%0 Journal Article %J Nat Genet %D 2010 %T Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. %A Speliotes, Elizabeth K %A Willer, Cristen J %A Berndt, Sonja I %A Monda, Keri L %A Thorleifsson, Gudmar %A Jackson, Anne U %A Lango Allen, Hana %A Lindgren, Cecilia M %A Luan, Jian'an %A Mägi, Reedik %A Randall, Joshua C %A Vedantam, Sailaja %A Winkler, Thomas W %A Qi, Lu %A Workalemahu, Tsegaselassie %A Heid, Iris M %A Steinthorsdottir, Valgerdur %A Stringham, Heather M %A Weedon, Michael N %A Wheeler, Eleanor %A Wood, Andrew R %A Ferreira, Teresa %A Weyant, Robert J %A Segrè, Ayellet V %A Estrada, Karol %A Liang, Liming %A Nemesh, James %A Park, Ju-Hyun %A Gustafsson, Stefan %A Kilpeläinen, Tuomas O %A Yang, Jian %A Bouatia-Naji, Nabila %A Esko, Tõnu %A Feitosa, Mary F %A Kutalik, Zoltán %A Mangino, Massimo %A Raychaudhuri, Soumya %A Scherag, Andre %A Smith, Albert Vernon %A Welch, Ryan %A Zhao, Jing Hua %A Aben, Katja K %A Absher, Devin M %A Amin, Najaf %A Dixon, Anna L %A Fisher, Eva %A Glazer, Nicole L %A Goddard, Michael E %A Heard-Costa, Nancy L %A Hoesel, Volker %A Hottenga, Jouke-Jan %A Johansson, Asa %A Johnson, Toby %A Ketkar, Shamika %A Lamina, Claudia %A Li, Shengxu %A Moffatt, Miriam F %A Myers, Richard H %A Narisu, Narisu %A Perry, John R B %A Peters, Marjolein J %A Preuss, Michael %A Ripatti, Samuli %A Rivadeneira, Fernando %A Sandholt, Camilla %A Scott, Laura J %A Timpson, Nicholas J %A Tyrer, Jonathan P %A van Wingerden, Sophie %A Watanabe, Richard M %A White, Charles C %A Wiklund, Fredrik %A Barlassina, Christina %A Chasman, Daniel I %A Cooper, Matthew N %A Jansson, John-Olov %A Lawrence, Robert W %A Pellikka, Niina %A Prokopenko, Inga %A Shi, Jianxin %A Thiering, Elisabeth %A Alavere, Helene %A Alibrandi, Maria T S %A Almgren, Peter %A Arnold, Alice M %A Aspelund, Thor %A Atwood, Larry D %A Balkau, Beverley %A Balmforth, Anthony J %A Bennett, Amanda J %A Ben-Shlomo, Yoav %A Bergman, Richard N %A Bergmann, Sven %A Biebermann, Heike %A Blakemore, Alexandra I F %A Boes, Tanja %A Bonnycastle, Lori L %A Bornstein, Stefan R %A Brown, Morris J %A Buchanan, Thomas A %A Busonero, Fabio %A Campbell, Harry %A Cappuccio, Francesco P %A Cavalcanti-Proença, Christine %A Chen, Yii-Der Ida %A Chen, Chih-Mei %A Chines, Peter S %A Clarke, Robert %A Coin, Lachlan %A Connell, John %A Day, Ian N M %A den Heijer, Martin %A Duan, Jubao %A Ebrahim, Shah %A Elliott, Paul %A Elosua, Roberto %A Eiriksdottir, Gudny %A Erdos, Michael R %A Eriksson, Johan G %A Facheris, Maurizio F %A Felix, Stephan B %A Fischer-Posovszky, Pamela %A Folsom, Aaron R %A Friedrich, Nele %A Freimer, Nelson B %A Fu, Mao %A Gaget, Stefan %A Gejman, Pablo V %A Geus, Eco J C %A Gieger, Christian %A Gjesing, Anette P %A Goel, Anuj %A Goyette, Philippe %A Grallert, Harald %A Grässler, Jürgen %A Greenawalt, Danielle M %A Groves, Christopher J %A Gudnason, Vilmundur %A Guiducci, Candace %A Hartikainen, Anna-Liisa %A Hassanali, Neelam %A Hall, Alistair S %A Havulinna, Aki S %A Hayward, Caroline %A Heath, Andrew C %A Hengstenberg, Christian %A Hicks, Andrew A %A Hinney, Anke %A Hofman, Albert %A Homuth, Georg %A Hui, Jennie %A Igl, Wilmar %A Iribarren, Carlos %A Isomaa, Bo %A Jacobs, Kevin B %A Jarick, Ivonne %A Jewell, Elizabeth %A John, Ulrich %A Jørgensen, Torben %A Jousilahti, Pekka %A Jula, Antti %A Kaakinen, Marika %A Kajantie, Eero %A Kaplan, Lee M %A Kathiresan, Sekar %A Kettunen, Johannes %A Kinnunen, Leena %A Knowles, Joshua W %A Kolcic, Ivana %A König, Inke R %A Koskinen, Seppo %A Kovacs, Peter %A Kuusisto, Johanna %A Kraft, Peter %A Kvaløy, Kirsti %A Laitinen, Jaana %A Lantieri, Olivier %A Lanzani, Chiara %A Launer, Lenore J %A Lecoeur, Cécile %A Lehtimäki, Terho %A Lettre, Guillaume %A Liu, Jianjun %A Lokki, Marja-Liisa %A Lorentzon, Mattias %A Luben, Robert N %A Ludwig, Barbara %A Manunta, Paolo %A Marek, Diana %A Marre, Michel %A Martin, Nicholas G %A McArdle, Wendy L %A McCarthy, Anne %A McKnight, Barbara %A Meitinger, Thomas %A Melander, Olle %A Meyre, David %A Midthjell, Kristian %A Montgomery, Grant W %A Morken, Mario A %A Morris, Andrew P %A Mulic, Rosanda %A Ngwa, Julius S %A Nelis, Mari %A Neville, Matt J %A Nyholt, Dale R %A O'Donnell, Christopher J %A O'Rahilly, Stephen %A Ong, Ken K %A Oostra, Ben %A Paré, Guillaume %A Parker, Alex N %A Perola, Markus %A Pichler, Irene %A Pietiläinen, Kirsi H %A Platou, Carl G P %A Polasek, Ozren %A Pouta, Anneli %A Rafelt, Suzanne %A Raitakari, Olli %A Rayner, Nigel W %A Ridderstråle, Martin %A Rief, Winfried %A Ruokonen, Aimo %A Robertson, Neil R %A Rzehak, Peter %A Salomaa, Veikko %A Sanders, Alan R %A Sandhu, Manjinder S %A Sanna, Serena %A Saramies, Jouko %A Savolainen, Markku J %A Scherag, Susann %A Schipf, Sabine %A Schreiber, Stefan %A Schunkert, Heribert %A Silander, Kaisa %A Sinisalo, Juha %A Siscovick, David S %A Smit, Jan H %A Soranzo, Nicole %A Sovio, Ulla %A Stephens, Jonathan %A Surakka, Ida %A Swift, Amy J %A Tammesoo, Mari-Liis %A Tardif, Jean-Claude %A Teder-Laving, Maris %A Teslovich, Tanya M %A Thompson, John R %A Thomson, Brian %A Tönjes, Anke %A Tuomi, Tiinamaija %A van Meurs, Joyce B J %A van Ommen, Gert-Jan %A Vatin, Vincent %A Viikari, Jorma %A Visvikis-Siest, Sophie %A Vitart, Veronique %A Vogel, Carla I G %A Voight, Benjamin F %A Waite, Lindsay L %A Wallaschofski, Henri %A Walters, G Bragi %A Widen, Elisabeth %A Wiegand, Susanna %A Wild, Sarah H %A Willemsen, Gonneke %A Witte, Daniel R %A Witteman, Jacqueline C %A Xu, Jianfeng %A Zhang, Qunyuan %A Zgaga, Lina %A Ziegler, Andreas %A Zitting, Paavo %A Beilby, John P %A Farooqi, I Sadaf %A Hebebrand, Johannes %A Huikuri, Heikki V %A James, Alan L %A Kähönen, Mika %A Levinson, Douglas F %A Macciardi, Fabio %A Nieminen, Markku S %A Ohlsson, Claes %A Palmer, Lyle J %A Ridker, Paul M %A Stumvoll, Michael %A Beckmann, Jacques S %A Boeing, Heiner %A Boerwinkle, Eric %A Boomsma, Dorret I %A Caulfield, Mark J %A Chanock, Stephen J %A Collins, Francis S %A Cupples, L Adrienne %A Smith, George Davey %A Erdmann, Jeanette %A Froguel, Philippe %A Grönberg, Henrik %A Gyllensten, Ulf %A Hall, Per %A Hansen, Torben %A Harris, Tamara B %A Hattersley, Andrew T %A Hayes, Richard B %A Heinrich, Joachim %A Hu, Frank B %A Hveem, Kristian %A Illig, Thomas %A Jarvelin, Marjo-Riitta %A Kaprio, Jaakko %A Karpe, Fredrik %A Khaw, Kay-Tee %A Kiemeney, Lambertus A %A Krude, Heiko %A Laakso, Markku %A Lawlor, Debbie A %A Metspalu, Andres %A Munroe, Patricia B %A Ouwehand, Willem H %A Pedersen, Oluf %A Penninx, Brenda W %A Peters, Annette %A Pramstaller, Peter P %A Quertermous, Thomas %A Reinehr, Thomas %A Rissanen, Aila %A Rudan, Igor %A Samani, Nilesh J %A Schwarz, Peter E H %A Shuldiner, Alan R %A Spector, Timothy D %A Tuomilehto, Jaakko %A Uda, Manuela %A Uitterlinden, Andre %A Valle, Timo T %A Wabitsch, Martin %A Waeber, Gérard %A Wareham, Nicholas J %A Watkins, Hugh %A Wilson, James F %A Wright, Alan F %A Zillikens, M Carola %A Chatterjee, Nilanjan %A McCarroll, Steven A %A Purcell, Shaun %A Schadt, Eric E %A Visscher, Peter M %A Assimes, Themistocles L %A Borecki, Ingrid B %A Deloukas, Panos %A Fox, Caroline S %A Groop, Leif C %A Haritunians, Talin %A Hunter, David J %A Kaplan, Robert C %A Mohlke, Karen L %A O'Connell, Jeffrey R %A Peltonen, Leena %A Schlessinger, David %A Strachan, David P %A van Duijn, Cornelia M %A Wichmann, H-Erich %A Frayling, Timothy M %A Thorsteinsdottir, Unnur %A Abecasis, Goncalo R %A Barroso, Inês %A Boehnke, Michael %A Stefansson, Kari %A North, Kari E %A McCarthy, Mark I %A Hirschhorn, Joel N %A Ingelsson, Erik %A Loos, Ruth J F %K Body Height %K Body Mass Index %K Body Size %K Body Weight %K Chromosome Mapping %K European Continental Ancestry Group %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Obesity %K Polymorphism, Single Nucleotide %X

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

%B Nat Genet %V 42 %P 937-48 %8 2010 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/20935630?dopt=Abstract %R 10.1038/ng.686 %0 Journal Article %J Nat Genet %D 2010 %T Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction. %A Sotoodehnia, Nona %A Isaacs, Aaron %A de Bakker, Paul I W %A Dörr, Marcus %A Newton-Cheh, Christopher %A Nolte, Ilja M %A van der Harst, Pim %A Müller, Martina %A Eijgelsheim, Mark %A Alonso, Alvaro %A Hicks, Andrew A %A Padmanabhan, Sandosh %A Hayward, Caroline %A Smith, Albert Vernon %A Polasek, Ozren %A Giovannone, Steven %A Fu, Jingyuan %A Magnani, Jared W %A Marciante, Kristin D %A Pfeufer, Arne %A Gharib, Sina A %A Teumer, Alexander %A Li, Man %A Bis, Joshua C %A Rivadeneira, Fernando %A Aspelund, Thor %A Köttgen, Anna %A Johnson, Toby %A Rice, Kenneth %A Sie, Mark P S %A Wang, Ying A %A Klopp, Norman %A Fuchsberger, Christian %A Wild, Sarah H %A Mateo Leach, Irene %A Estrada, Karol %A Völker, Uwe %A Wright, Alan F %A Asselbergs, Folkert W %A Qu, Jiaxiang %A Chakravarti, Aravinda %A Sinner, Moritz F %A Kors, Jan A %A Petersmann, Astrid %A Harris, Tamara B %A Soliman, Elsayed Z %A Munroe, Patricia B %A Psaty, Bruce M %A Oostra, Ben A %A Cupples, L Adrienne %A Perz, Siegfried %A de Boer, Rudolf A %A Uitterlinden, André G %A Völzke, Henry %A Spector, Timothy D %A Liu, Fang-Yu %A Boerwinkle, Eric %A Dominiczak, Anna F %A Rotter, Jerome I %A van Herpen, Gé %A Levy, Daniel %A Wichmann, H-Erich %A van Gilst, Wiek H %A Witteman, Jacqueline C M %A Kroemer, Heyo K %A Kao, W H Linda %A Heckbert, Susan R %A Meitinger, Thomas %A Hofman, Albert %A Campbell, Harry %A Folsom, Aaron R %A van Veldhuisen, Dirk J %A Schwienbacher, Christine %A O'Donnell, Christopher J %A Volpato, Claudia Beu %A Caulfield, Mark J %A Connell, John M %A Launer, Lenore %A Lu, Xiaowen %A Franke, Lude %A Fehrmann, Rudolf S N %A te Meerman, Gerard %A Groen, Harry J M %A Weersma, Rinse K %A van den Berg, Leonard H %A Wijmenga, Cisca %A Ophoff, Roel A %A Navis, Gerjan %A Rudan, Igor %A Snieder, Harold %A Wilson, James F %A Pramstaller, Peter P %A Siscovick, David S %A Wang, Thomas J %A Gudnason, Vilmundur %A van Duijn, Cornelia M %A Felix, Stephan B %A Fishman, Glenn I %A Jamshidi, Yalda %A Stricker, Bruno H Ch %A Samani, Nilesh J %A Kääb, Stefan %A Arking, Dan E %K Animals %K Animals, Newborn %K Chromosomes, Human %K Computational Biology %K Electrocardiography %K Genetic Loci %K Genome-Wide Association Study %K Heart Conduction System %K Humans %K Mice %K Mice, Transgenic %K Models, Animal %K Myocytes, Cardiac %K NAV1.8 Voltage-Gated Sodium Channel %K Polymorphism, Single Nucleotide %K Sodium Channels %X

The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genome-wide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration (P < 5 × 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.

%B Nat Genet %V 42 %P 1068-76 %8 2010 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/21076409?dopt=Abstract %R 10.1038/ng.716 %0 Journal Article %J PLoS Genet %D 2010 %T Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo. %A Ikram, M Kamran %A Sim, Xueling %A Xueling, Sim %A Jensen, Richard A %A Cotch, Mary Frances %A Hewitt, Alex W %A Ikram, M Arfan %A Wang, Jie Jin %A Klein, Ronald %A Klein, Barbara E K %A Breteler, Monique M B %A Cheung, Ning %A Liew, Gerald %A Mitchell, Paul %A Uitterlinden, André G %A Rivadeneira, Fernando %A Hofman, Albert %A de Jong, Paulus T V M %A van Duijn, Cornelia M %A Kao, Linda %A Cheng, Ching-Yu %A Smith, Albert Vernon %A Glazer, Nicole L %A Lumley, Thomas %A McKnight, Barbara %A Psaty, Bruce M %A Jonasson, Fridbert %A Eiriksdottir, Gudny %A Aspelund, Thor %A Harris, Tamara B %A Launer, Lenore J %A Taylor, Kent D %A Li, Xiaohui %A Iyengar, Sudha K %A Xi, Quansheng %A Sivakumaran, Theru A %A Mackey, David A %A Macgregor, Stuart %A Martin, Nicholas G %A Young, Terri L %A Bis, Josh C %A Wiggins, Kerri L %A Heckbert, Susan R %A Hammond, Christopher J %A Andrew, Toby %A Fahy, Samantha %A Attia, John %A Holliday, Elizabeth G %A Scott, Rodney J %A Islam, F M Amirul %A Rotter, Jerome I %A McAuley, Annie K %A Boerwinkle, Eric %A Tai, E Shyong %A Gudnason, Vilmundur %A Siscovick, David S %A Vingerling, Johannes R %A Wong, Tien Y %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Child %K Child, Preschool %K Chromosomes, Human, Pair 12 %K Chromosomes, Human, Pair 19 %K Chromosomes, Human, Pair 5 %K Chromosomes, Human, Pair 6 %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Meta-Analysis as Topic %K Microcirculation %K Middle Aged %K Polymorphism, Single Nucleotide %K Retinal Vessels %K Young Adult %X

There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n  =  6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10(-8)) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p  =  1.61×10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25×10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p  =  2.15×10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10(-16), adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.

%B PLoS Genet %V 6 %P e1001184 %8 2010 Oct 28 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/21060863?dopt=Abstract %R 10.1371/journal.pgen.1001184 %0 Journal Article %J Nat Genet %D 2010 %T Genome-wide association study of PR interval. %A Pfeufer, Arne %A van Noord, Charlotte %A Marciante, Kristin D %A Arking, Dan E %A Larson, Martin G %A Smith, Albert Vernon %A Tarasov, Kirill V %A Müller, Martina %A Sotoodehnia, Nona %A Sinner, Moritz F %A Verwoert, Germaine C %A Li, Man %A Kao, W H Linda %A Köttgen, Anna %A Coresh, Josef %A Bis, Joshua C %A Psaty, Bruce M %A Rice, Kenneth %A Rotter, Jerome I %A Rivadeneira, Fernando %A Hofman, Albert %A Kors, Jan A %A Stricker, Bruno H C %A Uitterlinden, André G %A van Duijn, Cornelia M %A Beckmann, Britt M %A Sauter, Wiebke %A Gieger, Christian %A Lubitz, Steven A %A Newton-Cheh, Christopher %A Wang, Thomas J %A Magnani, Jared W %A Schnabel, Renate B %A Chung, Mina K %A Barnard, John %A Smith, Jonathan D %A Van Wagoner, David R %A Vasan, Ramachandran S %A Aspelund, Thor %A Eiriksdottir, Gudny %A Harris, Tamara B %A Launer, Lenore J %A Najjar, Samer S %A Lakatta, Edward %A Schlessinger, David %A Uda, Manuela %A Abecasis, Goncalo R %A Müller-Myhsok, Bertram %A Ehret, Georg B %A Boerwinkle, Eric %A Chakravarti, Aravinda %A Soliman, Elsayed Z %A Lunetta, Kathryn L %A Perz, Siegfried %A Wichmann, H-Erich %A Meitinger, Thomas %A Levy, Daniel %A Gudnason, Vilmundur %A Ellinor, Patrick T %A Sanna, Serena %A Kääb, Stefan %A Witteman, Jacqueline C M %A Alonso, Alvaro %A Benjamin, Emelia J %A Heckbert, Susan R %K Aged %K Atrial Fibrillation %K Cohort Studies %K Electrocardiography %K Female %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Heart Conduction System %K Humans %K Male %K Meta-Analysis as Topic %X

The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 x 10(-8). At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.

%B Nat Genet %V 42 %P 153-9 %8 2010 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/20062060?dopt=Abstract %R 10.1038/ng.517 %0 Journal Article %J Nat Genet %D 2010 %T Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. %A Heid, Iris M %A Jackson, Anne U %A Randall, Joshua C %A Winkler, Thomas W %A Qi, Lu %A Steinthorsdottir, Valgerdur %A Thorleifsson, Gudmar %A Zillikens, M Carola %A Speliotes, Elizabeth K %A Mägi, Reedik %A Workalemahu, Tsegaselassie %A White, Charles C %A Bouatia-Naji, Nabila %A Harris, Tamara B %A Berndt, Sonja I %A Ingelsson, Erik %A Willer, Cristen J %A Weedon, Michael N %A Luan, Jian'an %A Vedantam, Sailaja %A Esko, Tõnu %A Kilpeläinen, Tuomas O %A Kutalik, Zoltán %A Li, Shengxu %A Monda, Keri L %A Dixon, Anna L %A Holmes, Christopher C %A Kaplan, Lee M %A Liang, Liming %A Min, Josine L %A Moffatt, Miriam F %A Molony, Cliona %A Nicholson, George %A Schadt, Eric E %A Zondervan, Krina T %A Feitosa, Mary F %A Ferreira, Teresa %A Lango Allen, Hana %A Weyant, Robert J %A Wheeler, Eleanor %A Wood, Andrew R %A Estrada, Karol %A Goddard, Michael E %A Lettre, Guillaume %A Mangino, Massimo %A Nyholt, Dale R %A Purcell, Shaun %A Smith, Albert Vernon %A Visscher, Peter M %A Yang, Jian %A McCarroll, Steven A %A Nemesh, James %A Voight, Benjamin F %A Absher, Devin %A Amin, Najaf %A Aspelund, Thor %A Coin, Lachlan %A Glazer, Nicole L %A Hayward, Caroline %A Heard-Costa, Nancy L %A Hottenga, Jouke-Jan %A Johansson, Asa %A Johnson, Toby %A Kaakinen, Marika %A Kapur, Karen %A Ketkar, Shamika %A Knowles, Joshua W %A Kraft, Peter %A Kraja, Aldi T %A Lamina, Claudia %A Leitzmann, Michael F %A McKnight, Barbara %A Morris, Andrew P %A Ong, Ken K %A Perry, John R B %A Peters, Marjolein J %A Polasek, Ozren %A Prokopenko, Inga %A Rayner, Nigel W %A Ripatti, Samuli %A Rivadeneira, Fernando %A Robertson, Neil R %A Sanna, Serena %A Sovio, Ulla %A Surakka, Ida %A Teumer, Alexander %A van Wingerden, Sophie %A Vitart, Veronique %A Zhao, Jing Hua %A Cavalcanti-Proença, Christine %A Chines, Peter S %A Fisher, Eva %A Kulzer, Jennifer R %A Lecoeur, Cécile %A Narisu, Narisu %A Sandholt, Camilla %A Scott, Laura J %A Silander, Kaisa %A Stark, Klaus %A Tammesoo, Mari-Liis %A Teslovich, Tanya M %A Timpson, Nicholas John %A Watanabe, Richard M %A Welch, Ryan %A Chasman, Daniel I %A Cooper, Matthew N %A Jansson, John-Olov %A Kettunen, Johannes %A Lawrence, Robert W %A Pellikka, Niina %A Perola, Markus %A Vandenput, Liesbeth %A Alavere, Helene %A Almgren, Peter %A Atwood, Larry D %A Bennett, Amanda J %A Biffar, Reiner %A Bonnycastle, Lori L %A Bornstein, Stefan R %A Buchanan, Thomas A %A Campbell, Harry %A Day, Ian N M %A Dei, Mariano %A Dörr, Marcus %A Elliott, Paul %A Erdos, Michael R %A Eriksson, Johan G %A Freimer, Nelson B %A Fu, Mao %A Gaget, Stefan %A Geus, Eco J C %A Gjesing, Anette P %A Grallert, Harald %A Grässler, Jürgen %A Groves, Christopher J %A Guiducci, Candace %A Hartikainen, Anna-Liisa %A Hassanali, Neelam %A Havulinna, Aki S %A Herzig, Karl-Heinz %A Hicks, Andrew A %A Hui, Jennie %A Igl, Wilmar %A Jousilahti, Pekka %A Jula, Antti %A Kajantie, Eero %A Kinnunen, Leena %A Kolcic, Ivana %A Koskinen, Seppo %A Kovacs, Peter %A Kroemer, Heyo K %A Krzelj, Vjekoslav %A Kuusisto, Johanna %A Kvaloy, Kirsti %A Laitinen, Jaana %A Lantieri, Olivier %A Lathrop, G Mark %A Lokki, Marja-Liisa %A Luben, Robert N %A Ludwig, Barbara %A McArdle, Wendy L %A McCarthy, Anne %A Morken, Mario A %A Nelis, Mari %A Neville, Matt J %A Paré, Guillaume %A Parker, Alex N %A Peden, John F %A Pichler, Irene %A Pietiläinen, Kirsi H %A Platou, Carl G P %A Pouta, Anneli %A Ridderstråle, Martin %A Samani, Nilesh J %A Saramies, Jouko %A Sinisalo, Juha %A Smit, Jan H %A Strawbridge, Rona J %A Stringham, Heather M %A Swift, Amy J %A Teder-Laving, Maris %A Thomson, Brian %A Usala, Gianluca %A van Meurs, Joyce B J %A van Ommen, Gert-Jan %A Vatin, Vincent %A Volpato, Claudia B %A Wallaschofski, Henri %A Walters, G Bragi %A Widen, Elisabeth %A Wild, Sarah H %A Willemsen, Gonneke %A Witte, Daniel R %A Zgaga, Lina %A Zitting, Paavo %A Beilby, John P %A James, Alan L %A Kähönen, Mika %A Lehtimäki, Terho %A Nieminen, Markku S %A Ohlsson, Claes %A Palmer, Lyle J %A Raitakari, Olli %A Ridker, Paul M %A Stumvoll, Michael %A Tönjes, Anke %A Viikari, Jorma %A Balkau, Beverley %A Ben-Shlomo, Yoav %A Bergman, Richard N %A Boeing, Heiner %A Smith, George Davey %A Ebrahim, Shah %A Froguel, Philippe %A Hansen, Torben %A Hengstenberg, Christian %A Hveem, Kristian %A Isomaa, Bo %A Jørgensen, Torben %A Karpe, Fredrik %A Khaw, Kay-Tee %A Laakso, Markku %A Lawlor, Debbie A %A Marre, Michel %A Meitinger, Thomas %A Metspalu, Andres %A Midthjell, Kristian %A Pedersen, Oluf %A Salomaa, Veikko %A Schwarz, Peter E H %A Tuomi, Tiinamaija %A Tuomilehto, Jaakko %A Valle, Timo T %A Wareham, Nicholas J %A Arnold, Alice M %A Beckmann, Jacques S %A Bergmann, Sven %A Boerwinkle, Eric %A Boomsma, Dorret I %A Caulfield, Mark J %A Collins, Francis S %A Eiriksdottir, Gudny %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Hamsten, Anders %A Hattersley, Andrew T %A Hofman, Albert %A Hu, Frank B %A Illig, Thomas %A Iribarren, Carlos %A Jarvelin, Marjo-Riitta %A Kao, W H Linda %A Kaprio, Jaakko %A Launer, Lenore J %A Munroe, Patricia B %A Oostra, Ben %A Penninx, Brenda W %A Pramstaller, Peter P %A Psaty, Bruce M %A Quertermous, Thomas %A Rissanen, Aila %A Rudan, Igor %A Shuldiner, Alan R %A Soranzo, Nicole %A Spector, Timothy D %A Syvänen, Ann-Christine %A Uda, Manuela %A Uitterlinden, Andre %A Völzke, Henry %A Vollenweider, Peter %A Wilson, James F %A Witteman, Jacqueline C %A Wright, Alan F %A Abecasis, Goncalo R %A Boehnke, Michael %A Borecki, Ingrid B %A Deloukas, Panos %A Frayling, Timothy M %A Groop, Leif C %A Haritunians, Talin %A Hunter, David J %A Kaplan, Robert C %A North, Kari E %A O'Connell, Jeffrey R %A Peltonen, Leena %A Schlessinger, David %A Strachan, David P %A Hirschhorn, Joel N %A Assimes, Themistocles L %A Wichmann, H-Erich %A Thorsteinsdottir, Unnur %A van Duijn, Cornelia M %A Stefansson, Kari %A Cupples, L Adrienne %A Loos, Ruth J F %A Barroso, Inês %A McCarthy, Mark I %A Fox, Caroline S %A Mohlke, Karen L %A Lindgren, Cecilia M %K Adipose Tissue %K Age Factors %K Chromosome Mapping %K Female %K Genome, Human %K Genome-Wide Association Study %K Humans %K Male %K Meta-Analysis as Topic %K Polymorphism, Single Nucleotide %K Sex Characteristics %K Waist-Hip Ratio %X

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

%B Nat Genet %V 42 %P 949-60 %8 2010 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/20935629?dopt=Abstract %R 10.1038/ng.685 %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 Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function. %A Soler Artigas, Maria %A Loth, Daan W %A Wain, Louise V %A Gharib, Sina A %A Obeidat, Ma'en %A Tang, Wenbo %A Zhai, Guangju %A Zhao, Jing Hua %A Smith, Albert Vernon %A Huffman, Jennifer E %A Albrecht, Eva %A Jackson, Catherine M %A Evans, David M %A Cadby, Gemma %A Fornage, Myriam %A Manichaikul, Ani %A Lopez, Lorna M %A Johnson, Toby %A Aldrich, Melinda C %A Aspelund, Thor %A Barroso, Inês %A Campbell, Harry %A Cassano, Patricia A %A Couper, David J %A Eiriksdottir, Gudny %A Franceschini, Nora %A Garcia, Melissa %A Gieger, Christian %A Gislason, Gauti Kjartan %A Grkovic, Ivica %A Hammond, Christopher J %A Hancock, Dana B %A Harris, Tamara B %A Ramasamy, Adaikalavan %A Heckbert, Susan R %A Heliövaara, Markku %A Homuth, Georg %A Hysi, Pirro G %A James, Alan L %A Jankovic, Stipan %A Joubert, Bonnie R %A Karrasch, Stefan %A Klopp, Norman %A Koch, Beate %A Kritchevsky, Stephen B %A Launer, Lenore J %A Liu, Yongmei %A Loehr, Laura R %A Lohman, Kurt %A Loos, Ruth J F %A Lumley, Thomas %A Al Balushi, Khalid A %A Ang, Wei Q %A Barr, R Graham %A Beilby, John %A Blakey, John D %A Boban, Mladen %A Boraska, Vesna %A Brisman, Jonas %A Britton, John R %A Brusselle, Guy G %A Cooper, Cyrus %A Curjuric, Ivan %A Dahgam, Santosh %A Deary, Ian J %A Ebrahim, Shah %A Eijgelsheim, Mark %A Francks, Clyde %A Gaysina, Darya %A Granell, Raquel %A Gu, Xiangjun %A Hankinson, John L %A Hardy, Rebecca %A Harris, Sarah E %A Henderson, John %A Henry, Amanda %A Hingorani, Aroon D %A Hofman, Albert %A Holt, Patrick G %A Hui, Jennie %A Hunter, Michael L %A Imboden, Medea %A Jameson, Karen A %A Kerr, Shona M %A Kolcic, Ivana %A Kronenberg, Florian %A Liu, Jason Z %A Marchini, Jonathan %A McKeever, Tricia %A Morris, Andrew D %A Olin, Anna-Carin %A Porteous, David J %A Postma, Dirkje S %A Rich, Stephen S %A Ring, Susan M %A Rivadeneira, Fernando %A Rochat, Thierry %A Sayer, Avan Aihie %A Sayers, Ian %A Sly, Peter D %A Smith, George Davey %A Sood, Akshay %A Starr, John M %A Uitterlinden, André G %A Vonk, Judith M %A Wannamethee, S Goya %A Whincup, Peter H %A Wijmenga, Cisca %A Williams, O Dale %A Wong, Andrew %A Mangino, Massimo %A Marciante, Kristin D %A McArdle, Wendy L %A Meibohm, Bernd %A Morrison, Alanna C %A North, Kari E %A Omenaas, Ernst %A Palmer, Lyle J %A Pietiläinen, Kirsi H %A Pin, Isabelle %A Pola Sbreve Ek, Ozren %A Pouta, Anneli %A Psaty, Bruce M %A Hartikainen, Anna-Liisa %A Rantanen, Taina %A Ripatti, Samuli %A Rotter, Jerome I %A Rudan, Igor %A Rudnicka, Alicja R %A Schulz, Holger %A Shin, So-Youn %A Spector, Tim D %A Surakka, Ida %A Vitart, Veronique %A Völzke, Henry %A Wareham, Nicholas J %A Warrington, Nicole M %A Wichmann, H-Erich %A Wild, Sarah H %A Wilk, Jemma B %A Wjst, Matthias %A Wright, Alan F %A Zgaga, Lina %A Zemunik, Tatijana %A Pennell, Craig E %A Nyberg, Fredrik %A Kuh, Diana %A Holloway, John W %A Boezen, H Marike %A Lawlor, Debbie A %A Morris, Richard W %A Probst-Hensch, Nicole %A Kaprio, Jaakko %A Wilson, James F %A Hayward, Caroline %A Kähönen, Mika %A Heinrich, Joachim %A Musk, Arthur W %A Jarvis, Deborah L %A Gläser, Sven %A Jarvelin, Marjo-Riitta %A Ch Stricker, Bruno H %A Elliott, Paul %A O'Connor, George T %A Strachan, David P %A London, Stephanie J %A Hall, Ian P %A Gudnason, Vilmundur %A Tobin, Martin D %K Child %K European Continental Ancestry Group %K Genome-Wide Association Study %K Humans %K Pulmonary Disease, Chronic Obstructive %K Respiratory Function Tests %X

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

%B Nat Genet %V 43 %P 1082-90 %8 2011 Sep 25 %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/21946350?dopt=Abstract %R 10.1038/ng.941 %0 Journal Article %J Nature %D 2012 %T FTO genotype is associated with phenotypic variability of body mass index. %A Yang, Jian %A Loos, Ruth J F %A Powell, Joseph E %A Medland, Sarah E %A Speliotes, Elizabeth K %A Chasman, Daniel I %A Rose, Lynda M %A Thorleifsson, Gudmar %A Steinthorsdottir, Valgerdur %A Mägi, Reedik %A Waite, Lindsay %A Smith, Albert Vernon %A Yerges-Armstrong, Laura M %A Monda, Keri L %A Hadley, David %A Mahajan, Anubha %A Li, Guo %A Kapur, Karen %A Vitart, Veronique %A Huffman, Jennifer E %A Wang, Sophie R %A Palmer, Cameron %A Esko, Tõnu %A Fischer, Krista %A Zhao, Jing Hua %A Demirkan, Ayse %A Isaacs, Aaron %A Feitosa, Mary F %A Luan, Jian'an %A Heard-Costa, Nancy L %A White, Charles %A Jackson, Anne U %A Preuss, Michael %A Ziegler, Andreas %A Eriksson, Joel %A Kutalik, Zoltán %A Frau, Francesca %A Nolte, Ilja M %A van Vliet-Ostaptchouk, Jana V %A Hottenga, Jouke-Jan %A Jacobs, Kevin B %A Verweij, Niek %A Goel, Anuj %A Medina-Gómez, Carolina %A Estrada, Karol %A Bragg-Gresham, Jennifer Lynn %A Sanna, Serena %A Sidore, Carlo %A Tyrer, Jonathan %A Teumer, Alexander %A Prokopenko, Inga %A Mangino, Massimo %A Lindgren, Cecilia M %A Assimes, Themistocles L %A Shuldiner, Alan R %A Hui, Jennie %A Beilby, John P %A McArdle, Wendy L %A Hall, Per %A Haritunians, Talin %A Zgaga, Lina %A Kolcic, Ivana %A Polasek, Ozren %A Zemunik, Tatijana %A Oostra, Ben A %A Junttila, M Juhani %A Grönberg, Henrik %A Schreiber, Stefan %A Peters, Annette %A Hicks, Andrew A %A Stephens, Jonathan %A Foad, Nicola S %A Laitinen, Jaana %A Pouta, Anneli %A Kaakinen, Marika %A Willemsen, Gonneke %A Vink, Jacqueline M %A Wild, Sarah H %A Navis, Gerjan %A Asselbergs, Folkert W %A Homuth, Georg %A John, Ulrich %A Iribarren, Carlos %A Harris, Tamara %A Launer, Lenore %A Gudnason, Vilmundur %A O'Connell, Jeffrey R %A Boerwinkle, Eric %A Cadby, Gemma %A Palmer, Lyle J %A James, Alan L %A Musk, Arthur W %A Ingelsson, Erik %A Psaty, Bruce M %A Beckmann, Jacques S %A Waeber, Gérard %A Vollenweider, Peter %A Hayward, Caroline %A Wright, Alan F %A Rudan, Igor %A Groop, Leif C %A Metspalu, Andres %A Khaw, Kay Tee %A van Duijn, Cornelia M %A Borecki, Ingrid B %A Province, Michael A %A Wareham, Nicholas J %A Tardif, Jean-Claude %A Huikuri, Heikki V %A Cupples, L Adrienne %A Atwood, Larry D %A Fox, Caroline S %A Boehnke, Michael %A Collins, Francis S %A Mohlke, Karen L %A Erdmann, Jeanette %A Schunkert, Heribert %A Hengstenberg, Christian %A Stark, Klaus %A Lorentzon, Mattias %A Ohlsson, Claes %A Cusi, Daniele %A Staessen, Jan A %A van der Klauw, Melanie M %A Pramstaller, Peter P %A Kathiresan, Sekar %A Jolley, Jennifer D %A Ripatti, Samuli %A Jarvelin, Marjo-Riitta %A de Geus, Eco J C %A Boomsma, Dorret I %A Penninx, Brenda %A Wilson, James F %A Campbell, Harry %A Chanock, Stephen J %A van der Harst, Pim %A Hamsten, Anders %A Watkins, Hugh %A Hofman, Albert %A Witteman, Jacqueline C %A Zillikens, M Carola %A Uitterlinden, André G %A Rivadeneira, Fernando %A Zillikens, M Carola %A Kiemeney, Lambertus A %A Vermeulen, Sita H %A Abecasis, Goncalo R %A Schlessinger, David %A Schipf, Sabine %A Stumvoll, Michael %A Tönjes, Anke %A Spector, Tim D %A North, Kari E %A Lettre, Guillaume %A McCarthy, Mark I %A Berndt, Sonja I %A Heath, Andrew C %A Madden, Pamela A F %A Nyholt, Dale R %A Montgomery, Grant W %A Martin, Nicholas G %A McKnight, Barbara %A Strachan, David P %A Hill, William G %A Snieder, Harold %A Ridker, Paul M %A Thorsteinsdottir, Unnur %A Stefansson, Kari %A Frayling, Timothy M %A Hirschhorn, Joel N %A Goddard, Michael E %A Visscher, Peter M %K Alpha-Ketoglutarate-Dependent Dioxygenase FTO %K Body Height %K Body Mass Index %K Co-Repressor Proteins %K Female %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Male %K Nerve Tissue Proteins %K Phenotype %K Polymorphism, Single Nucleotide %K Proteins %K Repressor Proteins %X

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

%B Nature %V 490 %P 267-72 %8 2012 Oct 11 %G eng %N 7419 %1 http://www.ncbi.nlm.nih.gov/pubmed/22982992?dopt=Abstract %R 10.1038/nature11401 %0 Journal Article %J Am J Respir Crit Care Med %D 2012 %T Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction. %A Wilk, Jemma B %A Shrine, Nick R G %A Loehr, Laura R %A Zhao, Jing Hua %A Manichaikul, Ani %A Lopez, Lorna M %A Smith, Albert Vernon %A Heckbert, Susan R %A Smolonska, Joanna %A Tang, Wenbo %A Loth, Daan W %A Curjuric, Ivan %A Hui, Jennie %A Cho, Michael H %A Latourelle, Jeanne C %A Henry, Amanda P %A Aldrich, Melinda %A Bakke, Per %A Beaty, Terri H %A Bentley, Amy R %A Borecki, Ingrid B %A Brusselle, Guy G %A Burkart, Kristin M %A Chen, Ting-Hsu %A Couper, David %A Crapo, James D %A Davies, Gail %A Dupuis, Josée %A Franceschini, Nora %A Gulsvik, Amund %A Hancock, Dana B %A Harris, Tamara B %A Hofman, Albert %A Imboden, Medea %A James, Alan L %A Khaw, Kay-Tee %A Lahousse, Lies %A Launer, Lenore J %A Litonjua, Augusto %A Liu, Yongmei %A Lohman, Kurt K %A Lomas, David A %A Lumley, Thomas %A Marciante, Kristin D %A McArdle, Wendy L %A Meibohm, Bernd %A Morrison, Alanna C %A Musk, Arthur W %A Myers, Richard H %A North, Kari E %A Postma, Dirkje S %A Psaty, Bruce M %A Rich, Stephen S %A Rivadeneira, Fernando %A Rochat, Thierry %A Rotter, Jerome I %A Soler Artigas, Maria %A Starr, John M %A Uitterlinden, André G %A Wareham, Nicholas J %A Wijmenga, Cisca %A Zanen, Pieter %A Province, Michael A %A Silverman, Edwin K %A Deary, Ian J %A Palmer, Lyle J %A Cassano, Patricia A %A Gudnason, Vilmundur %A Barr, R Graham %A Loos, Ruth J F %A Strachan, David P %A London, Stephanie J %A Boezen, H Marike %A Probst-Hensch, Nicole %A Gharib, Sina A %A Hall, Ian P %A O'Connor, George T %A Tobin, Martin D %A Stricker, Bruno H %K Aged %K Female %K Forced Expiratory Volume %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Nerve Tissue Proteins %K Polymorphism, Single Nucleotide %K Pulmonary Disease, Chronic Obstructive %K Receptors, Nicotinic %K Receptors, Serotonin, 5-HT4 %K Smoking %K Vital Capacity %X

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

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

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

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

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

%B Am J Respir Crit Care Med %V 186 %P 622-32 %8 2012 Oct 01 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/22837378?dopt=Abstract %R 10.1164/rccm.201202-0366OC %0 Journal Article %J PLoS One %D 2013 %T Genetic loci for retinal arteriolar microcirculation. %A Sim, Xueling %A Jensen, Richard A %A Ikram, M Kamran %A Cotch, Mary Frances %A Li, Xiaohui %A Macgregor, Stuart %A Xie, Jing %A Smith, Albert Vernon %A Boerwinkle, Eric %A Mitchell, Paul %A Klein, Ronald %A Klein, Barbara E K %A Glazer, Nicole L %A Lumley, Thomas %A McKnight, Barbara %A Psaty, Bruce M %A de Jong, Paulus T V M %A Hofman, Albert %A Rivadeneira, Fernando %A Uitterlinden, André G %A van Duijn, Cornelia M %A Aspelund, Thor %A Eiriksdottir, Gudny %A Harris, Tamara B %A Jonasson, Fridbert %A Launer, Lenore J %A Attia, John %A Baird, Paul N %A Harrap, Stephen %A Holliday, Elizabeth G %A Inouye, Michael %A Rochtchina, Elena %A Scott, Rodney J %A Viswanathan, Ananth %A Li, Guo %A Smith, Nicholas L %A Wiggins, Kerri L %A Kuo, Jane Z %A Taylor, Kent D %A Hewitt, Alex W %A Martin, Nicholas G %A Montgomery, Grant W %A Sun, Cong %A Young, Terri L %A Mackey, David A %A van Zuydam, Natalie R %A Doney, Alex S F %A Palmer, Colin N A %A Morris, Andrew D %A Rotter, Jerome I %A Tai, E Shyong %A Gudnason, Vilmundur %A Vingerling, Johannes R %A Siscovick, David S %A Wang, Jie Jin %A Wong, Tien Y %K Aged %K Aged, 80 and over %K Arterioles %K Chromosomes, Human, Pair 5 %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K MEF2 Transcription Factors %K Microcirculation %K Middle Aged %K Models, Genetic %K Retinal Vessels %X

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10(-8). This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10(-12) in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.

%B PLoS One %V 8 %P e65804 %8 2013 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23776548?dopt=Abstract %R 10.1371/journal.pone.0065804 %0 Journal Article %J PLoS One %D 2013 %T Genome-wide association study of retinopathy in individuals without diabetes. %A Jensen, Richard A %A Sim, Xueling %A Li, Xiaohui %A Cotch, Mary Frances %A Ikram, M Kamran %A Holliday, Elizabeth G %A Eiriksdottir, Gudny %A Harris, Tamara B %A Jonasson, Fridbert %A Klein, Barbara E K %A Launer, Lenore J %A Smith, Albert Vernon %A Boerwinkle, Eric %A Cheung, Ning %A Hewitt, Alex W %A Liew, Gerald %A Mitchell, Paul %A Wang, Jie Jin %A Attia, John %A Scott, Rodney %A Glazer, Nicole L %A Lumley, Thomas %A McKnight, Barbara %A Psaty, Bruce M %A Taylor, Kent %A Hofman, Albert %A de Jong, Paulus T V M %A Rivadeneira, Fernando %A Uitterlinden, André G %A Tay, Wan-Ting %A Teo, Yik Ying %A Seielstad, Mark %A Liu, Jianjun %A Cheng, Ching-Yu %A Saw, Seang-Mei %A Aung, Tin %A Ganesh, Santhi K %A O'Donnell, Christopher J %A Nalls, Mike A %A Wiggins, Kerri L %A Kuo, Jane Z %A van Duijn, Cornelia M %A Gudnason, Vilmundur %A Klein, Ronald %A Siscovick, David S %A Rotter, Jerome I %A Tai, E Shong %A Vingerling, Johannes %A Wong, Tien Y %K Aged %K Aged, 80 and over %K Female %K Genome-Wide Association Study %K Genotype %K Histone Deacetylases %K Humans %K Hypertension %K Male %K Polymorphism, Single Nucleotide %K Repressor Proteins %K Retinal Diseases %X

BACKGROUND: Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes.

METHODS: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy.

RESULTS: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3±0.23 (beta ± standard error), p = 6.6×10(-9). Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r(2) ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension.

CONCLUSIONS: This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.

%B PLoS One %V 8 %P e54232 %8 2013 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23393555?dopt=Abstract %R 10.1371/journal.pone.0054232 %0 Journal Article %J Nat Genet %D 2013 %T Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. %A Berndt, Sonja I %A Gustafsson, Stefan %A Mägi, Reedik %A Ganna, Andrea %A Wheeler, Eleanor %A Feitosa, Mary F %A Justice, Anne E %A Monda, Keri L %A Croteau-Chonka, Damien C %A Day, Felix R %A Esko, Tõnu %A Fall, Tove %A Ferreira, Teresa %A Gentilini, Davide %A Jackson, Anne U %A Luan, Jian'an %A Randall, Joshua C %A Vedantam, Sailaja %A Willer, Cristen J %A Winkler, Thomas W %A Wood, Andrew R %A Workalemahu, Tsegaselassie %A Hu, Yi-Juan %A Lee, Sang Hong %A Liang, Liming %A Lin, Dan-Yu %A Min, Josine L %A Neale, Benjamin M %A Thorleifsson, Gudmar %A Yang, Jian %A Albrecht, Eva %A Amin, Najaf %A Bragg-Gresham, Jennifer L %A Cadby, Gemma %A den Heijer, Martin %A Eklund, Niina %A Fischer, Krista %A Goel, Anuj %A Hottenga, Jouke-Jan %A Huffman, Jennifer E %A Jarick, Ivonne %A Johansson, Asa %A Johnson, Toby %A Kanoni, Stavroula %A Kleber, Marcus E %A König, Inke R %A Kristiansson, Kati %A Kutalik, Zoltán %A Lamina, Claudia %A Lecoeur, Cécile %A Li, Guo %A Mangino, Massimo %A McArdle, Wendy L %A Medina-Gómez, Carolina %A Müller-Nurasyid, Martina %A Ngwa, Julius S %A Nolte, Ilja M %A Paternoster, Lavinia %A Pechlivanis, Sonali %A Perola, Markus %A Peters, Marjolein J %A Preuss, Michael %A Rose, Lynda M %A Shi, Jianxin %A Shungin, Dmitry %A Smith, Albert Vernon %A Strawbridge, Rona J %A Surakka, Ida %A Teumer, Alexander %A Trip, Mieke D %A Tyrer, Jonathan %A van Vliet-Ostaptchouk, Jana V %A Vandenput, Liesbeth %A Waite, Lindsay L %A Zhao, Jing Hua %A Absher, Devin %A Asselbergs, Folkert W %A Atalay, Mustafa %A Attwood, Antony P %A Balmforth, Anthony J %A Basart, Hanneke %A Beilby, John %A Bonnycastle, Lori L %A Brambilla, Paolo %A Bruinenberg, Marcel %A Campbell, Harry %A Chasman, Daniel I %A Chines, Peter S %A Collins, Francis S %A Connell, John M %A Cookson, William O %A de Faire, Ulf %A de Vegt, Femmie %A Dei, Mariano %A Dimitriou, Maria %A Edkins, Sarah %A Estrada, Karol %A Evans, David M %A Farrall, Martin %A Ferrario, Marco M %A Ferrieres, Jean %A Franke, Lude %A Frau, Francesca %A Gejman, Pablo V %A Grallert, Harald %A Grönberg, Henrik %A Gudnason, Vilmundur %A Hall, Alistair S %A Hall, Per %A Hartikainen, Anna-Liisa %A Hayward, Caroline %A Heard-Costa, Nancy L %A Heath, Andrew C %A Hebebrand, Johannes %A Homuth, Georg %A Hu, Frank B %A Hunt, Sarah E %A Hyppönen, Elina %A Iribarren, Carlos %A Jacobs, Kevin B %A Jansson, John-Olov %A Jula, Antti %A Kähönen, Mika %A Kathiresan, Sekar %A Kee, Frank %A Khaw, Kay-Tee %A Kivimaki, Mika %A Koenig, Wolfgang %A Kraja, Aldi T %A Kumari, Meena %A Kuulasmaa, Kari %A Kuusisto, Johanna %A Laitinen, Jaana H %A Lakka, Timo A %A Langenberg, Claudia %A Launer, Lenore J %A Lind, Lars %A Lindström, Jaana %A Liu, Jianjun %A Liuzzi, Antonio %A Lokki, Marja-Liisa %A Lorentzon, Mattias %A Madden, Pamela A %A Magnusson, Patrik K %A Manunta, Paolo %A Marek, Diana %A März, Winfried %A Mateo Leach, Irene %A McKnight, Barbara %A Medland, Sarah E %A Mihailov, Evelin %A Milani, Lili %A Montgomery, Grant W %A Mooser, Vincent %A Mühleisen, Thomas W %A Munroe, Patricia B %A Musk, Arthur W %A Narisu, Narisu %A Navis, Gerjan %A Nicholson, George %A Nohr, Ellen A %A Ong, Ken K %A Oostra, Ben A %A Palmer, Colin N A %A Palotie, Aarno %A Peden, John F %A Pedersen, Nancy %A Peters, Annette %A Polasek, Ozren %A Pouta, Anneli %A Pramstaller, Peter P %A Prokopenko, Inga %A Pütter, Carolin %A Radhakrishnan, Aparna %A Raitakari, Olli %A Rendon, Augusto %A Rivadeneira, Fernando %A Rudan, Igor %A Saaristo, Timo E %A Sambrook, Jennifer G %A Sanders, Alan R %A Sanna, Serena %A Saramies, Jouko %A Schipf, Sabine %A Schreiber, Stefan %A Schunkert, Heribert %A Shin, So-Youn %A Signorini, Stefano %A Sinisalo, Juha %A Skrobek, Boris %A Soranzo, Nicole %A Stančáková, Alena %A Stark, Klaus %A Stephens, Jonathan C %A Stirrups, Kathleen %A Stolk, Ronald P %A Stumvoll, Michael %A Swift, Amy J %A Theodoraki, Eirini V %A Thorand, Barbara %A Trégouët, David-Alexandre %A Tremoli, Elena %A van der Klauw, Melanie M %A van Meurs, Joyce B J %A Vermeulen, Sita H %A Viikari, Jorma %A Virtamo, Jarmo %A Vitart, Veronique %A Waeber, Gérard %A Wang, Zhaoming %A Widen, Elisabeth %A Wild, Sarah H %A Willemsen, Gonneke %A Winkelmann, Bernhard R %A Witteman, Jacqueline C M %A Wolffenbuttel, Bruce H R %A Wong, Andrew %A Wright, Alan F %A Zillikens, M Carola %A Amouyel, Philippe %A Boehm, Bernhard O %A Boerwinkle, Eric %A Boomsma, Dorret I %A Caulfield, Mark J %A Chanock, Stephen J %A Cupples, L Adrienne %A Cusi, Daniele %A Dedoussis, George V %A Erdmann, Jeanette %A Eriksson, Johan G %A Franks, Paul W %A Froguel, Philippe %A Gieger, Christian %A Gyllensten, Ulf %A Hamsten, Anders %A Harris, Tamara B %A Hengstenberg, Christian %A Hicks, Andrew A %A Hingorani, Aroon %A Hinney, Anke %A Hofman, Albert %A Hovingh, Kees G %A Hveem, Kristian %A Illig, Thomas %A Jarvelin, Marjo-Riitta %A Jöckel, Karl-Heinz %A Keinanen-Kiukaanniemi, Sirkka M %A Kiemeney, Lambertus A %A Kuh, Diana %A Laakso, Markku %A Lehtimäki, Terho %A Levinson, Douglas F %A Martin, Nicholas G %A Metspalu, Andres %A Morris, Andrew D %A Nieminen, Markku S %A Njølstad, Inger %A Ohlsson, Claes %A Oldehinkel, Albertine J %A Ouwehand, Willem H %A Palmer, Lyle J %A Penninx, Brenda %A Power, Chris %A Province, Michael A %A Psaty, Bruce M %A Qi, Lu %A Rauramaa, Rainer %A Ridker, Paul M %A Ripatti, Samuli %A Salomaa, Veikko %A Samani, Nilesh J %A Snieder, Harold %A Sørensen, Thorkild I A %A Spector, Timothy D %A Stefansson, Kari %A Tönjes, Anke %A Tuomilehto, Jaakko %A Uitterlinden, André G %A Uusitupa, Matti %A van der Harst, Pim %A Vollenweider, Peter %A Wallaschofski, Henri %A Wareham, Nicholas J %A Watkins, Hugh %A Wichmann, H-Erich %A Wilson, James F %A Abecasis, Goncalo R %A Assimes, Themistocles L %A Barroso, Inês %A Boehnke, Michael %A Borecki, Ingrid B %A Deloukas, Panos %A Fox, Caroline S %A Frayling, Timothy %A Groop, Leif C %A Haritunian, Talin %A Heid, Iris M %A Hunter, David %A Kaplan, Robert C %A Karpe, Fredrik %A Moffatt, Miriam F %A Mohlke, Karen L %A O'Connell, Jeffrey R %A Pawitan, Yudi %A Schadt, Eric E %A Schlessinger, David %A Steinthorsdottir, Valgerdur %A Strachan, David P %A Thorsteinsdottir, Unnur %A van Duijn, Cornelia M %A Visscher, Peter M %A Di Blasio, Anna Maria %A Hirschhorn, Joel N %A Lindgren, Cecilia M %A Morris, Andrew P %A Meyre, David %A Scherag, Andre %A McCarthy, Mark I %A Speliotes, Elizabeth K %A North, Kari E %A Loos, Ruth J F %A Ingelsson, Erik %K Anthropometry %K Body Height %K Body Mass Index %K Case-Control Studies %K European Continental Ancestry Group %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Meta-Analysis as Topic %K Obesity %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Waist-Hip Ratio %X

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

%B Nat Genet %V 45 %P 501-12 %8 2013 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/23563607?dopt=Abstract %R 10.1038/ng.2606 %0 Journal Article %J PLoS Genet %D 2013 %T Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits. %A Randall, Joshua C %A Winkler, Thomas W %A Kutalik, Zoltán %A Berndt, Sonja I %A Jackson, Anne U %A Monda, Keri L %A Kilpeläinen, Tuomas O %A Esko, Tõnu %A Mägi, Reedik %A Li, Shengxu %A Workalemahu, Tsegaselassie %A Feitosa, Mary F %A Croteau-Chonka, Damien C %A Day, Felix R %A Fall, Tove %A Ferreira, Teresa %A Gustafsson, Stefan %A Locke, Adam E %A Mathieson, Iain %A Scherag, Andre %A Vedantam, Sailaja %A Wood, Andrew R %A Liang, Liming %A Steinthorsdottir, Valgerdur %A Thorleifsson, Gudmar %A Dermitzakis, Emmanouil T %A Dimas, Antigone S %A Karpe, Fredrik %A Min, Josine L %A Nicholson, George %A Clegg, Deborah J %A Person, Thomas %A Krohn, Jon P %A Bauer, Sabrina %A Buechler, Christa %A Eisinger, Kristina %A Bonnefond, Amélie %A Froguel, Philippe %A Hottenga, Jouke-Jan %A Prokopenko, Inga %A Waite, Lindsay L %A Harris, Tamara B %A Smith, Albert Vernon %A Shuldiner, Alan R %A McArdle, Wendy L %A Caulfield, Mark J %A Munroe, Patricia B %A Grönberg, Henrik %A Chen, Yii-Der Ida %A Li, Guo %A Beckmann, Jacques S %A Johnson, Toby %A Thorsteinsdottir, Unnur %A Teder-Laving, Maris %A Khaw, Kay-Tee %A Wareham, Nicholas J %A Zhao, Jing Hua %A Amin, Najaf %A Oostra, Ben A %A Kraja, Aldi T %A Province, Michael A %A Cupples, L Adrienne %A Heard-Costa, Nancy L %A Kaprio, Jaakko %A Ripatti, Samuli %A Surakka, Ida %A Collins, Francis S %A Saramies, Jouko %A Tuomilehto, Jaakko %A Jula, Antti %A Salomaa, Veikko %A Erdmann, Jeanette %A Hengstenberg, Christian %A Loley, Christina %A Schunkert, Heribert %A Lamina, Claudia %A Wichmann, H Erich %A Albrecht, Eva %A Gieger, Christian %A Hicks, Andrew A %A Johansson, Asa %A Pramstaller, Peter P %A Kathiresan, Sekar %A Speliotes, Elizabeth K %A Penninx, Brenda %A Hartikainen, Anna-Liisa %A Jarvelin, Marjo-Riitta %A Gyllensten, Ulf %A Boomsma, Dorret I %A Campbell, Harry %A Wilson, James F %A Chanock, Stephen J %A Farrall, Martin %A Goel, Anuj %A Medina-Gómez, Carolina %A Rivadeneira, Fernando %A Estrada, Karol %A Uitterlinden, André G %A Hofman, Albert %A Zillikens, M Carola %A den Heijer, Martin %A Kiemeney, Lambertus A %A Maschio, Andrea %A Hall, Per %A Tyrer, Jonathan %A Teumer, Alexander %A Völzke, Henry %A Kovacs, Peter %A Tönjes, Anke %A Mangino, Massimo %A Spector, Tim D %A Hayward, Caroline %A Rudan, Igor %A Hall, Alistair S %A Samani, Nilesh J %A Attwood, Antony Paul %A Sambrook, Jennifer G %A Hung, Joseph %A Palmer, Lyle J %A Lokki, Marja-Liisa %A Sinisalo, Juha %A Boucher, Gabrielle %A Huikuri, Heikki %A Lorentzon, Mattias %A Ohlsson, Claes %A Eklund, Niina %A Eriksson, Johan G %A Barlassina, Cristina %A Rivolta, Carlo %A Nolte, Ilja M %A Snieder, Harold %A van der Klauw, Melanie M %A van Vliet-Ostaptchouk, Jana V %A Gejman, Pablo V %A Shi, Jianxin %A Jacobs, Kevin B %A Wang, Zhaoming %A Bakker, Stephan J L %A Mateo Leach, Irene %A Navis, Gerjan %A van der Harst, Pim %A Martin, Nicholas G %A Medland, Sarah E %A Montgomery, Grant W %A Yang, Jian %A Chasman, Daniel I %A Ridker, Paul M %A Rose, Lynda M %A Lehtimäki, Terho %A Raitakari, Olli %A Absher, Devin %A Iribarren, Carlos %A Basart, Hanneke %A Hovingh, Kees G %A Hyppönen, Elina %A Power, Chris %A Anderson, Denise %A Beilby, John P %A Hui, Jennie %A Jolley, Jennifer %A Sager, Hendrik %A Bornstein, Stefan R %A Schwarz, Peter E H %A Kristiansson, Kati %A Perola, Markus %A Lindström, Jaana %A Swift, Amy J %A Uusitupa, Matti %A Atalay, Mustafa %A Lakka, Timo A %A Rauramaa, Rainer %A Bolton, Jennifer L %A Fowkes, Gerry %A Fraser, Ross M %A Price, Jackie F %A Fischer, Krista %A Krjutå Kov, Kaarel %A Metspalu, Andres %A Mihailov, Evelin %A Langenberg, Claudia %A Luan, Jian'an %A Ong, Ken K %A Chines, Peter S %A Keinanen-Kiukaanniemi, Sirkka M %A Saaristo, Timo E %A Edkins, Sarah %A Franks, Paul W %A Hallmans, Göran %A Shungin, Dmitry %A Morris, Andrew David %A Palmer, Colin N A %A Erbel, Raimund %A Moebus, Susanne %A Nöthen, Markus M %A Pechlivanis, Sonali %A Hveem, Kristian %A Narisu, Narisu %A Hamsten, Anders %A Humphries, Steve E %A Strawbridge, Rona J %A Tremoli, Elena %A Grallert, Harald %A Thorand, Barbara %A Illig, Thomas %A Koenig, Wolfgang %A Müller-Nurasyid, Martina %A Peters, Annette %A Boehm, Bernhard O %A Kleber, Marcus E %A März, Winfried %A Winkelmann, Bernhard R %A Kuusisto, Johanna %A Laakso, Markku %A Arveiler, Dominique %A Cesana, Giancarlo %A Kuulasmaa, Kari %A Virtamo, Jarmo %A Yarnell, John W G %A Kuh, Diana %A Wong, Andrew %A Lind, Lars %A de Faire, Ulf %A Gigante, Bruna %A Magnusson, Patrik K E %A Pedersen, Nancy L %A Dedoussis, George %A Dimitriou, Maria %A Kolovou, Genovefa %A Kanoni, Stavroula %A Stirrups, Kathleen %A Bonnycastle, Lori L %A Njølstad, Inger %A Wilsgaard, Tom %A Ganna, Andrea %A Rehnberg, Emil %A Hingorani, Aroon %A Kivimaki, Mika %A Kumari, Meena %A Assimes, Themistocles L %A Barroso, Inês %A Boehnke, Michael %A Borecki, Ingrid B %A Deloukas, Panos %A Fox, Caroline S %A Frayling, Timothy %A Groop, Leif C %A Haritunians, Talin %A Hunter, David %A Ingelsson, Erik %A Kaplan, Robert %A Mohlke, Karen L %A O'Connell, Jeffrey R %A Schlessinger, David %A Strachan, David P %A Stefansson, Kari %A van Duijn, Cornelia M %A Abecasis, Goncalo R %A McCarthy, Mark I %A Hirschhorn, Joel N %A Qi, Lu %A Loos, Ruth J F %A Lindgren, Cecilia M %A North, Kari E %A Heid, Iris M %K Anthropometry %K Body Height %K Body Mass Index %K Body Weight %K Body Weights and Measures %K Female %K Genetic Loci %K Genome, Human %K Genome-Wide Association Study %K Humans %K Male %K Polymorphism, Single Nucleotide %K Sex Characteristics %K Waist Circumference %K Waist-Hip Ratio %X

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

%B PLoS Genet %V 9 %P e1003500 %8 2013 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23754948?dopt=Abstract %R 10.1371/journal.pgen.1003500 %0 Journal Article %J Nat Genet %D 2014 %T Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. %A Arking, Dan E %A Pulit, Sara L %A Crotti, Lia %A van der Harst, Pim %A Munroe, Patricia B %A Koopmann, Tamara T %A Sotoodehnia, Nona %A Rossin, Elizabeth J %A Morley, Michael %A Wang, Xinchen %A Johnson, Andrew D %A Lundby, Alicia %A Gudbjartsson, Daniel F %A Noseworthy, Peter A %A Eijgelsheim, Mark %A Bradford, Yuki %A Tarasov, Kirill V %A Dörr, Marcus %A Müller-Nurasyid, Martina %A Lahtinen, Annukka M %A Nolte, Ilja M %A Smith, Albert Vernon %A Bis, Joshua C %A Isaacs, Aaron %A Newhouse, Stephen J %A Evans, Daniel S %A Post, Wendy S %A Waggott, Daryl %A Lyytikäinen, Leo-Pekka %A Hicks, Andrew A %A Eisele, Lewin %A Ellinghaus, David %A Hayward, Caroline %A Navarro, Pau %A Ulivi, Sheila %A Tanaka, Toshiko %A Tester, David J %A Chatel, Stéphanie %A Gustafsson, Stefan %A Kumari, Meena %A Morris, Richard W %A Naluai, Åsa T %A Padmanabhan, Sandosh %A Kluttig, Alexander %A Strohmer, Bernhard %A Panayiotou, Andrie G %A Torres, Maria %A Knoflach, Michael %A Hubacek, Jaroslav A %A Slowikowski, Kamil %A Raychaudhuri, Soumya %A Kumar, Runjun D %A Harris, Tamara B %A Launer, Lenore J %A Shuldiner, Alan R %A Alonso, Alvaro %A Bader, Joel S %A Ehret, Georg %A Huang, Hailiang %A Kao, W H Linda %A Strait, James B %A Macfarlane, Peter W %A Brown, Morris %A Caulfield, Mark J %A Samani, Nilesh J %A Kronenberg, Florian %A Willeit, Johann %A Smith, J Gustav %A Greiser, Karin H %A Meyer Zu Schwabedissen, Henriette %A Werdan, Karl %A Carella, Massimo %A Zelante, Leopoldo %A Heckbert, Susan R %A Psaty, Bruce M %A Rotter, Jerome I %A Kolcic, Ivana %A Polasek, Ozren %A Wright, Alan F %A Griffin, Maura %A Daly, Mark J %A Arnar, David O %A Holm, Hilma %A Thorsteinsdottir, Unnur %A Denny, Joshua C %A Roden, Dan M %A Zuvich, Rebecca L %A Emilsson, Valur %A Plump, Andrew S %A Larson, Martin G %A O'Donnell, Christopher J %A Yin, Xiaoyan %A Bobbo, Marco %A D'Adamo, Adamo P %A Iorio, Annamaria %A Sinagra, Gianfranco %A Carracedo, Angel %A Cummings, Steven R %A Nalls, Michael A %A Jula, Antti %A Kontula, Kimmo K %A Marjamaa, Annukka %A Oikarinen, Lasse %A Perola, Markus %A Porthan, Kimmo %A Erbel, Raimund %A Hoffmann, Per %A Jöckel, Karl-Heinz %A Kälsch, Hagen %A Nöthen, Markus M %A den Hoed, Marcel %A Loos, Ruth J F %A Thelle, Dag S %A Gieger, Christian %A Meitinger, Thomas %A Perz, Siegfried %A Peters, Annette %A Prucha, Hanna %A Sinner, Moritz F %A Waldenberger, Melanie %A de Boer, Rudolf A %A Franke, Lude %A van der Vleuten, Pieter A %A Beckmann, Britt Maria %A Martens, Eimo %A Bardai, Abdennasser %A Hofman, Nynke %A Wilde, Arthur A M %A Behr, Elijah R %A Dalageorgou, Chrysoula %A Giudicessi, John R %A Medeiros-Domingo, Argelia %A Barc, Julien %A Kyndt, Florence %A Probst, Vincent %A Ghidoni, Alice %A Insolia, Roberto %A Hamilton, Robert M %A Scherer, Stephen W %A Brandimarto, Jeffrey %A Margulies, Kenneth %A Moravec, Christine E %A del Greco M, Fabiola %A Fuchsberger, Christian %A O'Connell, Jeffrey R %A Lee, Wai K %A Watt, Graham C M %A Campbell, Harry %A Wild, Sarah H %A El Mokhtari, Nour E %A Frey, Norbert %A Asselbergs, Folkert W %A Mateo Leach, Irene %A Navis, Gerjan %A van den Berg, Maarten P %A van Veldhuisen, Dirk J %A Kellis, Manolis %A Krijthe, Bouwe P %A Franco, Oscar H %A Hofman, Albert %A Kors, Jan A %A Uitterlinden, André G %A Witteman, Jacqueline C M %A Kedenko, Lyudmyla %A Lamina, Claudia %A Oostra, Ben A %A Abecasis, Goncalo R %A Lakatta, Edward G %A Mulas, Antonella %A Orrù, Marco %A Schlessinger, David %A Uda, Manuela %A Markus, Marcello R P %A Völker, Uwe %A Snieder, Harold %A Spector, Timothy D %A Arnlöv, Johan %A Lind, Lars %A Sundström, Johan %A Syvänen, Ann-Christine %A Kivimaki, Mika %A Kähönen, Mika %A Mononen, Nina %A Raitakari, Olli T %A Viikari, Jorma S %A Adamkova, Vera %A Kiechl, Stefan %A Brion, Maria %A Nicolaides, Andrew N %A Paulweber, Bernhard %A Haerting, Johannes %A Dominiczak, Anna F %A Nyberg, Fredrik %A Whincup, Peter H %A Hingorani, Aroon D %A Schott, Jean-Jacques %A Bezzina, Connie R %A Ingelsson, Erik %A Ferrucci, Luigi %A Gasparini, Paolo %A Wilson, James F %A Rudan, Igor %A Franke, Andre %A Mühleisen, Thomas W %A Pramstaller, Peter P %A Lehtimäki, Terho J %A Paterson, Andrew D %A Parsa, Afshin %A Liu, Yongmei %A van Duijn, Cornelia M %A Siscovick, David S %A Gudnason, Vilmundur %A Jamshidi, Yalda %A Salomaa, Veikko %A Felix, Stephan B %A Sanna, Serena %A Ritchie, Marylyn D %A Stricker, Bruno H %A Stefansson, Kari %A Boyer, Laurie A %A Cappola, Thomas P %A Olsen, Jesper V %A Lage, Kasper %A Schwartz, Peter J %A Kääb, Stefan %A Chakravarti, Aravinda %A Ackerman, Michael J %A Pfeufer, Arne %A de Bakker, Paul I W %A Newton-Cheh, Christopher %K Adult %K Aged %K Arrhythmias, Cardiac %K Calcium Signaling %K Death, Sudden, Cardiac %K Electrocardiography %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Heart Ventricles %K Humans %K Long QT Syndrome %K Male %K Middle Aged %K Myocardium %K Polymorphism, Single Nucleotide %X

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

%B Nat Genet %V 46 %P 826-36 %8 2014 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/24952745?dopt=Abstract %R 10.1038/ng.3014 %0 Journal Article %J BMC Genet %D 2014 %T Genetic diversity is a predictor of mortality in humans. %A Bihlmeyer, Nathan A %A Brody, Jennifer A %A Smith, Albert Vernon %A Lunetta, Kathryn L %A Nalls, Mike %A Smith, Jennifer A %A Tanaka, Toshiko %A Davies, Gail %A Yu, Lei %A Mirza, Saira Saeed %A Teumer, Alexander %A Coresh, Josef %A Pankow, James S %A Franceschini, Nora %A Scaria, Anish %A Oshima, Junko %A Psaty, Bruce M %A Gudnason, Vilmundur %A Eiriksdottir, Gudny %A Harris, Tamara B %A Li, Hanyue %A Karasik, David %A Kiel, Douglas P %A Garcia, Melissa %A Liu, Yongmei %A Faul, Jessica D %A Kardia, Sharon Lr %A Zhao, Wei %A Ferrucci, Luigi %A Allerhand, Michael %A Liewald, David C %A Redmond, Paul %A Starr, John M %A De Jager, Philip L %A Evans, Denis A %A Direk, Nese %A Ikram, Mohammed Arfan %A Uitterlinden, Andre %A Homuth, Georg %A Lorbeer, Roberto %A Grabe, Hans J %A Launer, Lenore %A Murabito, Joanne M %A Singleton, Andrew B %A Weir, David R %A Bandinelli, Stefania %A Deary, Ian J %A Bennett, David A %A Tiemeier, Henning %A Kocher, Thomas %A Lumley, Thomas %A Arking, Dan E %K Genome-Wide Association Study %K Heterozygote %K Humans %K Mortality %K Polymorphism, Single Nucleotide %K Proportional Hazards Models %X

BACKGROUND: It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic diversity provides a survival advantage. However, given the limitations of both sample size and genome-wide metrics, this hypothesis has not been comprehensively tested in human populations. Moreover, the presence of numerous segregating small effect alleles that influence traits that directly impact health directly raises the question as to whether global measures of genomic variation are themselves associated with human health and disease.

RESULTS: We performed a meta-analysis of 17 cohorts followed prospectively, with a combined sample size of 46,716 individuals, including a total of 15,234 deaths. We find a significant association between increased heterozygosity and survival (P = 0.03). We estimate that within a single population, every standard deviation of heterozygosity an individual has over the mean decreases that person's risk of death by 1.57%.

CONCLUSIONS: This effect was consistent between European and African ancestry cohorts, men and women, and major causes of death (cancer and cardiovascular disease), demonstrating the broad positive impact of genomic diversity on human survival.

%B BMC Genet %V 15 %P 159 %8 2014 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/25543667?dopt=Abstract %R 10.1186/s12863-014-0159-7 %0 Journal Article %J Nat Genet %D 2014 %T Genome-wide association analysis identifies six new loci associated with forced vital capacity. %A Loth, Daan W %A Soler Artigas, Maria %A Gharib, Sina A %A Wain, Louise V %A Franceschini, Nora %A Koch, Beate %A Pottinger, Tess D %A Smith, Albert Vernon %A Duan, Qing %A Oldmeadow, Chris %A Lee, Mi Kyeong %A Strachan, David P %A James, Alan L %A Huffman, Jennifer E %A Vitart, Veronique %A Ramasamy, Adaikalavan %A Wareham, Nicholas J %A Kaprio, Jaakko %A Wang, Xin-Qun %A Trochet, Holly %A Kähönen, Mika %A Flexeder, Claudia %A Albrecht, Eva %A Lopez, Lorna M %A de Jong, Kim %A Thyagarajan, Bharat %A Alves, Alexessander Couto %A Enroth, Stefan %A Omenaas, Ernst %A Joshi, Peter K %A Fall, Tove %A Viñuela, Ana %A Launer, Lenore J %A Loehr, Laura R %A Fornage, Myriam %A Li, Guo %A Wilk, Jemma B %A Tang, Wenbo %A Manichaikul, Ani %A Lahousse, Lies %A Harris, Tamara B %A North, Kari E %A Rudnicka, Alicja R %A Hui, Jennie %A Gu, Xiangjun %A Lumley, Thomas %A Wright, Alan F %A Hastie, Nicholas D %A Campbell, Susan %A Kumar, Rajesh %A Pin, Isabelle %A Scott, Robert A %A Pietiläinen, Kirsi H %A Surakka, Ida %A Liu, Yongmei %A Holliday, Elizabeth G %A Schulz, Holger %A Heinrich, Joachim %A Davies, Gail %A Vonk, Judith M %A Wojczynski, Mary %A Pouta, Anneli %A Johansson, Asa %A Wild, Sarah H %A Ingelsson, Erik %A Rivadeneira, Fernando %A Völzke, Henry %A Hysi, Pirro G %A Eiriksdottir, Gudny %A Morrison, Alanna C %A Rotter, Jerome I %A Gao, Wei %A Postma, Dirkje S %A White, Wendy B %A Rich, Stephen S %A Hofman, Albert %A Aspelund, Thor %A Couper, David %A Smith, Lewis J %A Psaty, Bruce M %A Lohman, Kurt %A Burchard, Esteban G %A Uitterlinden, André G %A Garcia, Melissa %A Joubert, Bonnie R %A McArdle, Wendy L %A Musk, A Bill %A Hansel, Nadia %A Heckbert, Susan R %A Zgaga, Lina %A van Meurs, Joyce B J %A Navarro, Pau %A Rudan, Igor %A Oh, Yeon-Mok %A Redline, Susan %A Jarvis, Deborah L %A Zhao, Jing Hua %A Rantanen, Taina %A O'Connor, George T %A Ripatti, Samuli %A Scott, Rodney J %A Karrasch, Stefan %A Grallert, Harald %A Gaddis, Nathan C %A Starr, John M %A Wijmenga, Cisca %A Minster, Ryan L %A Lederer, David J %A Pekkanen, Juha %A Gyllensten, Ulf %A Campbell, Harry %A Morris, Andrew P %A Gläser, Sven %A Hammond, Christopher J %A Burkart, Kristin M %A Beilby, John %A Kritchevsky, Stephen B %A Gudnason, Vilmundur %A Hancock, Dana B %A Williams, O Dale %A Polasek, Ozren %A Zemunik, Tatijana %A Kolcic, Ivana %A Petrini, Marcy F %A Wjst, Matthias %A Kim, Woo Jin %A Porteous, David J %A Scotland, Generation %A Smith, Blair H %A Viljanen, Anne %A Heliövaara, Markku %A Attia, John R %A Sayers, Ian %A Hampel, Regina %A Gieger, Christian %A Deary, Ian J %A Boezen, H Marike %A Newman, Anne %A Jarvelin, Marjo-Riitta %A Wilson, James F %A Lind, Lars %A Stricker, Bruno H %A Teumer, Alexander %A Spector, Timothy D %A Melén, Erik %A Peters, Marjolein J %A Lange, Leslie A %A Barr, R Graham %A Bracke, Ken R %A Verhamme, Fien M %A Sung, Joohon %A Hiemstra, Pieter S %A Cassano, Patricia A %A Sood, Akshay %A Hayward, Caroline %A Dupuis, Josée %A Hall, Ian P %A Brusselle, Guy G %A Tobin, Martin D %A London, Stephanie J %K Cohort Studies %K Databases, Genetic %K Follow-Up Studies %K Forced Expiratory Volume %K Genetic Loci %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Humans %K Lung Diseases %K Meta-Analysis as Topic %K Polymorphism, Single Nucleotide %K Prognosis %K Quantitative Trait Loci %K Respiratory Function Tests %K Spirometry %K Vital Capacity %X

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

%B Nat Genet %V 46 %P 669-77 %8 2014 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/24929828?dopt=Abstract %R 10.1038/ng.3011 %0 Journal Article %J Neurobiol Aging %D 2015 %T Association of Alzheimer's disease GWAS loci with MRI markers of brain aging. %A Chauhan, Ganesh %A Adams, Hieab H H %A Bis, Joshua C %A Weinstein, Galit %A Yu, Lei %A Töglhofer, Anna Maria %A Smith, Albert Vernon %A van der Lee, Sven J %A Gottesman, Rebecca F %A Thomson, Russell %A Wang, Jing %A Yang, Qiong %A Niessen, Wiro J %A Lopez, Oscar L %A Becker, James T %A Phan, Thanh G %A Beare, Richard J %A Arfanakis, Konstantinos %A Fleischman, Debra %A Vernooij, Meike W %A Mazoyer, Bernard %A Schmidt, Helena %A Srikanth, Velandai %A Knopman, David S %A Jack, Clifford R %A Amouyel, Philippe %A Hofman, Albert %A DeCarli, Charles %A Tzourio, Christophe %A van Duijn, Cornelia M %A Bennett, David A %A Schmidt, Reinhold %A Longstreth, William T %A Mosley, Thomas H %A Fornage, Myriam %A Launer, Lenore J %A Seshadri, Sudha %A Ikram, M Arfan %A Debette, Stephanie %K Aging %K Alleles %K Alzheimer Disease %K Apolipoproteins E %K Brain %K Female %K Genome-Wide Association Study %K Hippocampus %K Humans %K Magnetic Resonance Imaging %K Male %K Organ Size %K Polymorphism, Single Nucleotide %K Risk %K Sialic Acid Binding Ig-like Lectin 3 %X

Whether novel risk variants of Alzheimer's disease (AD) identified through genome-wide association studies also influence magnetic resonance imaging-based intermediate phenotypes of AD in the general population is unclear. We studied association of 24 AD risk loci with intracranial volume, total brain volume, hippocampal volume (HV), white matter hyperintensity burden, and brain infarcts in a meta-analysis of genetic association studies from large population-based samples (N = 8175-11,550). In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (p = 0.0054) and CD33 (rs3865444) with smaller intracranial volume (p = 0.0058). In gene-based tests, there was associations of HLA-DRB1 with total brain volume (p = 0.0006) and BIN1 with HV (p = 0.00089). A weighted AD genetic risk score was associated with smaller HV (beta ± SE = -0.047 ± 0.013, p = 0.00041), even after excluding the APOE locus (p = 0.029). However, only association of AD genetic risk score with HV, including APOE, was significant after multiple testing correction (including number of independent phenotypes tested). These results suggest that novel AD genetic risk variants may contribute to structural brain aging in nondemented older community persons.

%B Neurobiol Aging %V 36 %P 1765.e7-16 %8 2015 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/25670335?dopt=Abstract %R 10.1016/j.neurobiolaging.2014.12.028 %0 Journal Article %J PLoS One %D 2015 %T Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium. %A Bis, Joshua C %A Sitlani, Colleen %A Irvin, Ryan %A Avery, Christy L %A Smith, Albert Vernon %A Sun, Fangui %A Evans, Daniel S %A Musani, Solomon K %A Li, Xiaohui %A Trompet, Stella %A Krijthe, Bouwe P %A Harris, Tamara B %A Quibrera, P Miguel %A Brody, Jennifer A %A Demissie, Serkalem %A Davis, Barry R %A Wiggins, Kerri L %A Tranah, Gregory J %A Lange, Leslie A %A Sotoodehnia, Nona %A Stott, David J %A Franco, Oscar H %A Launer, Lenore J %A Stürmer, Til %A Taylor, Kent D %A Cupples, L Adrienne %A Eckfeldt, John H %A Smith, Nicholas L %A Liu, Yongmei %A Wilson, James G %A Heckbert, Susan R %A Buckley, Brendan M %A Ikram, M Arfan %A Boerwinkle, Eric %A Chen, Yii-Der Ida %A de Craen, Anton J M %A Uitterlinden, André G %A Rotter, Jerome I %A Ford, Ian %A Hofman, Albert %A Sattar, Naveed %A Slagboom, P Eline %A Westendorp, Rudi G J %A Gudnason, Vilmundur %A Vasan, Ramachandran S %A Lumley, Thomas %A Cummings, Steven R %A Taylor, Herman A %A Post, Wendy %A Jukema, J Wouter %A Stricker, Bruno H %A Whitsel, Eric A %A Psaty, Bruce M %A Arnett, Donna %K African Americans %K Aged %K Antihypertensive Agents %K Cardiovascular Diseases %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Hypertension %K Incidence %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Treatment Outcome %X

BACKGROUND: Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.

METHODS: Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).

RESULTS: Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.

%B PLoS One %V 10 %P e0140496 %8 2015 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/26516778?dopt=Abstract %R 10.1371/journal.pone.0140496 %0 Journal Article %J Hum Mol Genet %D 2015 %T Integrative pathway genomics of lung function and airflow obstruction. %A Gharib, Sina A %A Loth, Daan W %A Soler Artigas, Maria %A Birkland, Timothy P %A Wilk, Jemma B %A Wain, Louise V %A Brody, Jennifer A %A Obeidat, Ma'en %A Hancock, Dana B %A Tang, Wenbo %A Rawal, Rajesh %A Boezen, H Marike %A Imboden, Medea %A Huffman, Jennifer E %A Lahousse, Lies %A Alves, Alexessander C %A Manichaikul, Ani %A Hui, Jennie %A Morrison, Alanna C %A Ramasamy, Adaikalavan %A Smith, Albert Vernon %A Gudnason, Vilmundur %A Surakka, Ida %A Vitart, Veronique %A Evans, David M %A Strachan, David P %A Deary, Ian J %A Hofman, Albert %A Gläser, Sven %A Wilson, James F %A North, Kari E %A Zhao, Jing Hua %A Heckbert, Susan R %A Jarvis, Deborah L %A Probst-Hensch, Nicole %A Schulz, Holger %A Barr, R Graham %A Jarvelin, Marjo-Riitta %A O'Connor, George T %A Kähönen, Mika %A Cassano, Patricia A %A Hysi, Pirro G %A Dupuis, Josée %A Hayward, Caroline %A Psaty, Bruce M %A Hall, Ian P %A Parks, William C %A Tobin, Martin D %A London, Stephanie J %K Airway Obstruction %K Animals %K Cell Proliferation %K European Continental Ancestry Group %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genomics %K Humans %K Immune System %K Lung %K Male %K Metabolic Networks and Pathways %K Mice %K Phenotype %K Polymorphism, Single Nucleotide %K Signal Transduction %X

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

%B Hum Mol Genet %V 24 %P 6836-48 %8 2015 Dec 1 %G eng %N 23 %1 http://www.ncbi.nlm.nih.gov/pubmed/26395457?dopt=Abstract %R 10.1093/hmg/ddv378 %0 Journal Article %J Am J Hum Genet %D 2016 %T Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits. %A Chami, Nathalie %A Chen, Ming-Huei %A Slater, Andrew J %A Eicher, John D %A Evangelou, Evangelos %A Tajuddin, Salman M %A Love-Gregory, Latisha %A Kacprowski, Tim %A Schick, Ursula M %A Nomura, Akihiro %A Giri, Ayush %A Lessard, Samuel %A Brody, Jennifer A %A Schurmann, Claudia %A Pankratz, Nathan %A Yanek, Lisa R %A Manichaikul, Ani %A Pazoki, Raha %A Mihailov, Evelin %A Hill, W David %A Raffield, Laura M %A Burt, Amber %A Bartz, Traci M %A Becker, Diane M %A Becker, Lewis C %A Boerwinkle, Eric %A Bork-Jensen, Jette %A Bottinger, Erwin P %A O'Donoghue, Michelle L %A Crosslin, David R %A de Denus, Simon %A Dubé, Marie-Pierre %A Elliott, Paul %A Engström, Gunnar %A Evans, Michele K %A Floyd, James S %A Fornage, Myriam %A Gao, He %A Greinacher, Andreas %A Gudnason, Vilmundur %A Hansen, Torben %A Harris, Tamara B %A Hayward, Caroline %A Hernesniemi, Jussi %A Highland, Heather M %A Hirschhorn, Joel N %A Hofman, Albert %A Irvin, Marguerite R %A Kähönen, Mika %A Lange, Ethan %A Launer, Lenore J %A Lehtimäki, Terho %A Li, Jin %A Liewald, David C M %A Linneberg, Allan %A Liu, Yongmei %A Lu, Yingchang %A Lyytikäinen, Leo-Pekka %A Mägi, Reedik %A Mathias, Rasika A %A Melander, Olle %A Metspalu, Andres %A Mononen, Nina %A Nalls, Mike A %A Nickerson, Deborah A %A Nikus, Kjell %A O'Donnell, Chris J %A Orho-Melander, Marju %A Pedersen, Oluf %A Petersmann, Astrid %A Polfus, Linda %A Psaty, Bruce M %A Raitakari, Olli T %A Raitoharju, Emma %A Richard, Melissa %A Rice, Kenneth M %A Rivadeneira, Fernando %A Rotter, Jerome I %A Schmidt, Frank %A Smith, Albert Vernon %A Starr, John M %A Taylor, Kent D %A Teumer, Alexander %A Thuesen, Betina H %A Torstenson, Eric S %A Tracy, Russell P %A Tzoulaki, Ioanna %A Zakai, Neil A %A Vacchi-Suzzi, Caterina %A van Duijn, Cornelia M %A van Rooij, Frank J A %A Cushman, Mary %A Deary, Ian J %A Velez Edwards, Digna R %A Vergnaud, Anne-Claire %A Wallentin, Lars %A Waterworth, Dawn M %A White, Harvey D %A Wilson, James G %A Zonderman, Alan B %A Kathiresan, Sekar %A Grarup, Niels %A Esko, Tõnu %A Loos, Ruth J F %A Lange, Leslie A %A Faraday, Nauder %A Abumrad, Nada A %A Edwards, Todd L %A Ganesh, Santhi K %A Auer, Paul L %A Johnson, Andrew D %A Reiner, Alexander P %A Lettre, Guillaume %X

Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.

%B Am J Hum Genet %V 99 %P 8-21 %8 2016 Jul 7 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27346685?dopt=Abstract %R 10.1016/j.ajhg.2016.05.007 %0 Journal Article %J PLoS One %D 2016 %T Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium. %A Dehghan, Abbas %A Bis, Joshua C %A White, Charles C %A Smith, Albert Vernon %A Morrison, Alanna C %A Cupples, L Adrienne %A Trompet, Stella %A Chasman, Daniel I %A Lumley, Thomas %A Völker, Uwe %A Buckley, Brendan M %A Ding, Jingzhong %A Jensen, Majken K %A Folsom, Aaron R %A Kritchevsky, Stephen B %A Girman, Cynthia J %A Ford, Ian %A Dörr, Marcus %A Salomaa, Veikko %A Uitterlinden, André G %A Eiriksdottir, Gudny %A Vasan, Ramachandran S %A Franceschini, Nora %A Carty, Cara L %A Virtamo, Jarmo %A Demissie, Serkalem %A Amouyel, Philippe %A Arveiler, Dominique %A Heckbert, Susan R %A Ferrieres, Jean %A Ducimetiere, Pierre %A Smith, Nicholas L %A Wang, Ying A %A Siscovick, David S %A Rice, Kenneth M %A Wiklund, Per-Gunnar %A Taylor, Kent D %A Evans, Alun %A Kee, Frank %A Rotter, Jerome I %A Karvanen, Juha %A Kuulasmaa, Kari %A Heiss, Gerardo %A Kraft, Peter %A Launer, Lenore J %A Hofman, Albert %A Markus, Marcello R P %A Rose, Lynda M %A Silander, Kaisa %A Wagner, Peter %A Benjamin, Emelia J %A Lohman, Kurt %A Stott, David J %A Rivadeneira, Fernando %A Harris, Tamara B %A Levy, Daniel %A Liu, Yongmei %A Rimm, Eric B %A Jukema, J Wouter %A Völzke, Henry %A Ridker, Paul M %A Blankenberg, Stefan %A Franco, Oscar H %A Gudnason, Vilmundur %A Psaty, Bruce M %A Boerwinkle, Eric %A O'Donnell, Christopher J %K Aged %K Cohort Studies %K Cooperative Behavior %K Coronary Artery Disease %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Myocardial Infarction %K Polymorphism, Single Nucleotide %K Prospective Studies %X

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

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

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

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

%B PLoS One %V 11 %P e0144997 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26950853?dopt=Abstract %R 10.1371/journal.pone.0144997 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2016 %T KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference. %A Schumann, Gunter %A Liu, Chunyu %A O'Reilly, Paul %A Gao, He %A Song, Parkyong %A Xu, Bing %A Ruggeri, Barbara %A Amin, Najaf %A Jia, Tianye %A Preis, Sarah %A Segura Lepe, Marcelo %A Akira, Shizuo %A Barbieri, Caterina %A Baumeister, Sebastian %A Cauchi, Stephane %A Clarke, Toni-Kim %A Enroth, Stefan %A Fischer, Krista %A Hällfors, Jenni %A Harris, Sarah E %A Hieber, Saskia %A Hofer, Edith %A Hottenga, Jouke-Jan %A Johansson, Asa %A Joshi, Peter K %A Kaartinen, Niina %A Laitinen, Jaana %A Lemaitre, Rozenn %A Loukola, Anu %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A Mangino, Massimo %A Manichaikul, Ani %A Mbarek, Hamdi %A Milaneschi, Yuri %A Moayyeri, Alireza %A Mukamal, Kenneth %A Nelson, Christopher %A Nettleton, Jennifer %A Partinen, Eemil %A Rawal, Rajesh %A Robino, Antonietta %A Rose, Lynda %A Sala, Cinzia %A Satoh, Takashi %A Schmidt, Reinhold %A Schraut, Katharina %A Scott, Robert %A Smith, Albert Vernon %A Starr, John M %A Teumer, Alexander %A Trompet, Stella %A Uitterlinden, André G %A Venturini, Cristina %A Vergnaud, Anne-Claire %A Verweij, Niek %A Vitart, Veronique %A Vuckovic, Dragana %A Wedenoja, Juho %A Yengo, Loic %A Yu, Bing %A Zhang, Weihua %A Zhao, Jing Hua %A Boomsma, Dorret I %A Chambers, John %A Chasman, Daniel I %A Daniela, Toniolo %A de Geus, Eco %A Deary, Ian %A Eriksson, Johan G %A Esko, Tõnu %A Eulenburg, Volker %A Franco, Oscar H %A Froguel, Philippe %A Gieger, Christian %A Grabe, Hans J %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Harris, Tamara B %A Hartikainen, Anna-Liisa %A Heath, Andrew C %A Hocking, Lynne %A Hofman, Albert %A Huth, Cornelia %A Jarvelin, Marjo-Riitta %A Jukema, J Wouter %A Kaprio, Jaakko %A Kooner, Jaspal S %A Kutalik, Zoltán %A Lahti, Jari %A Langenberg, Claudia %A Lehtimäki, Terho %A Liu, Yongmei %A Madden, Pamela A F %A Martin, Nicholas %A Morrison, Alanna %A Penninx, Brenda %A Pirastu, Nicola %A Psaty, Bruce %A Raitakari, Olli %A Ridker, Paul %A Rose, Richard %A Rotter, Jerome I %A Samani, Nilesh J %A Schmidt, Helena %A Spector, Tim D %A Stott, David %A Strachan, David %A Tzoulaki, Ioanna %A van der Harst, Pim %A van Duijn, Cornelia M %A Marques-Vidal, Pedro %A Vollenweider, Peter %A Wareham, Nicholas J %A Whitfield, John B %A Wilson, James %A Wolffenbuttel, Bruce %A Bakalkin, Georgy %A Evangelou, Evangelos %A Liu, Yun %A Rice, Kenneth M %A Desrivières, Sylvane %A Kliewer, Steven A %A Mangelsdorf, David J %A Müller, Christian P %A Levy, Daniel %A Elliott, Paul %X

Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified β-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10(-12)). β-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific β-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.

%B Proc Natl Acad Sci U S A %V 113 %P 14372-14377 %8 2016 Dec 13 %G eng %N 50 %R 10.1073/pnas.1611243113 %0 Journal Article %J Am J Hum Genet %D 2016 %T Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases. %A Tajuddin, Salman M %A Schick, Ursula M %A Eicher, John D %A Chami, Nathalie %A Giri, Ayush %A Brody, Jennifer A %A Hill, W David %A Kacprowski, Tim %A Li, Jin %A Lyytikäinen, Leo-Pekka %A Manichaikul, Ani %A Mihailov, Evelin %A O'Donoghue, Michelle L %A Pankratz, Nathan %A Pazoki, Raha %A Polfus, Linda M %A Smith, Albert Vernon %A Schurmann, Claudia %A Vacchi-Suzzi, Caterina %A Waterworth, Dawn M %A Evangelou, Evangelos %A Yanek, Lisa R %A Burt, Amber %A Chen, Ming-Huei %A van Rooij, Frank J A %A Floyd, James S %A Greinacher, Andreas %A Harris, Tamara B %A Highland, Heather M %A Lange, Leslie A %A Liu, Yongmei %A Mägi, Reedik %A Nalls, Mike A %A Mathias, Rasika A %A Nickerson, Deborah A %A Nikus, Kjell %A Starr, John M %A Tardif, Jean-Claude %A Tzoulaki, Ioanna %A Velez Edwards, Digna R %A Wallentin, Lars %A Bartz, Traci M %A Becker, Lewis C %A Denny, Joshua C %A Raffield, Laura M %A Rioux, John D %A Friedrich, Nele %A Fornage, Myriam %A Gao, He %A Hirschhorn, Joel N %A Liewald, David C M %A Rich, Stephen S %A Uitterlinden, Andre %A Bastarache, Lisa %A Becker, Diane M %A Boerwinkle, Eric %A de Denus, Simon %A Bottinger, Erwin P %A Hayward, Caroline %A Hofman, Albert %A Homuth, Georg %A Lange, Ethan %A Launer, Lenore J %A Lehtimäki, Terho %A Lu, Yingchang %A Metspalu, Andres %A O'Donnell, Chris J %A Quarells, Rakale C %A Richard, Melissa %A Torstenson, Eric S %A Taylor, Kent D %A Vergnaud, Anne-Claire %A Zonderman, Alan B %A Crosslin, David R %A Deary, Ian J %A Dörr, Marcus %A Elliott, Paul %A Evans, Michele K %A Gudnason, Vilmundur %A Kähönen, Mika %A Psaty, Bruce M %A Rotter, Jerome I %A Slater, Andrew J %A Dehghan, Abbas %A White, Harvey D %A Ganesh, Santhi K %A Loos, Ruth J F %A Esko, Tõnu %A Faraday, Nauder %A Wilson, James G %A Cushman, Mary %A Johnson, Andrew D %A Edwards, Todd L %A Zakai, Neil A %A Lettre, Guillaume %A Reiner, Alex P %A Auer, Paul L %X

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

%B Am J Hum Genet %V 99 %P 22-39 %8 2016 Jul 7 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27346689?dopt=Abstract %R 10.1016/j.ajhg.2016.05.003 %0 Journal Article %J Circ Cardiovasc Genet %D 2016 %T Novel Genetic Loci Associated With Retinal Microvascular Diameter. %A Jensen, Richard A %A Sim, Xueling %A Smith, Albert Vernon %A Li, Xiaohui %A Jakobsdottir, Johanna %A Cheng, Ching-Yu %A Brody, Jennifer A %A Cotch, Mary Frances %A McKnight, Barbara %A Klein, Ronald %A Wang, Jie Jin %A Kifley, Annette %A Harris, Tamara B %A Launer, Lenore J %A Taylor, Kent D %A Klein, Barbara E K %A Raffel, Leslie J %A Li, Xiang %A Ikram, M Arfan %A Klaver, Caroline C %A van der Lee, Sven J %A Mutlu, Unal %A Hofman, Albert %A Uitterlinden, André G %A Liu, Chunyu %A Kraja, Aldi T %A Mitchell, Paul %A Gudnason, Vilmundur %A Rotter, Jerome I %A Boerwinkle, Eric %A van Duijn, Cornelia M %A Psaty, Bruce M %A Wong, Tien Y %X

BACKGROUND: There is increasing evidence that retinal microvascular diameters are associated with cardiovascular and cerebrovascular conditions. The shared genetic effects of these associations are currently unknown. The aim of this study was to increase our understanding of the genetic factors that mediate retinal vessel size.

METHODS AND RESULTS: This study extends previous genome-wide association study results using 24 000+ multiethnic participants from 7 discovery cohorts and 5000+ subjects of European ancestry from 2 replication cohorts. Using the Illumina HumanExome BeadChip, we investigate the association of single-nucleotide polymorphisms and variants collectively across genes with summary measures of retinal vessel diameters, referred to as the central retinal venule equivalent and the central retinal arteriole equivalent. We report 4 new loci associated with central retinal venule equivalent, one of which is also associated with central retinal arteriole equivalent. The 4 single-nucleotide polymorphisms are rs7926971 in TEAD1 (P=3.1×10(-) (11); minor allele frequency=0.43), rs201259422 in TSPAN10 (P=4.4×10(-9); minor allele frequency=0.27), rs5442 in GNB3 (P=7.0×10(-10); minor allele frequency=0.05), and rs1800407 in OCA2 (P=3.4×10(-8); minor allele frequency=0.05). The latter single-nucleotide polymorphism, rs1800407, was also associated with central retinal arteriole equivalent (P=6.5×10(-12)). Results from the gene-based burden tests were null. In phenotype look-ups, single-nucleotide polymorphism rs201255422 was associated with both systolic (P=0.001) and diastolic blood pressures (P=8.3×10(-04)).

CONCLUSIONS: Our study expands the understanding of genetic factors influencing the size of the retinal microvasculature. These findings may also provide insight into the relationship between retinal and systemic microvascular disease.

%B Circ Cardiovasc Genet %V 9 %P 45-54 %8 2016 Feb %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26567291?dopt=Abstract %R 10.1161/CIRCGENETICS.115.001142 %0 Journal Article %J Am J Hum Genet %D 2016 %T Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals. %A Eicher, John D %A Chami, Nathalie %A Kacprowski, Tim %A Nomura, Akihiro %A Chen, Ming-Huei %A Yanek, Lisa R %A Tajuddin, Salman M %A Schick, Ursula M %A Slater, Andrew J %A Pankratz, Nathan %A Polfus, Linda %A Schurmann, Claudia %A Giri, Ayush %A Brody, Jennifer A %A Lange, Leslie A %A Manichaikul, Ani %A Hill, W David %A Pazoki, Raha %A Elliot, Paul %A Evangelou, Evangelos %A Tzoulaki, Ioanna %A Gao, He %A Vergnaud, Anne-Claire %A Mathias, Rasika A %A Becker, Diane M %A Becker, Lewis C %A Burt, Amber %A Crosslin, David R %A Lyytikäinen, Leo-Pekka %A Nikus, Kjell %A Hernesniemi, Jussi %A Kähönen, Mika %A Raitoharju, Emma %A Mononen, Nina %A Raitakari, Olli T %A Lehtimäki, Terho %A Cushman, Mary %A Zakai, Neil A %A Nickerson, Deborah A %A Raffield, Laura M %A Quarells, Rakale %A Willer, Cristen J %A Peloso, Gina M %A Abecasis, Goncalo R %A Liu, Dajiang J %A Deloukas, Panos %A Samani, Nilesh J %A Schunkert, Heribert %A Erdmann, Jeanette %A Fornage, Myriam %A Richard, Melissa %A Tardif, Jean-Claude %A Rioux, John D %A Dubé, Marie-Pierre %A de Denus, Simon %A Lu, Yingchang %A Bottinger, Erwin P %A Loos, Ruth J F %A Smith, Albert Vernon %A Harris, Tamara B %A Launer, Lenore J %A Gudnason, Vilmundur %A Velez Edwards, Digna R %A Torstenson, Eric S %A Liu, Yongmei %A Tracy, Russell P %A Rotter, Jerome I %A Rich, Stephen S %A Highland, Heather M %A Boerwinkle, Eric %A Li, Jin %A Lange, Ethan %A Wilson, James G %A Mihailov, Evelin %A Mägi, Reedik %A Hirschhorn, Joel %A Metspalu, Andres %A Esko, Tõnu %A Vacchi-Suzzi, Caterina %A Nalls, Mike A %A Zonderman, Alan B %A Evans, Michele K %A Engström, Gunnar %A Orho-Melander, Marju %A Melander, Olle %A O'Donoghue, Michelle L %A Waterworth, Dawn M %A Wallentin, Lars %A White, Harvey D %A Floyd, James S %A Bartz, Traci M %A Rice, Kenneth M %A Psaty, Bruce M %A Starr, J M %A Liewald, David C M %A Hayward, Caroline %A Deary, Ian J %A Greinacher, Andreas %A Völker, Uwe %A Thiele, Thomas %A Völzke, Henry %A van Rooij, Frank J A %A Uitterlinden, André G %A Franco, Oscar H %A Dehghan, Abbas %A Edwards, Todd L %A Ganesh, Santhi K %A Kathiresan, Sekar %A Faraday, Nauder %A Auer, Paul L %A Reiner, Alex P %A Lettre, Guillaume %A Johnson, Andrew D %X

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

%B Am J Hum Genet %V 99 %P 40-55 %8 2016 Jul 7 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/27346686?dopt=Abstract %R 10.1016/j.ajhg.2016.05.005 %0 Journal Article %J Sci Rep %D 2017 %T Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium. %A Weng, Lu-Chen %A Lunetta, Kathryn L %A Müller-Nurasyid, Martina %A Smith, Albert Vernon %A Thériault, Sébastien %A Weeke, Peter E %A Barnard, John %A Bis, Joshua C %A Lyytikäinen, Leo-Pekka %A Kleber, Marcus E %A Martinsson, Andreas %A Lin, Henry J %A Rienstra, Michiel %A Trompet, Stella %A Krijthe, Bouwe P %A Dörr, Marcus %A Klarin, Derek %A Chasman, Daniel I %A Sinner, Moritz F %A Waldenberger, Melanie %A Launer, Lenore J %A Harris, Tamara B %A Soliman, Elsayed Z %A Alonso, Alvaro %A Paré, Guillaume %A Teixeira, Pedro L %A Denny, Joshua C %A Shoemaker, M Benjamin %A Van Wagoner, David R %A Smith, Jonathan D %A Psaty, Bruce M %A Sotoodehnia, Nona %A Taylor, Kent D %A Kähönen, Mika %A Nikus, Kjell %A Delgado, Graciela E %A Melander, Olle %A Engström, Gunnar %A Yao, Jie %A Guo, Xiuqing %A Christophersen, Ingrid E %A Ellinor, Patrick T %A Geelhoed, Bastiaan %A Verweij, Niek %A Macfarlane, Peter %A Ford, Ian %A Heeringa, Jan %A Franco, Oscar H %A Uitterlinden, André G %A Völker, Uwe %A Teumer, Alexander %A Rose, Lynda M %A Kääb, Stefan %A Gudnason, Vilmundur %A Arking, Dan E %A Conen, David %A Roden, Dan M %A Chung, Mina K %A Heckbert, Susan R %A Benjamin, Emelia J %A Lehtimäki, Terho %A März, Winfried %A Smith, J Gustav %A Rotter, Jerome I %A van der Harst, Pim %A Jukema, J Wouter %A Stricker, Bruno H %A Felix, Stephan B %A Albert, Christine M %A Lubitz, Steven A %X

It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.

%B Sci Rep %V 7 %P 11303 %8 2017 Sep 12 %G eng %N 1 %R 10.1038/s41598-017-09396-7 %0 Journal Article %J J Clin Invest %D 2017 %T Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function. %A Wild, Philipp S %A Felix, Janine F %A Schillert, Arne %A Teumer, Alexander %A Chen, Ming-Huei %A Leening, Maarten J G %A Völker, Uwe %A Großmann, Vera %A Brody, Jennifer A %A Irvin, Marguerite R %A Shah, Sanjiv J %A Pramana, Setia %A Lieb, Wolfgang %A Schmidt, Reinhold %A Stanton, Alice V %A Malzahn, Dörthe %A Smith, Albert Vernon %A Sundström, Johan %A Minelli, Cosetta %A Ruggiero, Daniela %A Lyytikäinen, Leo-Pekka %A Tiller, Daniel %A Smith, J Gustav %A Monnereau, Claire %A Di Tullio, Marco R %A Musani, Solomon K %A Morrison, Alanna C %A Pers, Tune H %A Morley, Michael %A Kleber, Marcus E %A Aragam, Jayashri %A Benjamin, Emelia J %A Bis, Joshua C %A Bisping, Egbert %A Broeckel, Ulrich %A Cheng, Susan %A Deckers, Jaap W %A del Greco M, Fabiola %A Edelmann, Frank %A Fornage, Myriam %A Franke, Lude %A Friedrich, Nele %A Harris, Tamara B %A Hofer, Edith %A Hofman, Albert %A Huang, Jie %A Hughes, Alun D %A Kähönen, Mika %A Investigators, Knhi %A Kruppa, Jochen %A Lackner, Karl J %A Lannfelt, Lars %A Laskowski, Rafael %A Launer, Lenore J %A Leosdottir, Margrét %A Lin, Honghuang %A Lindgren, Cecilia M %A Loley, Christina %A MacRae, Calum A %A Mascalzoni, Deborah %A Mayet, Jamil %A Medenwald, Daniel %A Morris, Andrew P %A Müller, Christian %A Müller-Nurasyid, Martina %A Nappo, Stefania %A Nilsson, Peter M %A Nuding, Sebastian %A Nutile, Teresa %A Peters, Annette %A Pfeufer, Arne %A Pietzner, Diana %A Pramstaller, Peter P %A Raitakari, Olli T %A Rice, Kenneth M %A Rivadeneira, Fernando %A Rotter, Jerome I %A Ruohonen, Saku T %A Sacco, Ralph L %A Samdarshi, Tandaw E %A Schmidt, Helena %A Sharp, Andrew S P %A Shields, Denis C %A Sorice, Rossella %A Sotoodehnia, Nona %A Stricker, Bruno H %A Surendran, Praveen %A Thom, Simon %A Töglhofer, Anna M %A Uitterlinden, André G %A Wachter, Rolf %A Völzke, Henry %A Ziegler, Andreas %A Münzel, Thomas %A März, Winfried %A Cappola, Thomas P %A Hirschhorn, Joel N %A Mitchell, Gary F %A Smith, Nicholas L %A Fox, Ervin R %A Dueker, Nicole D %A Jaddoe, Vincent W V %A Melander, Olle %A Russ, Martin %A Lehtimäki, Terho %A Ciullo, Marina %A Hicks, Andrew A %A Lind, Lars %A Gudnason, Vilmundur %A Pieske, Burkert %A Barron, Anthony J %A Zweiker, Robert %A Schunkert, Heribert %A Ingelsson, Erik %A Liu, Kiang %A Arnett, Donna K %A Psaty, Bruce M %A Blankenberg, Stefan %A Larson, Martin G %A Felix, Stephan B %A Franco, Oscar H %A Zeller, Tanja %A Vasan, Ramachandran S %A Dörr, Marcus %X

BACKGROUND: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function.

METHODS: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function.

RESULTS: The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue.

CONCLUSION: The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies.

FUNDING: For detailed information per study, see Acknowledgments.

%B J Clin Invest %V 127 %P 1798-1812 %8 2017 May 01 %G eng %N 5 %R 10.1172/JCI84840 %0 Journal Article %J Circ Cardiovasc Genet %D 2017 %T New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals. %A Kraja, Aldi T %A Cook, James P %A Warren, Helen R %A Surendran, Praveen %A Liu, Chunyu %A Evangelou, Evangelos %A Manning, Alisa K %A Grarup, Niels %A Drenos, Fotios %A Sim, Xueling %A Smith, Albert Vernon %A Amin, Najaf %A Blakemore, Alexandra I F %A Bork-Jensen, Jette %A Brandslund, Ivan %A Farmaki, Aliki-Eleni %A Fava, Cristiano %A Ferreira, Teresa %A Herzig, Karl-Heinz %A Giri, Ayush %A Giulianini, Franco %A Grove, Megan L %A Guo, Xiuqing %A Harris, Sarah E %A Have, Christian T %A Havulinna, Aki S %A Zhang, He %A Jørgensen, Marit E %A Käräjämäki, AnneMari %A Kooperberg, Charles %A Linneberg, Allan %A Little, Louis %A Liu, Yongmei %A Bonnycastle, Lori L %A Lu, Yingchang %A Mägi, Reedik %A Mahajan, Anubha %A Malerba, Giovanni %A Marioni, Riccardo E %A Mei, Hao %A Menni, Cristina %A Morrison, Alanna C %A Padmanabhan, Sandosh %A Palmas, Walter %A Poveda, Alaitz %A Rauramaa, Rainer %A Rayner, Nigel William %A Riaz, Muhammad %A Rice, Ken %A Richard, Melissa A %A Smith, Jennifer A %A Southam, Lorraine %A Stančáková, Alena %A Stirrups, Kathleen E %A Tragante, Vinicius %A Tuomi, Tiinamaija %A Tzoulaki, Ioanna %A Varga, Tibor V %A Weiss, Stefan %A Yiorkas, Andrianos M %A Young, Robin %A Zhang, Weihua %A Barnes, Michael R %A Cabrera, Claudia P %A Gao, He %A Boehnke, Michael %A Boerwinkle, Eric %A Chambers, John C %A Connell, John M %A Christensen, Cramer K %A de Boer, Rudolf A %A Deary, Ian J %A Dedoussis, George %A Deloukas, Panos %A Dominiczak, Anna F %A Dörr, Marcus %A Joehanes, Roby %A Edwards, Todd L %A Esko, Tõnu %A Fornage, Myriam %A Franceschini, Nora %A Franks, Paul W %A Gambaro, Giovanni %A Groop, Leif %A Hallmans, Göran %A Hansen, Torben %A Hayward, Caroline %A Heikki, Oksa %A Ingelsson, Erik %A Tuomilehto, Jaakko %A Jarvelin, Marjo-Riitta %A Kardia, Sharon L R %A Karpe, Fredrik %A Kooner, Jaspal S %A Lakka, Timo A %A Langenberg, Claudia %A Lind, Lars %A Loos, Ruth J F %A Laakso, Markku %A McCarthy, Mark I %A Melander, Olle %A Mohlke, Karen L %A Morris, Andrew P %A Palmer, Colin N A %A Pedersen, Oluf %A Polasek, Ozren %A Poulter, Neil R %A Province, Michael A %A Psaty, Bruce M %A Ridker, Paul M %A Rotter, Jerome I %A Rudan, Igor %A Salomaa, Veikko %A Samani, Nilesh J %A Sever, Peter J %A Skaaby, Tea %A Stafford, Jeanette M %A Starr, John M %A van der Harst, Pim %A van der Meer, Peter %A van Duijn, Cornelia M %A Vergnaud, Anne-Claire %A Gudnason, Vilmundur %A Wareham, Nicholas J %A Wilson, James G %A Willer, Cristen J %A Witte, Daniel R %A Zeggini, Eleftheria %A Saleheen, Danish %A Butterworth, Adam S %A Danesh, John %A Asselbergs, Folkert W %A Wain, Louise V %A Ehret, Georg B %A Chasman, Daniel I %A Caulfield, Mark J %A Elliott, Paul %A Lindgren, Cecilia M %A Levy, Daniel %A Newton-Cheh, Christopher %A Munroe, Patricia B %A Howson, Joanna M M %X

BACKGROUND: Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.

METHODS AND RESULTS: Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.

CONCLUSIONS: We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.

%B Circ Cardiovasc Genet %V 10 %8 2017 Oct %G eng %N 5 %R 10.1161/CIRCGENETICS.117.001778 %0 Journal Article %J Circ Genom Precis Med %D 2018 %T ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals. %A Bihlmeyer, Nathan A %A Brody, Jennifer A %A Smith, Albert Vernon %A Warren, Helen R %A Lin, Honghuang %A Isaacs, Aaron %A Liu, Ching-Ti %A Marten, Jonathan %A Radmanesh, Farid %A Hall, Leanne M %A Grarup, Niels %A Mei, Hao %A Müller-Nurasyid, Martina %A Huffman, Jennifer E %A Verweij, Niek %A Guo, Xiuqing %A Yao, Jie %A Li-Gao, Ruifang %A van den Berg, Marten %A Weiss, Stefan %A Prins, Bram P %A van Setten, Jessica %A Haessler, Jeffrey %A Lyytikäinen, Leo-Pekka %A Li, Man %A Alonso, Alvaro %A Soliman, Elsayed Z %A Bis, Joshua C %A Austin, Tom %A Chen, Yii-Der Ida %A Psaty, Bruce M %A Harrris, Tamara B %A Launer, Lenore J %A Padmanabhan, Sandosh %A Dominiczak, Anna %A Huang, Paul L %A Xie, Zhijun %A Ellinor, Patrick T %A Kors, Jan A %A Campbell, Archie %A Murray, Alison D %A Nelson, Christopher P %A Tobin, Martin D %A Bork-Jensen, Jette %A Hansen, Torben %A Pedersen, Oluf %A Linneberg, Allan %A Sinner, Moritz F %A Peters, Annette %A Waldenberger, Melanie %A Meitinger, Thomas %A Perz, Siegfried %A Kolcic, Ivana %A Rudan, Igor %A de Boer, Rudolf A %A van der Meer, Peter %A Lin, Henry J %A Taylor, Kent D %A de Mutsert, Renée %A Trompet, Stella %A Jukema, J Wouter %A Maan, Arie C %A Stricker, Bruno H C %A Rivadeneira, Fernando %A Uitterlinden, Andre %A Völker, Uwe %A Homuth, Georg %A Völzke, Henry %A Felix, Stephan B %A Mangino, Massimo %A Spector, Timothy D %A Bots, Michiel L %A Perez, Marco %A Raitakari, Olli T %A Kähönen, Mika %A Mononen, Nina %A Gudnason, Vilmundur %A Munroe, Patricia B %A Lubitz, Steven A %A van Duijn, Cornelia M %A Newton-Cheh, Christopher H %A Hayward, Caroline %A Rosand, Jonathan %A Samani, Nilesh J %A Kanters, Jørgen K %A Wilson, James G %A Kääb, Stefan %A Polasek, Ozren %A van der Harst, Pim %A Heckbert, Susan R %A Rotter, Jerome I %A Mook-Kanamori, Dennis O %A Eijgelsheim, Mark %A Dörr, Marcus %A Jamshidi, Yalda %A Asselbergs, Folkert W %A Kooperberg, Charles %A Lehtimäki, Terho %A Arking, Dan E %A Sotoodehnia, Nona %X

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

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

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

%B Circ Genom Precis Med %V 11 %P e001758 %8 2018 Jan %G eng %N 1 %R 10.1161/CIRCGEN.117.001758 %0 Journal Article %J Nat Commun %D 2018 %T Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume. %A Vojinovic, Dina %A Adams, Hieab H %A Jian, Xueqiu %A Yang, Qiong %A Smith, Albert Vernon %A Bis, Joshua C %A Teumer, Alexander %A Scholz, Markus %A Armstrong, Nicola J %A Hofer, Edith %A Saba, Yasaman %A Luciano, Michelle %A Bernard, Manon %A Trompet, Stella %A Yang, Jingyun %A Gillespie, Nathan A %A van der Lee, Sven J %A Neumann, Alexander %A Ahmad, Shahzad %A Andreassen, Ole A %A Ames, David %A Amin, Najaf %A Arfanakis, Konstantinos %A Bastin, Mark E %A Becker, Diane M %A Beiser, Alexa S %A Beyer, Frauke %A Brodaty, Henry %A Bryan, R Nick %A Bülow, Robin %A Dale, Anders M %A De Jager, Philip L %A Deary, Ian J %A DeCarli, Charles %A Fleischman, Debra A %A Gottesman, Rebecca F %A van der Grond, Jeroen %A Gudnason, Vilmundur %A Harris, Tamara B %A Homuth, Georg %A Knopman, David S %A Kwok, John B %A Lewis, Cora E %A Li, Shuo %A Loeffler, Markus %A Lopez, Oscar L %A Maillard, Pauline %A El Marroun, Hanan %A Mather, Karen A %A Mosley, Thomas H %A Muetzel, Ryan L %A Nauck, Matthias %A Nyquist, Paul A %A Panizzon, Matthew S %A Pausova, Zdenka %A Psaty, Bruce M %A Rice, Ken %A Rotter, Jerome I %A Royle, Natalie %A Satizabal, Claudia L %A Schmidt, Reinhold %A Schofield, Peter R %A Schreiner, Pamela J %A Sidney, Stephen %A Stott, David J %A Thalamuthu, Anbupalam %A Uitterlinden, André G %A Valdés Hernández, Maria C %A Vernooij, Meike W %A Wen, Wei %A White, Tonya %A Witte, A Veronica %A Wittfeld, Katharina %A Wright, Margaret J %A Yanek, Lisa R %A Tiemeier, Henning %A Kremen, William S %A Bennett, David A %A Jukema, J Wouter %A Paus, Tomáš %A Wardlaw, Joanna M %A Schmidt, Helena %A Sachdev, Perminder S %A Villringer, Arno %A Grabe, Hans Jörgen %A Longstreth, W T %A van Duijn, Cornelia M %A Launer, Lenore J %A Seshadri, Sudha %A Ikram, M Arfan %A Fornage, Myriam %X

The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρ = -0.59, p-value = 3.14 × 10), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.

%B Nat Commun %V 9 %P 3945 %8 2018 Sep 26 %G eng %N 1 %R 10.1038/s41467-018-06234-w %0 Journal Article %J Am J Hum Genet %D 2018 %T A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. %A Sung, Yun J %A Winkler, Thomas W %A de Las Fuentes, Lisa %A Bentley, Amy R %A Brown, Michael R %A Kraja, Aldi T %A Schwander, Karen %A Ntalla, Ioanna %A Guo, Xiuqing %A Franceschini, Nora %A Lu, Yingchang %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Marten, Jonathan %A Musani, Solomon K %A Li, Changwei %A Feitosa, Mary F %A Kilpeläinen, Tuomas O %A Richard, Melissa A %A Noordam, Raymond %A Aslibekyan, Stella %A Aschard, Hugues %A Bartz, Traci M %A Dorajoo, Rajkumar %A Liu, Yongmei %A Manning, Alisa K %A Rankinen, Tuomo %A Smith, Albert Vernon %A Tajuddin, Salman M %A Tayo, Bamidele O %A Warren, Helen R %A Zhao, Wei %A Zhou, Yanhua %A Matoba, Nana %A Sofer, Tamar %A Alver, Maris %A Amini, Marzyeh %A Boissel, Mathilde %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Gandin, Ilaria %A Gao, Chuan %A Giulianini, Franco %A Goel, Anuj %A Harris, Sarah E %A Hartwig, Fernando Pires %A Horimoto, Andrea R V R %A Hsu, Fang-Chi %A Jackson, Anne U %A Kähönen, Mika %A Kasturiratne, Anuradhani %A Kuhnel, Brigitte %A Leander, Karin %A Lee, Wen-Jane %A Lin, Keng-Hung %A 'an Luan, Jian %A McKenzie, Colin A %A Meian, He %A Nelson, Christopher P %A Rauramaa, Rainer %A Schupf, Nicole %A Scott, Robert A %A Sheu, Wayne H H %A Stančáková, Alena %A Takeuchi, Fumihiko %A van der Most, Peter J %A Varga, Tibor V %A Wang, Heming %A Wang, Yajuan %A Ware, Erin B %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Afaq, Saima %A Alfred, Tamuno %A Amin, Najaf %A Arking, Dan %A Aung, Tin %A Barr, R Graham %A Bielak, Lawrence F %A Boerwinkle, Eric %A Bottinger, Erwin P %A Braund, Peter S %A Brody, Jennifer A %A Broeckel, Ulrich %A Cabrera, Claudia P %A Cade, Brian %A Caizheng, Yu %A Campbell, Archie %A Canouil, Mickaël %A Chakravarti, Aravinda %A Chauhan, Ganesh %A Christensen, Kaare %A Cocca, Massimiliano %A Collins, Francis S %A Connell, John M %A de Mutsert, Renée %A de Silva, H Janaka %A Debette, Stephanie %A Dörr, Marcus %A Duan, Qing %A Eaton, Charles B %A Ehret, Georg %A Evangelou, Evangelos %A Faul, Jessica D %A Fisher, Virginia A %A Forouhi, Nita G %A Franco, Oscar H %A Friedlander, Yechiel %A Gao, He %A Gigante, Bruna %A Graff, Misa %A Gu, C Charles %A Gu, Dongfeng %A Gupta, Preeti %A Hagenaars, Saskia P %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hirata, Makoto %A Hofman, Albert %A Howard, Barbara V %A Hunt, Steven %A Irvin, Marguerite R %A Jia, Yucheng %A Joehanes, Roby %A Justice, Anne E %A Katsuya, Tomohiro %A Kaufman, Joel %A Kerrison, Nicola D %A Khor, Chiea Chuen %A Koh, Woon-Puay %A Koistinen, Heikki A %A Komulainen, Pirjo %A Kooperberg, Charles %A Krieger, Jose E %A Kubo, Michiaki %A Kuusisto, Johanna %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lehne, Benjamin %A Lewis, Cora E %A Li, Yize %A Lim, Sing Hui %A Lin, Shiow %A Liu, Ching-Ti %A Liu, Jianjun %A Liu, Jingmin %A Liu, Kiang %A Liu, Yeheng %A Loh, Marie %A Lohman, Kurt K %A Long, Jirong %A Louie, Tin %A Mägi, Reedik %A Mahajan, Anubha %A Meitinger, Thomas %A Metspalu, Andres %A Milani, Lili %A Momozawa, Yukihide %A Morris, Andrew P %A Mosley, Thomas H %A Munson, Peter %A Murray, Alison D %A Nalls, Mike A %A Nasri, Ubaydah %A Norris, Jill M %A North, Kari %A Ogunniyi, Adesola %A Padmanabhan, Sandosh %A Palmas, Walter R %A Palmer, Nicholette D %A Pankow, James S %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A Raitakari, Olli T %A Renstrom, Frida %A Rice, Treva K %A Ridker, Paul M %A Robino, Antonietta %A Robinson, Jennifer G %A Rose, Lynda M %A Rudan, Igor %A Sabanayagam, Charumathi %A Salako, Babatunde L %A Sandow, Kevin %A Schmidt, Carsten O %A Schreiner, Pamela J %A Scott, William R %A Seshadri, Sudha %A Sever, Peter %A Sitlani, Colleen M %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Tang, Hua %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Uitterlinden, André G %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Ya X %A Wei, Wen Bin %A Williams, Christine %A Wilson, Gregory %A Wojczynski, Mary K %A Yao, Jie %A Yuan, Jian-Min %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Chen, Yii-Der Ida %A de Faire, Ulf %A Deary, Ian J %A Esko, Tõnu %A Farrall, Martin %A Forrester, Terrence %A Franks, Paul W %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Horta, Bernardo Lessa %A Hung, Yi-Jen %A Jonas, Jost B %A Kato, Norihiro %A Kooner, Jaspal S %A Laakso, Markku %A Lehtimäki, Terho %A Liang, Kae-Woei %A Magnusson, Patrik K E %A Newman, Anne B %A Oldehinkel, Albertine J %A Pereira, Alexandre C %A Redline, Susan %A Rettig, Rainer %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wareham, Nicholas J %A Watkins, Hugh %A Weir, David R %A Wickremasinghe, Ananda R %A Wu, Tangchun %A Zheng, Wei %A Kamatani, Yoichiro %A Laurie, Cathy C %A Bouchard, Claude %A Cooper, Richard S %A Evans, Michele K %A Gudnason, Vilmundur %A Kardia, Sharon L R %A Kritchevsky, Stephen B %A Levy, Daniel %A O'Connell, Jeff R %A Psaty, Bruce M %A van Dam, Rob M %A Sims, Mario %A Arnett, Donna K %A Mook-Kanamori, Dennis O %A Kelly, Tanika N %A Fox, Ervin R %A Hayward, Caroline %A Fornage, Myriam %A Rotimi, Charles N %A Province, Michael A %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Loos, Ruth J F %A Reiner, Alex P %A Rotter, Jerome I %A Zhu, Xiaofeng %A Bierut, Laura J %A Gauderman, W James %A Caulfield, Mark J %A Elliott, Paul %A Rice, Kenneth %A Munroe, Patricia B %A Morrison, Alanna C %A Cupples, L Adrienne %A Rao, Dabeeru C %A Chasman, Daniel I %X

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

%B Am J Hum Genet %V 102 %P 375-400 %8 2018 Mar 01 %G eng %N 3 %R 10.1016/j.ajhg.2018.01.015 %0 Journal Article %J Nat Commun %D 2018 %T Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function. %A Wyss, Annah B %A Sofer, Tamar %A Lee, Mi Kyeong %A Terzikhan, Natalie %A Nguyen, Jennifer N %A Lahousse, Lies %A Latourelle, Jeanne C %A Smith, Albert Vernon %A Bartz, Traci M %A Feitosa, Mary F %A Gao, Wei %A Ahluwalia, Tarunveer S %A Tang, Wenbo %A Oldmeadow, Christopher %A Duan, Qing %A de Jong, Kim %A Wojczynski, Mary K %A Wang, Xin-Qun %A Noordam, Raymond %A Hartwig, Fernando Pires %A Jackson, Victoria E %A Wang, Tianyuan %A Obeidat, Ma'en %A Hobbs, Brian D %A Huan, Tianxiao %A Gui, Hongsheng %A Parker, Margaret M %A Hu, Donglei %A Mogil, Lauren S %A Kichaev, Gleb %A Jin, Jianping %A Graff, Mariaelisa %A Harris, Tamara B %A Kalhan, Ravi %A Heckbert, Susan R %A Paternoster, Lavinia %A Burkart, Kristin M %A Liu, Yongmei %A Holliday, Elizabeth G %A Wilson, James G %A Vonk, Judith M %A Sanders, Jason L %A Barr, R Graham %A de Mutsert, Renée %A Menezes, Ana Maria Baptista %A Adams, Hieab H H %A van den Berge, Maarten %A Joehanes, Roby %A Levin, Albert M %A Liberto, Jennifer %A Launer, Lenore J %A Morrison, Alanna C %A Sitlani, Colleen M %A Celedón, Juan C %A Kritchevsky, Stephen B %A Scott, Rodney J %A Christensen, Kaare %A Rotter, Jerome I %A Bonten, Tobias N %A Wehrmeister, Fernando César %A Bossé, Yohan %A Xiao, Shujie %A Oh, Sam %A Franceschini, Nora %A Brody, Jennifer A %A Kaplan, Robert C %A Lohman, Kurt %A McEvoy, Mark %A Province, Michael A %A Rosendaal, Frits R %A Taylor, Kent D %A Nickle, David C %A Williams, L Keoki %A Burchard, Esteban G %A Wheeler, Heather E %A Sin, Don D %A Gudnason, Vilmundur %A North, Kari E %A Fornage, Myriam %A Psaty, Bruce M %A Myers, Richard H %A O'Connor, George %A Hansen, Torben %A Laurie, Cathy C %A Cassano, Patricia A %A Sung, Joohon %A Kim, Woo Jin %A Attia, John R %A Lange, Leslie %A Boezen, H Marike %A Thyagarajan, Bharat %A Rich, Stephen S %A Mook-Kanamori, Dennis O %A Horta, Bernardo Lessa %A Uitterlinden, André G %A Im, Hae Kyung %A Cho, Michael H %A Brusselle, Guy G %A Gharib, Sina A %A Dupuis, Josée %A Manichaikul, Ani %A London, Stephanie J %X

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

%B Nat Commun %V 9 %P 2976 %8 2018 Jul 30 %G eng %N 1 %R 10.1038/s41467-018-05369-0 %0 Journal Article %J Nat Genet %D 2018 %T Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. %A Mahajan, Anubha %A Wessel, Jennifer %A Willems, Sara M %A Zhao, Wei %A Robertson, Neil R %A Chu, Audrey Y %A Gan, Wei %A Kitajima, Hidetoshi %A Taliun, Daniel %A Rayner, N William %A Guo, Xiuqing %A Lu, Yingchang %A Li, Man %A Jensen, Richard A %A Hu, Yao %A Huo, Shaofeng %A Lohman, Kurt K %A Zhang, Weihua %A Cook, James P %A Prins, Bram Peter %A Flannick, Jason %A Grarup, Niels %A Trubetskoy, Vassily Vladimirovich %A Kravic, Jasmina %A Kim, Young Jin %A Rybin, Denis V %A Yaghootkar, Hanieh %A Müller-Nurasyid, Martina %A Meidtner, Karina %A Li-Gao, Ruifang %A Varga, Tibor V %A Marten, Jonathan %A Li, Jin %A Smith, Albert Vernon %A An, Ping %A Ligthart, Symen %A Gustafsson, Stefan %A Malerba, Giovanni %A Demirkan, Ayse %A Tajes, Juan Fernandez %A Steinthorsdottir, Valgerdur %A Wuttke, Matthias %A Lecoeur, Cécile %A Preuss, Michael %A Bielak, Lawrence F %A Graff, Marielisa %A Highland, Heather M %A Justice, Anne E %A Liu, Dajiang J %A Marouli, Eirini %A Peloso, Gina Marie %A Warren, Helen R %A Afaq, Saima %A Afzal, Shoaib %A Ahlqvist, Emma %A Almgren, Peter %A Amin, Najaf %A Bang, Lia B %A Bertoni, Alain G %A Bombieri, Cristina %A Bork-Jensen, Jette %A Brandslund, Ivan %A Brody, Jennifer A %A Burtt, Noel P %A Canouil, Mickaël %A Chen, Yii-Der Ida %A Cho, Yoon Shin %A Christensen, Cramer %A Eastwood, Sophie V %A Eckardt, Kai-Uwe %A Fischer, Krista %A Gambaro, Giovanni %A Giedraitis, Vilmantas %A Grove, Megan L %A de Haan, Hugoline G %A Hackinger, Sophie %A Hai, Yang %A Han, Sohee %A Tybjærg-Hansen, Anne %A Hivert, Marie-France %A Isomaa, Bo %A Jäger, Susanne %A Jørgensen, Marit E %A Jørgensen, Torben %A Käräjämäki, AnneMari %A Kim, Bong-Jo %A Kim, Sung Soo %A Koistinen, Heikki A %A Kovacs, Peter %A Kriebel, Jennifer %A Kronenberg, Florian %A Läll, Kristi %A Lange, Leslie A %A Lee, Jung-Jin %A Lehne, Benjamin %A Li, Huaixing %A Lin, Keng-Hung %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Jun %A Loh, Marie %A Mägi, Reedik %A Mamakou, Vasiliki %A McKean-Cowdin, Roberta %A Nadkarni, Girish %A Neville, Matt %A Nielsen, Sune F %A Ntalla, Ioanna %A Peyser, Patricia A %A Rathmann, Wolfgang %A Rice, Kenneth %A Rich, Stephen S %A Rode, Line %A Rolandsson, Olov %A Schönherr, Sebastian %A Selvin, Elizabeth %A Small, Kerrin S %A Stančáková, Alena %A Surendran, Praveen %A Taylor, Kent D %A Teslovich, Tanya M %A Thorand, Barbara %A Thorleifsson, Gudmar %A Tin, Adrienne %A Tönjes, Anke %A Varbo, Anette %A Witte, Daniel R %A Wood, Andrew R %A Yajnik, Pranav %A Yao, Jie %A Yengo, Loic %A Young, Robin %A Amouyel, Philippe %A Boeing, Heiner %A Boerwinkle, Eric %A Bottinger, Erwin P %A Chowdhury, Rajiv %A Collins, Francis S %A Dedoussis, George %A Dehghan, Abbas %A Deloukas, Panos %A Ferrario, Marco M %A Ferrieres, Jean %A Florez, Jose C %A Frossard, Philippe %A Gudnason, Vilmundur %A Harris, Tamara B %A Heckbert, Susan R %A Howson, Joanna M M %A Ingelsson, Martin %A Kathiresan, Sekar %A Kee, Frank %A Kuusisto, Johanna %A Langenberg, Claudia %A Launer, Lenore J %A Lindgren, Cecilia M %A Männistö, Satu %A Meitinger, Thomas %A Melander, Olle %A Mohlke, Karen L %A Moitry, Marie %A Morris, Andrew D %A Murray, Alison D %A de Mutsert, Renée %A Orho-Melander, Marju %A Owen, Katharine R %A Perola, Markus %A Peters, Annette %A Province, Michael A %A Rasheed, Asif %A Ridker, Paul M %A Rivadineira, Fernando %A Rosendaal, Frits R %A Rosengren, Anders H %A Salomaa, Veikko %A Sheu, Wayne H-H %A Sladek, Rob %A Smith, Blair H %A Strauch, Konstantin %A Uitterlinden, André G %A Varma, Rohit %A Willer, Cristen J %A Blüher, Matthias %A Butterworth, Adam S %A Chambers, John Campbell %A Chasman, Daniel I %A Danesh, John %A van Duijn, Cornelia %A Dupuis, Josée %A Franco, Oscar H %A Franks, Paul W %A Froguel, Philippe %A Grallert, Harald %A Groop, Leif %A Han, Bok-Ghee %A Hansen, Torben %A Hattersley, Andrew T %A Hayward, Caroline %A Ingelsson, Erik %A Kardia, Sharon L R %A Karpe, Fredrik %A Kooner, Jaspal Singh %A Köttgen, Anna %A Kuulasmaa, Kari %A Laakso, Markku %A Lin, Xu %A Lind, Lars %A Liu, Yongmei %A Loos, Ruth J F %A Marchini, Jonathan %A Metspalu, Andres %A Mook-Kanamori, Dennis %A Nordestgaard, Børge G %A Palmer, Colin N A %A Pankow, James S %A Pedersen, Oluf %A Psaty, Bruce M %A Rauramaa, Rainer %A Sattar, Naveed %A Schulze, Matthias B %A Soranzo, Nicole %A Spector, Timothy D %A Stefansson, Kari %A Stumvoll, Michael %A Thorsteinsdottir, Unnur %A Tuomi, Tiinamaija %A Tuomilehto, Jaakko %A Wareham, Nicholas J %A Wilson, James G %A Zeggini, Eleftheria %A Scott, Robert A %A Barroso, Inês %A Frayling, Timothy M %A Goodarzi, Mark O %A Meigs, James B %A Boehnke, Michael %A Saleheen, Danish %A Morris, Andrew P %A Rotter, Jerome I %A McCarthy, Mark I %X

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

%B Nat Genet %V 50 %P 559-571 %8 2018 Apr %G eng %N 4 %R 10.1038/s41588-018-0084-1 %0 Journal Article %J Nat Commun %D 2019 %T Associations of autozygosity with a broad range of human phenotypes. %A Clark, David W %A Okada, Yukinori %A Moore, Kristjan H S %A Mason, Dan %A Pirastu, Nicola %A Gandin, Ilaria %A Mattsson, Hannele %A Barnes, Catriona L K %A Lin, Kuang %A Zhao, Jing Hua %A Deelen, Patrick %A Rohde, Rebecca %A Schurmann, Claudia %A Guo, Xiuqing %A Giulianini, Franco %A Zhang, Weihua %A Medina-Gómez, Carolina %A Karlsson, Robert %A Bao, Yanchun %A Bartz, Traci M %A Baumbach, Clemens %A Biino, Ginevra %A Bixley, Matthew J %A Brumat, Marco %A Chai, Jin-Fang %A Corre, Tanguy %A Cousminer, Diana L %A Dekker, Annelot M %A Eccles, David A %A van Eijk, Kristel R %A Fuchsberger, Christian %A Gao, He %A Germain, Marine %A Gordon, Scott D %A de Haan, Hugoline G %A Harris, Sarah E %A Hofer, Edith %A Huerta-Chagoya, Alicia %A Igartua, Catherine %A Jansen, Iris E %A Jia, Yucheng %A Kacprowski, Tim %A Karlsson, Torgny %A Kleber, Marcus E %A Li, Shengchao Alfred %A Li-Gao, Ruifang %A Mahajan, Anubha %A Matsuda, Koichi %A Meidtner, Karina %A Meng, Weihua %A Montasser, May E %A van der Most, Peter J %A Munz, Matthias %A Nutile, Teresa %A Palviainen, Teemu %A Prasad, Gauri %A Prasad, Rashmi B %A Priyanka, Tallapragada Divya Sri %A Rizzi, Federica %A Salvi, Erika %A Sapkota, Bishwa R %A Shriner, Daniel %A Skotte, Line %A Smart, Melissa C %A Smith, Albert Vernon %A van der Spek, Ashley %A Spracklen, Cassandra N %A Strawbridge, Rona J %A Tajuddin, Salman M %A Trompet, Stella %A Turman, Constance %A Verweij, Niek %A Viberti, Clara %A Wang, Lihua %A Warren, Helen R %A Wootton, Robyn E %A Yanek, Lisa R %A Yao, Jie %A Yousri, Noha A %A Zhao, Wei %A Adeyemo, Adebowale A %A Afaq, Saima %A Aguilar-Salinas, Carlos Alberto %A Akiyama, Masato %A Albert, Matthew L %A Allison, Matthew A %A Alver, Maris %A Aung, Tin %A Azizi, Fereidoun %A Bentley, Amy R %A Boeing, Heiner %A Boerwinkle, Eric %A Borja, Judith B %A de Borst, Gert J %A Bottinger, Erwin P %A Broer, Linda %A Campbell, Harry %A Chanock, Stephen %A Chee, Miao-Li %A Chen, Guanjie %A Chen, Yii-der I %A Chen, Zhengming %A Chiu, Yen-Feng %A Cocca, Massimiliano %A Collins, Francis S %A Concas, Maria Pina %A Corley, Janie %A Cugliari, Giovanni %A van Dam, Rob M %A Damulina, Anna %A Daneshpour, Maryam S %A Day, Felix R %A Delgado, Graciela E %A Dhana, Klodian %A Doney, Alexander S F %A Dörr, Marcus %A Doumatey, Ayo P %A Dzimiri, Nduna %A Ebenesersdóttir, S Sunna %A Elliott, Joshua %A Elliott, Paul %A Ewert, Ralf %A Felix, Janine F %A Fischer, Krista %A Freedman, Barry I %A Girotto, Giorgia %A Goel, Anuj %A Gögele, Martin %A Goodarzi, Mark O %A Graff, Mariaelisa %A Granot-Hershkovitz, Einat %A Grodstein, Francine %A Guarrera, Simonetta %A Gudbjartsson, Daniel F %A Guity, Kamran %A Gunnarsson, Bjarni %A Guo, Yu %A Hagenaars, Saskia P %A Haiman, Christopher A %A Halevy, Avner %A Harris, Tamara B %A Hedayati, Mehdi %A van Heel, David A %A Hirata, Makoto %A Höfer, Imo %A Hsiung, Chao Agnes %A Huang, Jinyan %A Hung, Yi-Jen %A Ikram, M Arfan %A Jagadeesan, Anuradha %A Jousilahti, Pekka %A Kamatani, Yoichiro %A Kanai, Masahiro %A Kerrison, Nicola D %A Kessler, Thorsten %A Khaw, Kay-Tee %A Khor, Chiea Chuen %A de Kleijn, Dominique P V %A Koh, Woon-Puay %A Kolcic, Ivana %A Kraft, Peter %A Krämer, Bernhard K %A Kutalik, Zoltán %A Kuusisto, Johanna %A Langenberg, Claudia %A Launer, Lenore J %A Lawlor, Deborah A %A Lee, I-Te %A Lee, Wen-Jane %A Lerch, Markus M %A Li, Liming %A Liu, Jianjun %A Loh, Marie %A London, Stephanie J %A Loomis, Stephanie %A Lu, Yingchang %A Luan, Jian'an %A Mägi, Reedik %A Manichaikul, Ani W %A Manunta, Paolo %A Másson, Gísli %A Matoba, Nana %A Mei, Xue W %A Meisinger, Christa %A Meitinger, Thomas %A Mezzavilla, Massimo %A Milani, Lili %A Millwood, Iona Y %A Momozawa, Yukihide %A Moore, Amy %A Morange, Pierre-Emmanuel %A Moreno-Macias, Hortensia %A Mori, Trevor A %A Morrison, Alanna C %A Muka, Taulant %A Murakami, Yoshinori %A Murray, Alison D %A de Mutsert, Renée %A Mychaleckyj, Josyf C %A Nalls, Mike A %A Nauck, Matthias %A Neville, Matt J %A Nolte, Ilja M %A Ong, Ken K %A Orozco, Lorena %A Padmanabhan, Sandosh %A Pálsson, Gunnar %A Pankow, James S %A Pattaro, Cristian %A Pattie, Alison %A Polasek, Ozren %A Poulter, Neil %A Pramstaller, Peter P %A Quintana-Murci, Lluis %A Räikkönen, Katri %A Ralhan, Sarju %A Rao, Dabeeru C %A van Rheenen, Wouter %A Rich, Stephen S %A Ridker, Paul M %A Rietveld, Cornelius A %A Robino, Antonietta %A van Rooij, Frank J A %A Ruggiero, Daniela %A Saba, Yasaman %A Sabanayagam, Charumathi %A Sabater-Lleal, Maria %A Sala, Cinzia Felicita %A Salomaa, Veikko %A Sandow, Kevin %A Schmidt, Helena %A Scott, Laura J %A Scott, William R %A Sedaghati-Khayat, Bahareh %A Sennblad, Bengt %A van Setten, Jessica %A Sever, Peter J %A Sheu, Wayne H-H %A Shi, Yuan %A Shrestha, Smeeta %A Shukla, Sharvari Rahul %A Sigurdsson, Jon K %A Sikka, Timo Tonis %A Singh, Jai Rup %A Smith, Blair H %A Stančáková, Alena %A Stanton, Alice %A Starr, John M %A Stefansdottir, Lilja %A Straker, Leon %A Sulem, Patrick %A Sveinbjornsson, Gardar %A Swertz, Morris A %A Taylor, Adele M %A Taylor, Kent D %A Terzikhan, Natalie %A Tham, Yih-Chung %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tillander, Annika %A Tracy, Russell P %A Tusié-Luna, Teresa %A Tzoulaki, Ioanna %A Vaccargiu, Simona %A Vangipurapu, Jagadish %A Veldink, Jan H %A Vitart, Veronique %A Völker, Uwe %A Vuoksimaa, Eero %A Wakil, Salma M %A Waldenberger, Melanie %A Wander, Gurpreet S %A Wang, Ya Xing %A Wareham, Nicholas J %A Wild, Sarah %A Yajnik, Chittaranjan S %A Yuan, Jian-Min %A Zeng, Lingyao %A Zhang, Liang %A Zhou, Jie %A Amin, Najaf %A Asselbergs, Folkert W %A Bakker, Stephan J L %A Becker, Diane M %A Lehne, Benjamin %A Bennett, David A %A van den Berg, Leonard H %A Berndt, Sonja I %A Bharadwaj, Dwaipayan %A Bielak, Lawrence F %A Bochud, Murielle %A Boehnke, Mike %A Bouchard, Claude %A Bradfield, Jonathan P %A Brody, Jennifer A %A Campbell, Archie %A Carmi, Shai %A Caulfield, Mark J %A Cesarini, David %A Chambers, John C %A Chandak, Giriraj Ratan %A Cheng, Ching-Yu %A Ciullo, Marina %A Cornelis, Marilyn %A Cusi, Daniele %A Smith, George Davey %A Deary, Ian J %A Dorajoo, Rajkumar %A van Duijn, Cornelia M %A Ellinghaus, David %A Erdmann, Jeanette %A Eriksson, Johan G %A Evangelou, Evangelos %A Evans, Michele K %A Faul, Jessica D %A Feenstra, Bjarke %A Feitosa, Mary %A Foisy, Sylvain %A Franke, Andre %A Friedlander, Yechiel %A Gasparini, Paolo %A Gieger, Christian %A Gonzalez, Clicerio %A Goyette, Philippe %A Grant, Struan F A %A Griffiths, Lyn R %A Groop, Leif %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Hakonarson, Hakon %A Hamsten, Anders %A van der Harst, Pim %A Heng, Chew-Kiat %A Hicks, Andrew A %A Hochner, Hagit %A Huikuri, Heikki %A Hunt, Steven C %A Jaddoe, Vincent W V %A De Jager, Philip L %A Johannesson, Magnus %A Johansson, Asa %A Jonas, Jost B %A Jukema, J Wouter %A Junttila, Juhani %A Kaprio, Jaakko %A Kardia, Sharon L R %A Karpe, Fredrik %A Kumari, Meena %A Laakso, Markku %A van der Laan, Sander W %A Lahti, Jari %A Laudes, Matthias %A Lea, Rodney A %A Lieb, Wolfgang %A Lumley, Thomas %A Martin, Nicholas G %A März, Winfried %A Matullo, Giuseppe %A McCarthy, Mark I %A Medland, Sarah E %A Merriman, Tony R %A Metspalu, Andres %A Meyer, Brian F %A Mohlke, Karen L %A Montgomery, Grant W %A Mook-Kanamori, Dennis %A Munroe, Patricia B %A North, Kari E %A Nyholt, Dale R %A O'Connell, Jeffery R %A Ober, Carole %A Oldehinkel, Albertine J %A Palmas, Walter %A Palmer, Colin %A Pasterkamp, Gerard G %A Patin, Etienne %A Pennell, Craig E %A Perusse, Louis %A Peyser, Patricia A %A Pirastu, Mario %A Polderman, Tinca J C %A Porteous, David J %A Posthuma, Danielle %A Psaty, Bruce M %A Rioux, John D %A Rivadeneira, Fernando %A Rotimi, Charles %A Rotter, Jerome I %A Rudan, Igor %A den Ruijter, Hester M %A Sanghera, Dharambir K %A Sattar, Naveed %A Schmidt, Reinhold %A Schulze, Matthias B %A Schunkert, Heribert %A Scott, Robert A %A Shuldiner, Alan R %A Sim, Xueling %A Small, Neil %A Smith, Jennifer A %A Sotoodehnia, Nona %A Tai, E-Shyong %A Teumer, Alexander %A Timpson, Nicholas J %A Toniolo, Daniela %A Trégouët, David-Alexandre %A Tuomi, Tiinamaija %A Vollenweider, Peter %A Wang, Carol A %A Weir, David R %A Whitfield, John B %A Wijmenga, Cisca %A Wong, Tien-Yin %A Wright, John %A Yang, Jingyun %A Yu, Lei %A Zemel, Babette S %A Zonderman, Alan B %A Perola, Markus %A Magnusson, Patrik K E %A Uitterlinden, André G %A Kooner, Jaspal S %A Chasman, Daniel I %A Loos, Ruth J F %A Franceschini, Nora %A Franke, Lude %A Haley, Chris S %A Hayward, Caroline %A Walters, Robin G %A Perry, John R B %A Esko, Tõnu %A Helgason, Agnar %A Stefansson, Kari %A Joshi, Peter K %A Kubo, Michiaki %A Wilson, James F %X

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

%B Nat Commun %V 10 %P 4957 %8 2019 Oct 31 %G eng %N 1 %R 10.1038/s41467-019-12283-6 %0 Journal Article %J PLoS One %D 2020 %T Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. %A Hahn, Julie %A Fu, Yi-Ping %A Brown, Michael R %A Bis, Joshua C %A de Vries, Paul S %A Feitosa, Mary F %A Yanek, Lisa R %A Weiss, Stefan %A Giulianini, Franco %A Smith, Albert Vernon %A Guo, Xiuqing %A Bartz, Traci M %A Becker, Diane M %A Becker, Lewis C %A Boerwinkle, Eric %A Brody, Jennifer A %A Chen, Yii-Der Ida %A Franco, Oscar H %A Grove, Megan %A Harris, Tamara B %A Hofman, Albert %A Hwang, Shih-Jen %A Kral, Brian G %A Launer, Lenore J %A Markus, Marcello R P %A Rice, Kenneth M %A Rich, Stephen S %A Ridker, Paul M %A Rivadeneira, Fernando %A Rotter, Jerome I %A Sotoodehnia, Nona %A Taylor, Kent D %A Uitterlinden, André G %A Völker, Uwe %A Völzke, Henry %A Yao, Jie %A Chasman, Daniel I %A Dörr, Marcus %A Gudnason, Vilmundur %A Mathias, Rasika A %A Post, Wendy %A Psaty, Bruce M %A Dehghan, Abbas %A O'Donnell, Christopher J %A Morrison, Alanna C %K Aging %K Coronary Artery Disease %K Cross-Sectional Studies %K Europe %K European Continental Ancestry Group %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Myocardial Infarction %K Polymorphism, Single Nucleotide %K Prospective Studies %X

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

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

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

%B PLoS One %V 15 %P e0230035 %8 2020 %G eng %N 11 %R 10.1371/journal.pone.0230035 %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