Susan R %A Laurie, Cathy C %X

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

%B Am J Epidemiol %8 2021 Apr 16 %G eng %R 10.1093/aje/kwab115 %0 Journal Article %J EBioMedicine %D 2021 %T Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium. %A Lin, Bridget M %A Grinde, Kelsey E %A Brody, Jennifer A %A Breeze, Charles E %A Raffield, Laura M %A Mychaleckyj, Josyf C %A Thornton, Timothy A %A Perry, James A %A Baier, Leslie J %A de Las Fuentes, Lisa %A Guo, Xiuqing %A Heavner, Benjamin D %A Hanson, Robert L %A Hung, Yi-Jen %A Qian, Huijun %A Hsiung, Chao A %A Hwang, Shih-Jen %A Irvin, Margaret R %A Jain, Deepti %A Kelly, Tanika N %A Kobes, Sayuko %A Lange, Leslie %A Lash, James P %A Li, Yun %A Liu, Xiaoming %A Mi, Xuenan %A Musani, Solomon K %A Papanicolaou, George J %A Parsa, Afshin %A Reiner, Alex P %A Salimi, Shabnam %A Sheu, Wayne H-H %A Shuldiner, Alan R %A Taylor, Kent D %A Smith, Albert V %A Smith, Jennifer A %A Tin, Adrienne %A Vaidya, Dhananjay %A Wallace, Robert B %A Yamamoto, Kenichi %A Sakaue, Saori %A Matsuda, Koichi %A Kamatani, Yoichiro %A Momozawa, Yukihide %A Yanek, Lisa R %A Young, Betsi A %A Zhao, Wei %A Okada, Yukinori %A Abecasis, Gonzalo %A Psaty, Bruce M %A Arnett, Donna K %A Boerwinkle, Eric %A Cai, Jianwen %A Yii-Der Chen, Ida %A Correa, Adolfo %A Cupples, L Adrienne %A He, Jiang %A Kardia, Sharon Lr %A Kooperberg, Charles %A Mathias, Rasika A %A Mitchell, Braxton D %A Nickerson, Deborah A %A Turner, Steve T %A Vasan, Ramachandran S %A Rotter, Jerome I %A Levy, Daniel %A Kramer, Holly J %A Köttgen, Anna %A Rich, Stephen S %A Lin, Dan-Yu %A Browning, Sharon R %A Franceschini, Nora %X

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

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

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

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

%B EBioMedicine %V 63 %P 103157 %8 2021 Jan %G eng %R 10.1016/j.ebiom.2020.103157 %0 Journal Article %J Hum Mol Genet %D 2021 %T Whole genome sequence analysis of platelet traits in the NHLBI trans-omics for precision medicine initiative. %A Little, Amarise %A Hu, Yao %A Sun, Quan %A Jain, Deepti %A Broome, Jai %A Chen, Ming-Huei %A Thibord, Florian %A McHugh, Caitlin %A Surendran, Praveen %A Blackwell, Thomas W %A Brody, Jennifer A %A Bhan, Arunoday %A Chami, Nathalie %A Vries, Paul S %A Ekunwe, Lynette %A Heard-Costa, Nancy %A Hobbs, Brian D %A Manichaikul, Ani %A Moon, Jee-Young %A Preuss, Michael H %A Ryan, Kathleen %A Wang, Zhe %A Wheeler, Marsha %A Yanek, Lisa R %A Abecasis, Goncalo R %A Almasy, Laura %A Beaty, Terri H %A Becker, Lewis C %A Blangero, John %A Boerwinkle, Eric %A Butterworth, Adam S %A Choquet, Helene %A Correa, Adolfo %A Curran, Joanne E %A Faraday, Nauder %A Fornage, Myriam %A Glahn, David C %A Hou, Lifang %A Jorgenson, Eric %A Kooperberg, Charles %A Lewis, Joshua P %A Lloyd-Jones, Donald M %A Loos, Ruth J F %A Min, Nancy %A Mitchell, Braxton D %A Morrison, Alanna C %A Nickerson, Debbie %A North, Kari E %A O'Connell, Jeffrey R %A Pankratz, Nathan %A Psaty, Bruce M %A Vasan, Ramachandran S %A Rich, Stephen S %A Rotter, Jerome I %A Smith, Albert V %A Smith, Nicholas L %A Tang, Hua %A Tracy, Russell P %A Conomos, Matthew P %A Laurie, Cecelia A %A Mathias, Rasika A %A Li, Yun %A Auer, Paul L %A Thornton, Timothy %A Reiner, Alexander P %A Johnson, Andrew D %A Raffield, Laura M %X

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

%B Hum Mol Genet %8 2021 Sep 06 %G eng %R 10.1093/hmg/ddab252 %0 Journal Article %J Am J Hum Genet %D 2021 %T Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program. %A Hu, Yao %A Stilp, Adrienne M %A McHugh, Caitlin P %A Rao, Shuquan %A Jain, Deepti %A Zheng, Xiuwen %A Lane, John %A Méric de Bellefon, Sébastian %A Raffield, Laura M %A Chen, Ming-Huei %A Yanek, Lisa R %A Wheeler, Marsha %A Yao, Yao %A Ren, Chunyan %A Broome, Jai %A Moon, Jee-Young %A de Vries, Paul S %A Hobbs, Brian D %A Sun, Quan %A Surendran, Praveen %A Brody, Jennifer A %A Blackwell, Thomas W %A Choquet, Helene %A Ryan, Kathleen %A Duggirala, Ravindranath %A Heard-Costa, Nancy %A Wang, Zhe %A Chami, Nathalie %A Preuss, Michael H %A Min, Nancy %A Ekunwe, Lynette %A Lange, Leslie A %A Cushman, Mary %A Faraday, Nauder %A Curran, Joanne E %A Almasy, Laura %A Kundu, Kousik %A Smith, Albert V %A Gabriel, Stacey %A Rotter, Jerome I %A Fornage, Myriam %A Lloyd-Jones, Donald M %A Vasan, Ramachandran S %A Smith, Nicholas L %A North, Kari E %A Boerwinkle, Eric %A Becker, Lewis C %A Lewis, Joshua P %A Abecasis, Goncalo R %A Hou, Lifang %A O'Connell, Jeffrey R %A Morrison, Alanna C %A Beaty, Terri H %A Kaplan, Robert %A Correa, Adolfo %A Blangero, John %A Jorgenson, Eric %A Psaty, Bruce M %A Kooperberg, Charles %A Walton, Russell T %A Kleinstiver, Benjamin P %A Tang, Hua %A Loos, Ruth J F %A Soranzo, Nicole %A Butterworth, Adam S %A Nickerson, Debbie %A Rich, Stephen S %A Mitchell, Braxton D %A Johnson, Andrew D %A Auer, Paul L %A Li, Yun %A Mathias, Rasika A %A Lettre, Guillaume %A Pankratz, Nathan %A Laurie, Cathy C %A Laurie, Cecelia A %A Bauer, Daniel E %A Conomos, Matthew P %A Reiner, Alexander P %K Adult %K Aged %K Chromosomes, Human, Pair 16 %K Datasets as Topic %K Erythrocytes %K Female %K Gene Editing %K Genetic Variation %K Genome-Wide Association Study %K HEK293 Cells %K Humans %K Male %K Middle Aged %K National Heart, Lung, and Blood Institute (U.S.) %K Phenotype %K Quality Control %K Reproducibility of Results %K United States %X

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

%B Am J Hum Genet %V 108 %P 874-893 %8 2021 05 06 %G eng %N 5 %R 10.1016/j.ajhg.2021.04.003 %0 Journal Article %J Am J Hum Genet %D 2021 %T Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program. %A Mikhaylova, Anna V %A McHugh, Caitlin P %A Polfus, Linda M %A Raffield, Laura M %A Boorgula, Meher Preethi %A Blackwell, Thomas W %A Brody, Jennifer A %A Broome, Jai %A Chami, Nathalie %A Chen, Ming-Huei %A Conomos, Matthew P %A Cox, Corey %A Curran, Joanne E %A Daya, Michelle %A Ekunwe, Lynette %A Glahn, David C %A Heard-Costa, Nancy %A Highland, Heather M %A Hobbs, Brian D %A Ilboudo, Yann %A Jain, Deepti %A Lange, Leslie A %A Miller-Fleming, Tyne W %A Min, Nancy %A Moon, Jee-Young %A Preuss, Michael H %A Rosen, Jonathon %A Ryan, Kathleen %A Smith, Albert V %A Sun, Quan %A Surendran, Praveen %A de Vries, Paul S %A Walter, Klaudia %A Wang, Zhe %A Wheeler, Marsha %A Yanek, Lisa R %A Zhong, Xue %A Abecasis, Goncalo R %A Almasy, Laura %A Barnes, Kathleen C %A Beaty, Terri H %A Becker, Lewis C %A Blangero, John %A Boerwinkle, Eric %A Butterworth, Adam S %A Chavan, Sameer %A Cho, Michael H %A Choquet, Helene %A Correa, Adolfo %A Cox, Nancy %A DeMeo, Dawn L %A Faraday, Nauder %A Fornage, Myriam %A Gerszten, Robert E %A Hou, Lifang %A Johnson, Andrew D %A Jorgenson, Eric %A Kaplan, Robert %A Kooperberg, Charles %A Kundu, Kousik %A Laurie, Cecelia A %A Lettre, Guillaume %A Lewis, Joshua P %A Li, Bingshan %A Li, Yun %A Lloyd-Jones, Donald M %A Loos, Ruth J F %A Manichaikul, Ani %A Meyers, Deborah A %A Mitchell, Braxton D %A Morrison, Alanna C %A Ngo, Debby %A Nickerson, Deborah A %A Nongmaithem, Suraj %A North, Kari E %A O'Connell, Jeffrey R %A Ortega, Victor E %A Pankratz, Nathan %A Perry, James A %A Psaty, Bruce M %A Rich, Stephen S %A Soranzo, Nicole %A Rotter, Jerome I %A Silverman, Edwin K %A Smith, Nicholas L %A Tang, Hua %A Tracy, Russell P %A Thornton, Timothy A %A Vasan, Ramachandran S %A Zein, Joe %A Mathias, Rasika A %A Reiner, Alexander P %A Auer, Paul L %K Asthma %K Biomarkers %K Dermatitis, Atopic %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Humans %K Leukocytes %K National Heart, Lung, and Blood Institute (U.S.) %K Phenotype %K Polymorphism, Single Nucleotide %K Prognosis %K Proteome %K Pulmonary Disease, Chronic Obstructive %K Quantitative Trait Loci %K United Kingdom %K United States %K Whole Genome Sequencing %X

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

%B Am J Hum Genet %V 108 %P 1836-1851 %8 2021 10 07 %G eng %N 10 %R 10.1016/j.ajhg.2021.08.007 %0 Journal Article %J Nat Genet %D 2022 %T Assessing the contribution of rare variants to complex trait heritability from whole-genome sequence data. %A Wainschtein, Pierrick %A Jain, Deepti %A Zheng, Zhili %A Cupples, L Adrienne %A Shadyab, Aladdin H %A McKnight, Barbara %A Shoemaker, Benjamin M %A Mitchell, Braxton D %A Psaty, Bruce M %A Kooperberg, Charles %A Liu, Ching-Ti %A Albert, Christine M %A Roden, Dan %A Chasman, Daniel I %A Darbar, Dawood %A Lloyd-Jones, Donald M %A Arnett, Donna K %A Regan, Elizabeth A %A Boerwinkle, Eric %A Rotter, Jerome I %A O'Connell, Jeffrey R %A Yanek, Lisa R %A de Andrade, Mariza %A Allison, Matthew A %A McDonald, Merry-Lynn N %A Chung, Mina K %A Fornage, Myriam %A Chami, Nathalie %A Smith, Nicholas L %A Ellinor, Patrick T %A Vasan, Ramachandran S %A Mathias, Rasika A %A Loos, Ruth J F %A Rich, Stephen S %A Lubitz, Steven A %A Heckbert, Susan R %A Redline, Susan %A Guo, Xiuqing %A Chen, Y -D Ida %A Laurie, Cecelia A %A Hernandez, Ryan D %A McGarvey, Stephen T %A Goddard, Michael E %A Laurie, Cathy C %A North, Kari E %A Lange, Leslie A %A Weir, Bruce S %A Yengo, Loic %A Yang, Jian %A Visscher, Peter M %X

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

%B Nat Genet %V 54 %P 263-273 %8 2022 Mar %G eng %N 3 %R 10.1038/s41588-021-00997-7 %0 Journal Article %J Nat Commun %D 2022 %T Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes. %A Halford, Jennifer L %A Morrill, Valerie N %A Choi, Seung Hoan %A Jurgens, Sean J %A Melloni, Giorgio %A Marston, Nicholas A %A Weng, Lu-Chen %A Nauffal, Victor %A Hall, Amelia W %A Gunn, Sophia %A Austin-Tse, Christina A %A Pirruccello, James P %A Khurshid, Shaan %A Rehm, Heidi L %A Benjamin, Emelia J %A Boerwinkle, Eric %A Brody, Jennifer A %A Correa, Adolfo %A Fornwalt, Brandon K %A Gupta, Namrata %A Haggerty, Christopher M %A Harris, Stephanie %A Heckbert, Susan R %A Hong, Charles C %A Kooperberg, Charles %A Lin, Henry J %A Loos, Ruth J F %A Mitchell, Braxton D %A Morrison, Alanna C %A Post, Wendy %A Psaty, Bruce M %A Redline, Susan %A Rice, Kenneth M %A Rich, Stephen S %A Rotter, Jerome I %A Schnatz, Peter F %A Soliman, Elsayed Z %A Sotoodehnia, Nona %A Wong, Eugene K %A Sabatine, Marc S %A Ruff, Christian T %A Lunetta, Kathryn L %A Ellinor, Patrick T %A Lubitz, Steven A %K Disease Susceptibility %K Endophenotypes %K Humans %K Long QT Syndrome %K Virulence %X

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

%B Nat Commun %V 13 %P 5106 %8 2022 08 30 %G eng %N 1 %R 10.1038/s41467-022-32009-5 %0 Journal Article %J Nat Methods %D 2022 %T A framework for detecting noncoding rare-variant associations of large-scale whole-genome sequencing studies. %A Li, Zilin %A Li, Xihao %A Zhou, Hufeng %A Gaynor, Sheila M %A Selvaraj, Margaret Sunitha %A Arapoglou, Theodore %A Quick, Corbin %A Liu, Yaowu %A Chen, Han %A Sun, Ryan %A Dey, Rounak %A Arnett, Donna K %A Auer, Paul L %A Bielak, Lawrence F %A Bis, Joshua C %A Blackwell, Thomas W %A Blangero, John %A Boerwinkle, Eric %A Bowden, Donald W %A Brody, Jennifer A %A Cade, Brian E %A Conomos, Matthew P %A Correa, Adolfo %A Cupples, L Adrienne %A Curran, Joanne E %A de Vries, Paul S %A Duggirala, Ravindranath %A Franceschini, Nora %A Freedman, Barry I %A Göring, Harald H H %A Guo, Xiuqing %A Kalyani, Rita R %A Kooperberg, Charles %A Kral, Brian G %A Lange, Leslie A %A Lin, Bridget M %A Manichaikul, Ani %A Manning, Alisa K %A Martin, Lisa W %A Mathias, Rasika A %A Meigs, James B %A Mitchell, Braxton D %A Montasser, May E %A Morrison, Alanna C %A Naseri, Take %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Peyser, Patricia A %A Psaty, Bruce M %A Raffield, Laura M %A Redline, Susan %A Reiner, Alexander P %A Reupena, Muagututi'a Sefuiva %A Rice, Kenneth M %A Rich, Stephen S %A Smith, Jennifer A %A Taylor, Kent D %A Taub, Margaret A %A Vasan, Ramachandran S %A Weeks, Daniel E %A Wilson, James G %A Yanek, Lisa R %A Zhao, Wei %A Rotter, Jerome I %A Willer, Cristen J %A Natarajan, Pradeep %A Peloso, Gina M %A Lin, Xihong %K Genetic Variation %K Genome %K Genome-Wide Association Study %K Humans %K Phenotype %K Whole Genome Sequencing %X

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

%B Nat Methods %V 19 %P 1599-1611 %8 2022 Dec %G eng %N 12 %R 10.1038/s41592-022-01640-x %0 Journal Article %J Hypertension %D 2022 %T Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension. %A Kelly, Tanika N %A Sun, Xiao %A He, Karen Y %A Brown, Michael R %A Taliun, Sarah A Gagliano %A Hellwege, Jacklyn N %A Irvin, Marguerite R %A Mi, Xuenan %A Brody, Jennifer A %A Franceschini, Nora %A Guo, Xiuqing %A Hwang, Shih-Jen %A de Vries, Paul S %A Gao, Yan %A Moscati, Arden %A Nadkarni, Girish N %A Yanek, Lisa R %A Elfassy, Tali %A Smith, Jennifer A %A Chung, Ren-Hua %A Beitelshees, Amber L %A Patki, Amit %A Aslibekyan, Stella %A Blobner, Brandon M %A Peralta, Juan M %A Assimes, Themistocles L %A Palmas, Walter R %A Liu, Chunyu %A Bress, Adam P %A Huang, Zhijie %A Becker, Lewis C %A Hwa, Chii-Min %A O'Connell, Jeffrey R %A Carlson, Jenna C %A Warren, Helen R %A Das, Sayantan %A Giri, Ayush %A Martin, Lisa W %A Craig Johnson, W %A Fox, Ervin R %A Bottinger, Erwin P %A Razavi, Alexander C %A Vaidya, Dhananjay %A Chuang, Lee-Ming %A Chang, Yen-Pei C %A Naseri, Take %A Jain, Deepti %A Kang, Hyun Min %A Hung, Adriana M %A Srinivasasainagendra, Vinodh %A Snively, Beverly M %A Gu, Dongfeng %A Montasser, May E %A Reupena, Muagututi'a Sefuiva %A Heavner, Benjamin D %A LeFaive, Jonathon %A Hixson, James E %A Rice, Kenneth M %A Wang, Fei Fei %A Nielsen, Jonas B %A Huang, Jianfeng %A Khan, Alyna T %A Zhou, Wei %A Nierenberg, Jovia L %A Laurie, Cathy C %A Armstrong, Nicole D %A Shi, Mengyao %A Pan, Yang %A Stilp, Adrienne M %A Emery, Leslie %A Wong, Quenna %A Hawley, Nicola L %A Minster, Ryan L %A Curran, Joanne E %A Munroe, Patricia B %A Weeks, Daniel E %A North, Kari E %A Tracy, Russell P %A Kenny, Eimear E %A Shimbo, Daichi %A Chakravarti, Aravinda %A Rich, Stephen S %A Reiner, Alex P %A Blangero, John %A Redline, Susan %A Mitchell, Braxton D %A Rao, Dabeeru C %A Ida Chen, Yii-Der %A Kardia, Sharon L R %A Kaplan, Robert C %A Mathias, Rasika A %A He, Jiang %A Psaty, Bruce M %A Fornage, Myriam %A Loos, Ruth J F %A Correa, Adolfo %A Boerwinkle, Eric %A Rotter, Jerome I %A Kooperberg, Charles %A Edwards, Todd L %A Abecasis, Goncalo R %A Zhu, Xiaofeng %A Levy, Daniel %A Arnett, Donna K %A Morrison, Alanna C %X

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

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

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

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

%B Hypertension %P 101161HYPERTENSIONAHA12219324 %8 2022 Jun 02 %G eng %R 10.1161/HYPERTENSIONAHA.122.19324 %0 Journal Article %J Circulation %D 2022 %T Monogenic and Polygenic Contributions to QTc Prolongation in the Population. %A Nauffal, Victor %A Morrill, Valerie N %A Jurgens, Sean J %A Choi, Seung Hoan %A Hall, Amelia W %A Weng, Lu-Chen %A Halford, Jennifer L %A Austin-Tse, Christina %A Haggerty, Christopher M %A Harris, Stephanie L %A Wong, Eugene K %A Alonso, Alvaro %A Arking, Dan E %A Benjamin, Emelia J %A Boerwinkle, Eric %A Min, Yuan-I %A Correa, Adolfo %A Fornwalt, Brandon K %A Heckbert, Susan R %A Kooperberg, Charles %A Lin, Henry J %A Loos, Ruth J F %A Rice, Kenneth M %A Gupta, Namrata %A Blackwell, Thomas W %A Mitchell, Braxton D %A Morrison, Alanna C %A Psaty, Bruce M %A Post, Wendy S %A Redline, Susan %A Rehm, Heidi L %A Rich, Stephen S %A Rotter, Jerome I %A Soliman, Elsayed Z %A Sotoodehnia, Nona %A Lunetta, Kathryn L %A Ellinor, Patrick T %A Lubitz, Steven A %X

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

%B Circulation %8 2022 Apr 07 %G eng %R 10.1161/CIRCULATIONAHA.121.057261 %0 Journal Article %J Nature %D 2022 %T Stroke genetics informs drug discovery and risk prediction across ancestries. %A Mishra, Aniket %A Malik, Rainer %A Hachiya, Tsuyoshi %A Jürgenson, Tuuli %A Namba, Shinichi %A Posner, Daniel C %A Kamanu, Frederick K %A Koido, Masaru %A Le Grand, Quentin %A Shi, Mingyang %A He, Yunye %A Georgakis, Marios K %A Caro, Ilana %A Krebs, Kristi %A Liaw, Yi-Ching %A Vaura, Felix C %A Lin, Kuang %A Winsvold, Bendik Slagsvold %A Srinivasasainagendra, Vinodh %A Parodi, Livia %A Bae, Hee-Joon %A Chauhan, Ganesh %A Chong, Michael R %A Tomppo, Liisa %A Akinyemi, Rufus %A Roshchupkin, Gennady V %A Habib, Naomi %A Jee, Yon Ho %A Thomassen, Jesper Qvist %A Abedi, Vida %A Cárcel-Márquez, Jara %A Nygaard, Marianne %A Leonard, Hampton L %A Yang, Chaojie %A Yonova-Doing, Ekaterina %A Knol, Maria J %A Lewis, Adam J %A Judy, Renae L %A Ago, Tetsuro %A Amouyel, Philippe %A Armstrong, Nicole D %A Bakker, Mark K %A Bartz, Traci M %A Bennett, David A %A Bis, Joshua C %A Bordes, Constance %A Børte, Sigrid %A Cain, Anael %A Ridker, Paul M %A Cho, Kelly %A Chen, Zhengming %A Cruchaga, Carlos %A Cole, John W %A De Jager, Phil L %A de Cid, Rafael %A Endres, Matthias %A Ferreira, Leslie E %A Geerlings, Mirjam I %A Gasca, Natalie C %A Gudnason, Vilmundur %A Hata, Jun %A He, Jing %A Heath, Alicia K %A Ho, Yuk-Lam %A Havulinna, Aki S %A Hopewell, Jemma C %A Hyacinth, Hyacinth I %A Inouye, Michael %A Jacob, Mina A %A Jeon, Christina E %A Jern, Christina %A Kamouchi, Masahiro %A Keene, Keith L %A Kitazono, Takanari %A Kittner, Steven J %A Konuma, Takahiro %A Kumar, Amit %A Lacaze, Paul %A Launer, Lenore J %A Lee, Keon-Joo %A Lepik, Kaido %A Li, Jiang %A Li, Liming %A Manichaikul, Ani %A Markus, Hugh S %A Marston, Nicholas A %A Meitinger, Thomas %A Mitchell, Braxton D %A Montellano, Felipe A %A Morisaki, Takayuki %A Mosley, Thomas H %A Nalls, Mike A %A Nordestgaard, Børge G %A O'Donnell, Martin J %A Okada, Yukinori %A Onland-Moret, N Charlotte %A Ovbiagele, Bruce %A Peters, Annette %A Psaty, Bruce M %A Rich, Stephen S %A Rosand, Jonathan %A Sabatine, Marc S %A Sacco, Ralph L %A Saleheen, Danish %A Sandset, Else Charlotte %A Salomaa, Veikko %A Sargurupremraj, Muralidharan %A Sasaki, Makoto %A Satizabal, Claudia L %A Schmidt, Carsten O %A Shimizu, Atsushi %A Smith, Nicholas L %A Sloane, Kelly L %A Sutoh, Yoichi %A Sun, Yan V %A Tanno, Kozo %A Tiedt, Steffen %A Tatlisumak, Turgut %A Torres-Aguila, Nuria P %A Tiwari, Hemant K %A Trégouët, David-Alexandre %A Trompet, Stella %A Tuladhar, Anil Man %A Tybjærg-Hansen, Anne %A van Vugt, Marion %A Vibo, Riina %A Verma, Shefali S %A Wiggins, Kerri L %A Wennberg, Patrik %A Woo, Daniel %A Wilson, Peter W F %A Xu, Huichun %A Yang, Qiong %A Yoon, Kyungheon %A Millwood, Iona Y %A Gieger, Christian %A Ninomiya, Toshiharu %A Grabe, Hans J %A Jukema, J Wouter %A Rissanen, Ina L %A Strbian, Daniel %A Kim, Young Jin %A Chen, Pei-Hsin %A Mayerhofer, Ernst %A Howson, Joanna M M %A Irvin, Marguerite R %A Adams, Hieab %A Wassertheil-Smoller, Sylvia %A Christensen, Kaare %A Ikram, Mohammad A %A Rundek, Tatjana %A Worrall, Bradford B %A Lathrop, G Mark %A Riaz, Moeen %A Simonsick, Eleanor M %A Kõrv, Janika %A França, Paulo H C %A Zand, Ramin %A Prasad, Kameshwar %A Frikke-Schmidt, Ruth %A de Leeuw, Frank-Erik %A Liman, Thomas %A Haeusler, Karl Georg %A Ruigrok, Ynte M %A Heuschmann, Peter Ulrich %A Longstreth, W T %A Jung, Keum Ji %A Bastarache, Lisa %A Paré, Guillaume %A Damrauer, Scott M %A Chasman, Daniel I %A Rotter, Jerome I %A Anderson, Christopher D %A Zwart, John-Anker %A Niiranen, Teemu J %A Fornage, Myriam %A Liaw, Yung-Po %A Seshadri, Sudha %A Fernandez-Cadenas, Israel %A Walters, Robin G %A Ruff, Christian T %A Owolabi, Mayowa O %A Huffman, Jennifer E %A Milani, Lili %A Kamatani, Yoichiro %A Dichgans, Martin %A Debette, Stephanie %X

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.

%B Nature %8 2022 Sep 30 %G eng %R 10.1038/s41586-022-05165-3 %0 Journal Article %J Commun Biol %D 2022 %T Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program. %A DiCorpo, Daniel %A Gaynor, Sheila M %A Russell, Emily M %A Westerman, Kenneth E %A Raffield, Laura M %A Majarian, Timothy D %A Wu, Peitao %A Sarnowski, Chloe %A Highland, Heather M %A Jackson, Anne %A Hasbani, Natalie R %A de Vries, Paul S %A Brody, Jennifer A %A Hidalgo, Bertha %A Guo, Xiuqing %A Perry, James A %A O'Connell, Jeffrey R %A Lent, Samantha %A Montasser, May E %A Cade, Brian E %A Jain, Deepti %A Wang, Heming %A D'Oliveira Albanus, Ricardo %A Varshney, Arushi %A Yanek, Lisa R %A Lange, Leslie %A Palmer, Nicholette D %A Almeida, Marcio %A Peralta, Juan M %A Aslibekyan, Stella %A Baldridge, Abigail S %A Bertoni, Alain G %A Bielak, Lawrence F %A Chen, Chung-Shiuan %A Chen, Yii-Der Ida %A Choi, Won Jung %A Goodarzi, Mark O %A Floyd, James S %A Irvin, Marguerite R %A Kalyani, Rita R %A Kelly, Tanika N %A Lee, Seonwook %A Liu, Ching-Ti %A Loesch, Douglas %A Manson, JoAnn E %A Minster, Ryan L %A Naseri, Take %A Pankow, James S %A Rasmussen-Torvik, Laura J %A Reiner, Alexander P %A Reupena, Muagututi'a Sefuiva %A Selvin, Elizabeth %A Smith, Jennifer A %A Weeks, Daniel E %A Xu, Huichun %A Yao, Jie %A Zhao, Wei %A Parker, Stephen %A Alonso, Alvaro %A Arnett, Donna K %A Blangero, John %A Boerwinkle, Eric %A Correa, Adolfo %A Cupples, L Adrienne %A Curran, Joanne E %A Duggirala, Ravindranath %A He, Jiang %A Heckbert, Susan R %A Kardia, Sharon L R %A Kim, Ryan W %A Kooperberg, Charles %A Liu, Simin %A Mathias, Rasika A %A McGarvey, Stephen T %A Mitchell, Braxton D %A Morrison, Alanna C %A Peyser, Patricia A %A Psaty, Bruce M %A Redline, Susan %A Shuldiner, Alan R %A Taylor, Kent D %A Vasan, Ramachandran S %A Viaud-Martinez, Karine A %A Florez, Jose C %A Wilson, James G %A Sladek, Robert %A Rich, Stephen S %A Rotter, Jerome I %A Lin, Xihong %A Dupuis, Josée %A Meigs, James B %A Wessel, Jennifer %A Manning, Alisa K %K Diabetes Mellitus, Type 2 %K Fasting %K Glucose %K Humans %K Insulin %K National Heart, Lung, and Blood Institute (U.S.) %K Nerve Tissue Proteins %K Polymorphism, Single Nucleotide %K Precision Medicine %K Receptors, Immunologic %K United States %X

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

%B Commun Biol %V 5 %P 756 %8 2022 07 28 %G eng %N 1 %R 10.1038/s42003-022-03702-4 %0 Journal Article %J Nat Commun %D 2022 %T Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program. %A Wheeler, Marsha M %A Stilp, Adrienne M %A Rao, Shuquan %A Halldorsson, Bjarni V %A Beyter, Doruk %A Wen, Jia %A Mihkaylova, Anna V %A McHugh, Caitlin P %A Lane, John %A Jiang, Min-Zhi %A Raffield, Laura M %A Jun, Goo %A Sedlazeck, Fritz J %A Metcalf, Ginger %A Yao, Yao %A Bis, Joshua B %A Chami, Nathalie %A de Vries, Paul S %A Desai, Pinkal %A Floyd, James S %A Gao, Yan %A Kammers, Kai %A Kim, Wonji %A Moon, Jee-Young %A Ratan, Aakrosh %A Yanek, Lisa R %A Almasy, Laura %A Becker, Lewis C %A Blangero, John %A Cho, Michael H %A Curran, Joanne E %A Fornage, Myriam %A Kaplan, Robert C %A Lewis, Joshua P %A Loos, Ruth J F %A Mitchell, Braxton D %A Morrison, Alanna C %A Preuss, Michael %A Psaty, Bruce M %A Rich, Stephen S %A Rotter, Jerome I %A Tang, Hua %A Tracy, Russell P %A Boerwinkle, Eric %A Abecasis, Goncalo R %A Blackwell, Thomas W %A Smith, Albert V %A Johnson, Andrew D %A Mathias, Rasika A %A Nickerson, Deborah A %A Conomos, Matthew P %A Li, Yun %A Þorsteinsdottir, Unnur %A Magnússon, Magnús K %A Stefansson, Kari %A Pankratz, Nathan D %A Bauer, Daniel E %A Auer, Paul L %A Reiner, Alex P %K Blood Cells %K Genome-Wide Association Study %K Humans %K Whole Genome Sequencing %X

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

%B Nat Commun %V 13 %P 7592 %8 2022 Dec 08 %G eng %N 1 %R 10.1038/s41467-022-35354-7 %0 Journal Article %J Hum Mol Genet %D 2022 %T Whole-Exome Sequencing Study Identifies Four Novel Gene Loci Associated with Diabetic Kidney Disease. %A Pan, Yang %A Sun, Xiao %A Mi, Xuenan %A Huang, Zhijie %A Hsu, Yenchih %A Hixson, James E %A Munzy, Donna %A Metcalf, Ginger %A Franceschini, Nora %A Tin, Adrienne %A Köttgen, Anna %A Francis, Michael %A Brody, Jennifer A %A Kestenbaum, Bryan %A Sitlani, Colleen M %A Mychaleckyj, Josyf C %A Kramer, Holly %A Lange, Leslie A %A Guo, Xiuqing %A Hwang, Shih-Jen %A Irvin, Marguerite R %A Smith, Jennifer A %A Yanek, Lisa R %A Vaidya, Dhananjay %A Chen, Yii-Der Ida %A Fornage, Myriam %A Lloyd-Jones, Donald M %A Hou, Lifang %A Mathias, Rasika A %A Mitchell, Braxton D %A Peyser, Patricia A %A Kardia, Sharon L R %A Arnett, Donna K %A Correa, Adolfo %A Raffield, Laura M %A Vasan, Ramachandran S %A Cupple, L Adrienne %A Levy, Daniel %A Kaplan, Robert C %A North, Kari E %A Rotter, Jerome I %A Kooperberg, Charles %A Reiner, Alexander P %A Psaty, Bruce M %A Tracy, Russell P %A Gibbs, Richard A %A Morrison, Alanna C %A Feldman, Harold %A Boerwinkle, Eric %A He, Jiang %A Kelly, Tanika N %X

Diabetic kidney disease (DKD) is recognized as an important public health challenge. However, its genomic mechanisms are poorly understood. To identify rare variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts well-phenotyped for chronic kidney disease (CKD) and diabetes. Our two-stage whole-exome sequencing study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort (CRIC) and Atherosclerosis Risk in Communities (ARIC) studies (stage-1) and 11 487 multi-ancestry Trans-Omics for Precision Medicine (TOPMed) participants (stage-2). Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex, and ancestry, were used to test associations between single variants and DKD. Gene-based aggregate rare variant analyses were conducted using an optimized sequence kernel association test (SKAT-O) implemented within our mixed model framework. We identified four novel exome-wide significant DKD-related loci through initiating diabetes. In single variant analyses, participants carrying a rare, in-frame insertion in the DIS3L2 gene (rs141560952) exhibited a 193-fold increased odds (95% confidence interval: 33.6, 1105) of DKD compared with non-carriers (P = 3.59 × 10-9). Likewise, each copy of a low-frequency KRT6B splice-site variant (rs425827) conferred a 5.31-fold higher odds (95% confidence interval: 3.06, 9.21) of DKD (P = 2.72 × 10-9). Aggregate gene-based analyses further identified ERAP2 (P = 4.03 × 10-8) and NPEPPS (P = 1.51 × 10-7), which are both expressed in the kidney and implicated in renin-angiotensin-aldosterone system modulated immune response. In the largest WES study of DKD, we identified novel rare variant loci attaining exome-wide significance. These findings provide new insights into the molecular mechanisms underlying DKD.

%B Hum Mol Genet %8 2022 Nov 29 %G eng %R 10.1093/hmg/ddac290 %0 Journal Article %J medRxiv %D 2023 %T Carriers of rare damaging genetic variants are at lower risk of atherosclerotic disease. %A Georgakis, Marios K %A Malik, Rainer %A Hasbani, Natalie R %A Shakt, Gabrielle %A Morrison, Alanna C %A Tsao, Noah L %A Judy, Renae %A Mitchell, Braxton D %A Xu, Huichun %A Montasser, May E %A Do, Ron %A Kenny, Eimear E %A Loos, Ruth J F %A Terry, James G %A Carr, John Jeffrey %A Bis, Joshua C %A Psaty, Bruce M %A Longstreth, W T %A Young, Kendra A %A Lutz, Sharon M %A Cho, Michael H %A Broome, Jai %A Khan, Alyna T %A Wang, Fei Fei %A Heard-Costa, Nancy %A Seshadri, Sudha %A Vasan, Ramachandran S %A Palmer, Nicholette D %A Freedman, Barry I %A Bowden, Donald W %A Yanek, Lisa R %A Kral, Brian G %A Becker, Lewis C %A Peyser, Patricia A %A Bielak, Lawrence F %A Ammous, Farah %A Carson, April P %A Hall, Michael E %A Raffield, Laura M %A Rich, Stephen S %A Post, Wendy S %A Tracy, Russel P %A Taylor, Kent D %A Guo, Xiuqing %A Mahaney, Michael C %A Curran, Joanne E %A Blangero, John %A Clarke, Shoa L %A Haessler, Jeffrey W %A Hu, Yao %A Assimes, Themistocles L %A Kooperberg, Charles %A Damrauer, Scott M %A Rotter, Jerome I %A de Vries, Paul S %A Dichgans, Martin %X

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

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

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

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

%B medRxiv %8 2023 Aug 16 %G eng %R 10.1101/2023.08.14.23294063 %0 Journal Article %J medRxiv %D 2023 %T Determinants of mosaic chromosomal alteration fitness. %A Pershad, Yash %A Mack, Taralynn %A Poisner, Hannah %A Jakubek, Yasminka A %A Stilp, Adrienne M %A Mitchell, Braxton D %A Lewis, Joshua P %A Boerwinkle, Eric %A Loos, Ruth J %A Chami, Nathalie %A Wang, Zhe %A Barnes, Kathleen %A Pankratz, Nathan %A Fornage, Myriam %A Redline, Susan %A Psaty, Bruce M %A Bis, Joshua C %A Shojaie, Ali %A Silverman, Edwin K %A Cho, Michael H %A Yun, Jeong %A DeMeo, Dawn %A Levy, Daniel %A Johnson, Andrew %A Mathias, Rasika %A Taub, Margaret %A Arnett, Donna %A North, Kari %A Raffield, Laura M %A Carson, April %A Doyle, Margaret F %A Rich, Stephen S %A Rotter, Jerome I %A Guo, Xiuqing %A Cox, Nancy %A Roden, Dan M %A Franceschini, Nora %A Desai, Pinkal %A Reiner, Alex %A Auer, Paul L %A Scheet, Paul %A Jaiswal, Siddhartha %A Weinstock, Joshua S %A Bick, Alexander G %X

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

%B medRxiv %8 2023 Oct 21 %G eng %R 10.1101/2023.10.20.23297280 %0 Journal Article %J Nat Commun %D 2023 %T Evaluating the use of blood pressure polygenic risk scores across race/ethnic background groups. %A Kurniansyah, Nuzulul %A Goodman, Matthew O %A Khan, Alyna T %A Wang, Jiongming %A Feofanova, Elena %A Bis, Joshua C %A Wiggins, Kerri L %A Huffman, Jennifer E %A Kelly, Tanika %A Elfassy, Tali %A Guo, Xiuqing %A Palmas, Walter %A Lin, Henry J %A Hwang, Shih-Jen %A Gao, Yan %A Young, Kendra %A Kinney, Gregory L %A Smith, Jennifer A %A Yu, Bing %A Liu, Simin %A Wassertheil-Smoller, Sylvia %A Manson, JoAnn E %A Zhu, Xiaofeng %A Chen, Yii-Der Ida %A Lee, I-Te %A Gu, C Charles %A Lloyd-Jones, Donald M %A Zöllner, Sebastian %A Fornage, Myriam %A Kooperberg, Charles %A Correa, Adolfo %A Psaty, Bruce M %A Arnett, Donna K %A Isasi, Carmen R %A Rich, Stephen S %A Kaplan, Robert C %A Redline, Susan %A Mitchell, Braxton D %A Franceschini, Nora %A Levy, Daniel %A Rotter, Jerome I %A Morrison, Alanna C %A Sofer, Tamar %K Blood Pressure %K Ethnicity %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Multifactorial Inheritance %K Population Health %K Risk Factors %X

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.

%B Nat Commun %V 14 %P 3202 %8 2023 Jun 02 %G eng %N 1 %R 10.1038/s41467-023-38990-9 %0 Journal Article %J bioRxiv %D 2023 %T Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants. %A Einson, Jonah %A Glinos, Dafni %A Boerwinkle, Eric %A Castaldi, Peter %A Darbar, Dawood %A de Andrade, Mariza %A Ellinor, Patrick %A Fornage, Myriam %A Gabriel, Stacey %A Germer, Soren %A Gibbs, Richard %A Hersh, Craig P %A Johnsen, Jill %A Kaplan, Robert %A Konkle, Barbara A %A Kooperberg, Charles %A Nassir, Rami %A Loos, Ruth J F %A Meyers, Deborah A %A Mitchell, Braxton D %A Psaty, Bruce %A Vasan, Ramachandran S %A Rich, Stephen S %A Rienstra, Michael %A Rotter, Jerome I %A Saferali, Aabida %A Shoemaker, M Benjamin %A Silverman, Edwin %A Smith, Albert Vernon %A Mohammadi, Pejman %A Castel, Stephane E %A Iossifov, Ivan %A Lappalainen, Tuuli %X

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

%B bioRxiv %8 2023 Jan 31 %G eng %R 10.1101/2023.01.31.526505 %0 Journal Article %J Nat Genet %D 2023 %T Mosaic chromosomal alterations in blood across ancestries using whole-genome sequencing. %A Jakubek, Yasminka A %A Zhou, Ying %A Stilp, Adrienne %A Bacon, Jason %A Wong, Justin W %A Ozcan, Zuhal %A Arnett, Donna %A Barnes, Kathleen %A Bis, Joshua C %A Boerwinkle, Eric %A Brody, Jennifer A %A Carson, April P %A Chasman, Daniel I %A Chen, Jiawen %A Cho, Michael %A Conomos, Matthew P %A Cox, Nancy %A Doyle, Margaret F %A Fornage, Myriam %A Guo, Xiuqing %A Kardia, Sharon L R %A Lewis, Joshua P %A Loos, Ruth J F %A Ma, Xiaolong %A Machiela, Mitchell J %A Mack, Taralynn M %A Mathias, Rasika A %A Mitchell, Braxton D %A Mychaleckyj, Josyf C %A North, Kari %A Pankratz, Nathan %A Peyser, Patricia A %A Preuss, Michael H %A Psaty, Bruce %A Raffield, Laura M %A Vasan, Ramachandran S %A Redline, Susan %A Rich, Stephen S %A Rotter, Jerome I %A Silverman, Edwin K %A Smith, Jennifer A %A Smith, Aaron P %A Taub, Margaret %A Taylor, Kent D %A Yun, Jeong %A Li, Yun %A Desai, Pinkal %A Bick, Alexander G %A Reiner, Alexander P %A Scheet, Paul %A Auer, Paul L %K Black People %K Genome, Human %K Genome-Wide Association Study %K Hispanic or Latino %K Humans %K Mosaicism %K Precision Medicine %X

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

%B Nat Genet %V 55 %P 1912-1919 %8 2023 Nov %G eng %N 11 %R 10.1038/s41588-023-01553-1 %0 Journal Article %J Nat Genet %D 2023 %T Powerful, scalable and resource-efficient meta-analysis of rare variant associations in large whole genome sequencing studies. %A Li, Xihao %A Quick, Corbin %A Zhou, Hufeng %A Gaynor, Sheila M %A Liu, Yaowu %A Chen, Han %A Selvaraj, Margaret Sunitha %A Sun, Ryan %A Dey, Rounak %A Arnett, Donna K %A Bielak, Lawrence F %A Bis, Joshua C %A Blangero, John %A Boerwinkle, Eric %A Bowden, Donald W %A Brody, Jennifer A %A Cade, Brian E %A Correa, Adolfo %A Cupples, L Adrienne %A Curran, Joanne E %A de Vries, Paul S %A Duggirala, Ravindranath %A Freedman, Barry I %A Göring, Harald H H %A Guo, Xiuqing %A Haessler, Jeffrey %A Kalyani, Rita R %A Kooperberg, Charles %A Kral, Brian G %A Lange, Leslie A %A Manichaikul, Ani %A Martin, Lisa W %A McGarvey, Stephen T %A Mitchell, Braxton D %A Montasser, May E %A Morrison, Alanna C %A Naseri, Take %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Peyser, Patricia A %A Psaty, Bruce M %A Raffield, Laura M %A Redline, Susan %A Reiner, Alexander P %A Reupena, Muagututi'a Sefuiva %A Rice, Kenneth M %A Rich, Stephen S %A Sitlani, Colleen M %A Smith, Jennifer A %A Taylor, Kent D %A Vasan, Ramachandran S %A Willer, Cristen J %A Wilson, James G %A Yanek, Lisa R %A Zhao, Wei %A Rotter, Jerome I %A Natarajan, Pradeep %A Peloso, Gina M %A Li, Zilin %A Lin, Xihong %K Exome Sequencing %K Genome-Wide Association Study %K Lipids %K Phenotype %K Whole Genome Sequencing %X

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

%B Nat Genet %V 55 %P 154-164 %8 2023 Jan %G eng %N 1 %R 10.1038/s41588-022-01225-6 %0 Journal Article %J medRxiv %D 2023 %T Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed Whole Genome Sequencing Study. %A Wang, Yuxuan %A Selvaraj, Margaret Sunitha %A Li, Xihao %A Li, Zilin %A Holdcraft, Jacob A %A Arnett, Donna K %A Bis, Joshua C %A Blangero, John %A Boerwinkle, Eric %A Bowden, Donald W %A Cade, Brian E %A Carlson, Jenna C %A Carson, April P %A Chen, Yii-Der Ida %A Curran, Joanne E %A de Vries, Paul S %A Dutcher, Susan K %A Ellinor, Patrick T %A Floyd, James S %A Fornage, Myriam %A Freedman, Barry I %A Gabriel, Stacey %A Germer, Soren %A Gibbs, Richard A %A Guo, Xiuqing %A He, Jiang %A Heard-Costa, Nancy %A Hildalgo, Bertha %A Hou, Lifang %A Irvin, Marguerite R %A Joehanes, Roby %A Kaplan, Robert C %A Kardia, Sharon Lr %A Kelly, Tanika N %A Kim, Ryan %A Kooperberg, Charles %A Kral, Brian G %A Levy, Daniel %A Li, Changwei %A Liu, Chunyu %A Lloyd-Jone, Don %A Loos, Ruth Jf %A Mahaney, Michael C %A Martin, Lisa W %A Mathias, Rasika A %A Minster, Ryan L %A Mitchell, Braxton D %A Montasser, May E %A Morrison, Alanna C %A Murabito, Joanne M %A Naseri, Take %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Preuss, Michael H %A Psaty, Bruce M %A Raffield, Laura M %A Rao, Dabeeru C %A Redline, Susan %A Reiner, Alexander P %A Rich, Stephen S %A Ruepena, Muagututi'a Sefuiva %A Sheu, Wayne H-H %A Smith, Jennifer A %A Smith, Albert %A Tiwari, Hemant K %A Tsai, Michael Y %A Viaud-Martinez, Karine A %A Wang, Zhe %A Yanek, Lisa R %A Zhao, Wei %A Rotter, Jerome I %A Lin, Xihong %A Natarajan, Pradeep %A Peloso, Gina M %X

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

%B medRxiv %8 2023 Jun 29 %G eng %R 10.1101/2023.06.28.23291966 %0 Journal Article %J bioRxiv %D 2023 %T A statistical framework for powerful multi-trait rare variant analysis in large-scale whole-genome sequencing studies. %A Li, Xihao %A Chen, Han %A Selvaraj, Margaret Sunitha %A Van Buren, Eric %A Zhou, Hufeng %A Wang, Yuxuan %A Sun, Ryan %A McCaw, Zachary R %A Yu, Zhi %A Arnett, Donna K %A Bis, Joshua C %A Blangero, John %A Boerwinkle, Eric %A Bowden, Donald W %A Brody, Jennifer A %A Cade, Brian E %A Carson, April P %A Carlson, Jenna C %A Chami, Nathalie %A Chen, Yii-Der Ida %A Curran, Joanne E %A de Vries, Paul S %A Fornage, Myriam %A Franceschini, Nora %A Freedman, Barry I %A Gu, Charles %A Heard-Costa, Nancy L %A He, Jiang %A Hou, Lifang %A Hung, Yi-Jen %A Irvin, Marguerite R %A Kaplan, Robert C %A Kardia, Sharon L R %A Kelly, Tanika %A Konigsberg, Iain %A Kooperberg, Charles %A Kral, Brian G %A Li, Changwei %A Loos, Ruth J F %A Mahaney, Michael C %A Martin, Lisa W %A Mathias, Rasika A %A Minster, Ryan L %A Mitchell, Braxton D %A Montasser, May E %A Morrison, Alanna C %A Palmer, Nicholette D %A Peyser, Patricia A %A Psaty, Bruce M %A Raffield, Laura M %A Redline, Susan %A Reiner, Alexander P %A Rich, Stephen S %A Sitlani, Colleen M %A Smith, Jennifer A %A Taylor, Kent D %A Tiwari, Hemant %A Vasan, Ramachandran S %A Wang, Zhe %A Yanek, Lisa R %A Yu, Bing %A Rice, Kenneth M %A Rotter, Jerome I %A Peloso, Gina M %A Natarajan, Pradeep %A Li, Zilin %A Liu, Zhonghua %A Lin, Xihong %X

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

%B bioRxiv %8 2023 Nov 02 %G eng %R 10.1101/2023.10.30.564764 %0 Journal Article %J Circ Genom Precis Med %D 2023 %T Type 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis. %A Hasbani, Natalie R %A Westerman, Kenneth E %A Heon Kwak, Soo %A Chen, Han %A Li, Xihao %A DiCorpo, Daniel %A Wessel, Jennifer %A Bis, Joshua C %A Sarnowski, Chloe %A Wu, Peitao %A Bielak, Lawrence F %A Guo, Xiuqing %A Heard-Costa, Nancy %A Kinney, Gregory %A Mahaney, Michael C %A Montasser, May E %A Palmer, Nicholette D %A Raffield, Laura M %A Terry, James G %A Yanek, Lisa R %A Bon, Jessica %A Bowden, Donald W %A Brody, Jennifer A %A Duggirala, Ravindranath %A Jacobs, David R %A Kalyani, Rita R %A Lange, Leslie A %A Mitchell, Braxton D %A Smith, Jennifer A %A Taylor, Kent D %A Carson, April %A Curran, Joanne E %A Fornage, Myriam %A Freedman, Barry I %A Gabriel, Stacey %A Gibbs, Richard A %A Gupta, Namrata %A Kardia, Sharon L R %A Kral, Brian G %A Momin, Zeineen %A Newman, Anne B %A Post, Wendy S %A Viaud-Martinez, Karine A %A Young, Kendra A %A Becker, Lewis C %A Bertoni, Alain %A Blangero, John %A Carr, John J %A Pratte, Katherine %A Psaty, Bruce M %A Rich, Stephen S %A Wu, Joseph C %A Malhotra, Rajeev %A Peyser, Patricia A %A Morrison, Alanna C %A Vasan, Ramachandran S %A Lin, Xihong %A Rotter, Jerome I %A Meigs, James B %A Manning, Alisa K %A de Vries, Paul S %X

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

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

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

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

%B Circ Genom Precis Med %P e004176 %8 2023 Nov 28 %G eng %R 10.1161/CIRCGEN.123.004176 %0 Journal Article %J medRxiv %D 2023 %T Whole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles. %A Huffman, Jennifer E %A Nicolas, Jayna %A Hahn, Julie %A Heath, Adam S %A Raffield, Laura M %A Yanek, Lisa R %A Brody, Jennifer A %A Thibord, Florian %A Almasy, Laura %A Bartz, Traci M %A Bielak, Lawrence F %A Bowler, Russell P %A Carrasquilla, Germán D %A Chasman, Daniel I %A Chen, Ming-Huei %A Emmert, David B %A Ghanbari, Mohsen %A Haessle, Jeffery %A Hottenga, Jouke-Jan %A Kleber, Marcus E %A Le, Ngoc-Quynh %A Lee, Jiwon %A Lewis, Joshua P %A Li-Gao, Ruifang %A Luan, Jian'an %A Malmberg, Anni %A Mangino, Massimo %A Marioni, Riccardo E %A Martinez-Perez, Angel %A Pankratz, Nathan %A Polasek, Ozren %A Richmond, Anne %A Rodriguez, Benjamin At %A Rotter, Jerome I %A Steri, Maristella %A Suchon, Pierre %A Trompet, Stella %A Weiss, Stefan %A Zare, Marjan %A Auer, Paul %A Cho, Michael H %A Christofidou, Paraskevi %A Davies, Gail %A de Geus, Eco %A Deleuze, Jean-Francois %A Delgado, Graciela E %A Ekunwe, Lynette %A Faraday, Nauder %A Gögele, Martin %A Greinacher, Andreas %A He, Gao %A Howard, Tom %A Joshi, Peter K %A Kilpeläinen, Tuomas O %A Lahti, Jari %A Linneberg, Allan %A Naitza, Silvia %A Noordam, Raymond %A Paüls-Vergés, Ferran %A Rich, Stephen S %A Rosendaal, Frits R %A Rudan, Igor %A Ryan, Kathleen A %A Souto, Juan Carlos %A van Rooij, Frank Ja %A Wang, Heming %A Zhao, Wei %A Becker, Lewis C %A Beswick, Andrew %A Brown, Michael R %A Cade, Brian E %A Campbell, Harry %A Cho, Kelly %A Crapo, James D %A Curran, Joanne E %A de Maat, Moniek Pm %A Doyle, Margaret %A Elliott, Paul %A Floyd, James S %A Fuchsberger, Christian %A Grarup, Niels %A Guo, Xiuqing %A Harris, Sarah E %A Hou, Lifang %A Kolcic, Ivana %A Kooperberg, Charles %A Menni, Cristina %A Nauck, Matthias %A O'Connell, Jeffrey R %A Orrù, Valeria %A Psaty, Bruce M %A Räikkönen, Katri %A Smith, Jennifer A %A Soria, José Manuel %A Stott, David J %A van Hylckama Vlieg, Astrid %A Watkins, Hugh %A Willemsen, Gonneke %A Wilson, Peter %A Ben-Shlomo, Yoav %A Blangero, John %A Boomsma, Dorret %A Cox, Simon R %A Dehghan, Abbas %A Eriksson, Johan G %A Fiorillo, Edoardo %A Fornage, Myriam %A Hansen, Torben %A Hayward, Caroline %A Ikram, M Arfan %A Jukema, J Wouter %A Kardia, Sharon Lr %A Lange, Leslie A %A März, Winfried %A Mathias, Rasika A %A Mitchell, Braxton D %A Mook-Kanamori, Dennis O %A Morange, Pierre-Emmanuel %A Pedersen, Oluf %A Pramstaller, Peter P %A Redline, Susan %A Reiner, Alexander %A Ridker, Paul M %A Silverman, Edwin K %A Spector, Tim D %A Völker, Uwe %A Wareham, Nick %A Wilson, James F %A Yao, Jie %A Trégouët, David-Alexandre %A Johnson, Andrew D %A Wolberg, Alisa S %A de Vries, Paul S %A Sabater-Lleal, Maria %A Morrison, Alanna C %A Smith, Nicholas L %X

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'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.

%B medRxiv %8 2023 Jun 12 %G eng %R 10.1101/2023.06.07.23291095 %0 Journal Article %J medRxiv %D 2023 %T WHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE. %A Zhang, Xinruo %A Brody, Jennifer A %A Graff, Mariaelisa %A Highland, Heather M %A Chami, Nathalie %A Xu, Hanfei %A Wang, Zhe %A Ferrier, Kendra %A Chittoor, Geetha %A Josyula, Navya S %A Li, Xihao %A Li, Zilin %A Allison, Matthew A %A Becker, Diane M %A Bielak, Lawrence F %A Bis, Joshua C %A Boorgula, Meher Preethi %A Bowden, Donald W %A Broome, Jai G %A Buth, Erin J %A Carlson, Christopher S %A Chang, Kyong-Mi %A Chavan, Sameer %A Chiu, Yen-Feng %A Chuang, Lee-Ming %A Conomos, Matthew P %A DeMeo, Dawn L %A Du, Margaret %A Duggirala, Ravindranath %A Eng, Celeste %A Fohner, Alison E %A Freedman, Barry I %A Garrett, Melanie E %A Guo, Xiuqing %A Haiman, Chris %A Heavner, Benjamin D %A Hidalgo, Bertha %A Hixson, James E %A Ho, Yuk-Lam %A Hobbs, Brian D %A Hu, Donglei %A Hui, Qin %A Hwu, Chii-Min %A Jackson, Rebecca D %A Jain, Deepti %A Kalyani, Rita R %A Kardia, Sharon L R %A Kelly, Tanika N %A Lange, Ethan M %A LeNoir, Michael %A Li, Changwei %A Marchand, Loic Le %A McDonald, Merry-Lynn N %A McHugh, Caitlin P %A Morrison, Alanna C %A Naseri, Take %A O'Connell, Jeffrey %A O'Donnell, Christopher J %A Palmer, Nicholette D %A Pankow, James S %A Perry, James A %A Peters, Ulrike %A Preuss, Michael H %A Rao, D C %A Regan, Elizabeth A %A Reupena, Sefuiva M %A Roden, Dan M %A Rodriguez-Santana, Jose %A Sitlani, Colleen M %A Smith, Jennifer A %A Tiwari, Hemant K %A Vasan, Ramachandran S %A Wang, Zeyuan %A Weeks, Daniel E %A Wessel, Jennifer %A Wiggins, Kerri L %A Wilkens, Lynne R %A Wilson, Peter W F %A Yanek, Lisa R %A Yoneda, Zachary T %A Zhao, Wei %A Zöllner, Sebastian %A Arnett, Donna K %A Ashley-Koch, Allison E %A Barnes, Kathleen C %A Blangero, John %A Boerwinkle, Eric %A Burchard, Esteban G %A Carson, April P %A Chasman, Daniel I %A Chen, Yii-Der Ida %A Curran, Joanne E %A Fornage, Myriam %A Gordeuk, Victor R %A He, Jiang %A Heckbert, Susan R %A Hou, Lifang %A Irvin, Marguerite R %A Kooperberg, Charles %A Minster, Ryan L %A Mitchell, Braxton D %A Nouraie, Mehdi %A Psaty, Bruce M %A Raffield, Laura M %A Reiner, Alexander P %A Rich, Stephen S %A Rotter, Jerome I %A Shoemaker, M Benjamin %A Smith, Nicholas L %A Taylor, Kent D %A Telen, Marilyn J %A Weiss, Scott T %A Zhang, Yingze %A Costa, Nancy Heard- %A Sun, Yan V %A Lin, Xihong %A Cupples, L Adrienne %A Lange, Leslie A %A Liu, Ching-Ti %A Loos, Ruth J F %A North, Kari E %A Justice, Anne E %X

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

%B medRxiv %8 2023 Aug 22 %G eng %R 10.1101/2023.08.21.23293271 %0 Journal Article %J bioRxiv %D 2023 %T Whole Genome Sequencing Based Analysis of Inflammation Biomarkers in the Trans-Omics for Precision Medicine (TOPMed) Consortium. %A Jiang, Min-Zhi %A Gaynor, Sheila M %A Li, Xihao %A Van Buren, Eric %A Stilp, Adrienne %A Buth, Erin %A Wang, Fei Fei %A Manansala, Regina %A Gogarten, Stephanie M %A Li, Zilin %A Polfus, Linda M %A Salimi, Shabnam %A Bis, Joshua C %A Pankratz, Nathan %A Yanek, Lisa R %A Durda, Peter %A Tracy, Russell P %A Rich, Stephen S %A Rotter, Jerome I %A Mitchell, Braxton D %A Lewis, Joshua P %A Psaty, Bruce M %A Pratte, Katherine A %A Silverman, Edwin K %A Kaplan, Robert C %A Avery, Christy %A North, Kari %A Mathias, Rasika A %A Faraday, Nauder %A Lin, Honghuang %A Wang, Biqi %A Carson, April P %A Norwood, Arnita F %A Gibbs, Richard A %A Kooperberg, Charles %A Lundin, Jessica %A Peters, Ulrike %A Dupuis, Josée %A Hou, Lifang %A Fornage, Myriam %A Benjamin, Emelia J %A Reiner, Alexander P %A Bowler, Russell P %A Lin, Xihong %A Auer, Paul L %A Raffield, Laura M %X

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

%B bioRxiv %8 2023 Sep 12 %G eng %R 10.1101/2023.09.10.555215