%0 Journal Article %J JAMA %D 2009 %T Genetic variants associated with cardiac structure and function: a meta-analysis and replication of genome-wide association data. %A Vasan, Ramachandran S %A Glazer, Nicole L %A Felix, Janine F %A Lieb, Wolfgang %A Wild, Philipp S %A Felix, Stephan B %A Watzinger, Norbert %A Larson, Martin G %A Smith, Nicholas L %A Dehghan, Abbas %A Grosshennig, Anika %A Schillert, Arne %A Teumer, Alexander %A Schmidt, Reinhold %A Kathiresan, Sekar %A Lumley, Thomas %A Aulchenko, Yurii S %A König, Inke R %A Zeller, Tanja %A Homuth, Georg %A Struchalin, Maksim %A Aragam, Jayashri %A Bis, Joshua C %A Rivadeneira, Fernando %A Erdmann, Jeanette %A Schnabel, Renate B %A Dörr, Marcus %A Zweiker, Robert %A Lind, Lars %A Rodeheffer, Richard J %A Greiser, Karin Halina %A Levy, Daniel %A Haritunians, Talin %A Deckers, Jaap W %A Stritzke, Jan %A Lackner, Karl J %A Völker, Uwe %A Ingelsson, Erik %A Kullo, Iftikhar %A Haerting, Johannes %A O'Donnell, Christopher J %A Heckbert, Susan R %A Stricker, Bruno H %A Ziegler, Andreas %A Reffelmann, Thorsten %A Redfield, Margaret M %A Werdan, Karl %A Mitchell, Gary F %A Rice, Kenneth %A Arnett, Donna K %A Hofman, Albert %A Gottdiener, John S %A Uitterlinden, André G %A Meitinger, Thomas %A Blettner, Maria %A Friedrich, Nele %A Wang, Thomas J %A Psaty, Bruce M %A van Duijn, Cornelia M %A Wichmann, H-Erich %A Munzel, Thomas F %A Kroemer, Heyo K %A Benjamin, Emelia J %A Rotter, Jerome I %A Witteman, Jacqueline C %A Schunkert, Heribert %A Schmidt, Helena %A Völzke, Henry %A Blankenberg, Stefan %K Adult %K Aged %K Aged, 80 and over %K Aorta %K Cardiovascular Diseases %K Echocardiography %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Genotype %K Heart Atria %K Heart Ventricles %K Humans %K Male %K Middle Aged %K Organ Size %K Phenotype %K Polymorphism, Single Nucleotide %K Risk Factors %K Ventricular Dysfunction, Left %K Ventricular Function, Left %X

CONTEXT: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease.

OBJECTIVE: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples.

DESIGN, SETTING, AND PARTICIPANTS: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort.

MAIN OUTCOME MEASURES: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size.

RESULTS: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance).

CONCLUSIONS: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.

%B JAMA %V 302 %P 168-78 %8 2009 Jul 08 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/19584346?dopt=Abstract %R 10.1001/jama.2009.978-a %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 Hum Mol Genet %D 2010 %T Genome-wide association analysis identifies multiple loci related to resting heart rate. %A Eijgelsheim, Mark %A Newton-Cheh, Christopher %A Sotoodehnia, Nona %A de Bakker, Paul I W %A Müller, Martina %A Morrison, Alanna C %A Smith, Albert V %A Isaacs, Aaron %A Sanna, Serena %A Dörr, Marcus %A Navarro, Pau %A Fuchsberger, Christian %A Nolte, Ilja M %A de Geus, Eco J C %A Estrada, Karol %A Hwang, Shih-Jen %A Bis, Joshua C %A Rückert, Ina-Maria %A Alonso, Alvaro %A Launer, Lenore J %A Hottenga, Jouke Jan %A Rivadeneira, Fernando %A Noseworthy, Peter A %A Rice, Kenneth M %A Perz, Siegfried %A Arking, Dan E %A Spector, Tim D %A Kors, Jan A %A Aulchenko, Yurii S %A Tarasov, Kirill V %A Homuth, Georg %A Wild, Sarah H %A Marroni, Fabio %A Gieger, Christian %A Licht, Carmilla M %A Prineas, Ronald J %A Hofman, Albert %A Rotter, Jerome I %A Hicks, Andrew A %A Ernst, Florian %A Najjar, Samer S %A Wright, Alan F %A Peters, Annette %A Fox, Ervin R %A Oostra, Ben A %A Kroemer, Heyo K %A Couper, David %A Völzke, Henry %A Campbell, Harry %A Meitinger, Thomas %A Uda, Manuela %A Witteman, Jacqueline C M %A Psaty, Bruce M %A Wichmann, H-Erich %A Harris, Tamara B %A Kääb, Stefan %A Siscovick, David S %A Jamshidi, Yalda %A Uitterlinden, André G %A Folsom, Aaron R %A Larson, Martin G %A Wilson, James F %A Penninx, Brenda W %A Snieder, Harold %A Pramstaller, Peter P %A van Duijn, Cornelia M %A Lakatta, Edward G %A Felix, Stephan B %A Gudnason, Vilmundur %A Pfeufer, Arne %A Heckbert, Susan R %A Stricker, Bruno H Ch %A Boerwinkle, Eric %A O'Donnell, Christopher J %K Adult %K Aged %K Base Pairing %K Cohort Studies %K Female %K Genetic Loci %K Genome, Human %K Genome-Wide Association Study %K Heart Rate %K Humans %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Rest %X

Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38,991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and approximately 2.5 million markers. Results with P < 5 × 10(-8) were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain approximately 0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10(-5) increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.

%B Hum Mol Genet %V 19 %P 3885-94 %8 2010 Oct 01 %G eng %N 19 %1 http://www.ncbi.nlm.nih.gov/pubmed/20639392?dopt=Abstract %R 10.1093/hmg/ddq303 %0 Journal Article %J PLoS Genet %D 2010 %T Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six Loci influencing serum magnesium levels. %A Meyer, Tamra E %A Verwoert, Germaine C %A Hwang, Shih-Jen %A Glazer, Nicole L %A Smith, Albert V %A van Rooij, Frank J A %A Ehret, Georg B %A Boerwinkle, Eric %A Felix, Janine F %A Leak, Tennille S %A Harris, Tamara B %A Yang, Qiong %A Dehghan, Abbas %A Aspelund, Thor %A Katz, Ronit %A Homuth, Georg %A Kocher, Thomas %A Rettig, Rainer %A Ried, Janina S %A Gieger, Christian %A Prucha, Hanna %A Pfeufer, Arne %A Meitinger, Thomas %A Coresh, Josef %A Hofman, Albert %A Sarnak, Mark J %A Chen, Yii-Der Ida %A Uitterlinden, André G %A Chakravarti, Aravinda %A Psaty, Bruce M %A van Duijn, Cornelia M %A Kao, W H Linda %A Witteman, Jacqueline C M %A Gudnason, Vilmundur %A Siscovick, David S %A Fox, Caroline S %A Köttgen, Anna %K Adult %K Aged %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Magnesium %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Potassium %K Sodium %X

Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using approximately 2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p<5 x 10(-8)) or suggestive associations (p<4 x 10(-7)) were evaluated for replication in an additional 8,463 subjects of European descent. The association of common variants at six genomic regions (in or near MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1) with serum magnesium levels was genome-wide significant when meta-analyzed with the replication dataset. All initially significant SNPs from the CHARGE Consortium showed nominal association with clinically defined hypomagnesemia, two showed association with kidney function, two with bone mineral density, and one of these also associated with fasting glucose levels. Common variants in CNNM2, a magnesium transporter studied only in model systems to date, as well as in CNNM3 and CNNM4, were also associated with magnesium concentrations in this study. We observed no associations with serum sodium or potassium levels exceeding p<4 x 10(-7). Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels.

%B PLoS Genet %V 6 %8 2010 Aug 05 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/20700443?dopt=Abstract %R 10.1371/journal.pgen.1001045 %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 Hum Mol Genet %D 2011 %T A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3. %A Kaplan, Robert C %A Petersen, Ann-Kristin %A Chen, Ming-Huei %A Teumer, Alexander %A Glazer, Nicole L %A Döring, Angela %A Lam, Carolyn S P %A Friedrich, Nele %A Newman, Anne %A Müller, Martina %A Yang, Qiong %A Homuth, Georg %A Cappola, Anne %A Klopp, Norman %A Smith, Holly %A Ernst, Florian %A Psaty, Bruce M %A Wichmann, H-Erich %A Sawyer, Douglas B %A Biffar, Reiner %A Rotter, Jerome I %A Gieger, Christian %A Sullivan, Lisa S %A Völzke, Henry %A Rice, Kenneth %A Spyroglou, Ariadni %A Kroemer, Heyo K %A Ida Chen, Y-D %A Manolopoulou, Jenny %A Nauck, Matthias %A Strickler, Howard D %A Goodarzi, Mark O %A Reincke, Martin %A Pollak, Michael N %A Bidlingmaier, Martin %A Vasan, Ramachandran S %A Wallaschofski, Henri %K Aged %K Chromosomes, Human, Pair 7 %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genome-Wide Association Study %K Humans %K Insulin-Like Growth Factor Binding Protein 3 %K Insulin-Like Growth Factor I %K Male %K Polymorphism, Single Nucleotide %X

Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 × 10(-8) (P = 3.3 × 10(-101)). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 × 10(-26)). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10(-21)) and higher IGF-I (P = 4.9 × 10(-9)) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 × 10(-11), IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 10(-10), SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 × 10(-7)), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.

%B Hum Mol Genet %V 20 %P 1241-51 %8 2011 Mar 15 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/21216879?dopt=Abstract %R 10.1093/hmg/ddq560 %0 Journal Article %J Nat Genet %D 2011 %T Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque. %A Bis, Joshua C %A Kavousi, Maryam %A Franceschini, Nora %A Isaacs, Aaron %A Abecasis, Goncalo R %A Schminke, Ulf %A Post, Wendy S %A Smith, Albert V %A Cupples, L Adrienne %A Markus, Hugh S %A Schmidt, Reinhold %A Huffman, Jennifer E %A Lehtimäki, Terho %A Baumert, Jens %A Münzel, Thomas %A Heckbert, Susan R %A Dehghan, Abbas %A North, Kari %A Oostra, Ben %A Bevan, Steve %A Stoegerer, Eva-Maria %A Hayward, Caroline %A Raitakari, Olli %A Meisinger, Christa %A Schillert, Arne %A Sanna, Serena %A Völzke, Henry %A Cheng, Yu-Ching %A Thorsson, Bolli %A Fox, Caroline S %A Rice, Kenneth %A Rivadeneira, Fernando %A Nambi, Vijay %A Halperin, Eran %A Petrovic, Katja E %A Peltonen, Leena %A Wichmann, H Erich %A Schnabel, Renate B %A Dörr, Marcus %A Parsa, Afshin %A Aspelund, Thor %A Demissie, Serkalem %A Kathiresan, Sekar %A Reilly, Muredach P %A Taylor, Kent %A Uitterlinden, Andre %A Couper, David J %A Sitzer, Matthias %A Kähönen, Mika %A Illig, Thomas %A Wild, Philipp S %A Orrù, Marco %A Lüdemann, Jan %A Shuldiner, Alan R %A Eiriksdottir, Gudny %A White, Charles C %A Rotter, Jerome I %A Hofman, Albert %A Seissler, Jochen %A Zeller, Tanja %A Usala, Gianluca %A Ernst, Florian %A Launer, Lenore J %A D'Agostino, Ralph B %A O'Leary, Daniel H %A Ballantyne, Christie %A Thiery, Joachim %A Ziegler, Andreas %A Lakatta, Edward G %A Chilukoti, Ravi Kumar %A Harris, Tamara B %A Wolf, Philip A %A Psaty, Bruce M %A Polak, Joseph F %A Li, Xia %A Rathmann, Wolfgang %A Uda, Manuela %A Boerwinkle, Eric %A Klopp, Norman %A Schmidt, Helena %A Wilson, James F %A Viikari, Jorma %A Koenig, Wolfgang %A Blankenberg, Stefan %A Newman, Anne B %A Witteman, Jacqueline %A Heiss, Gerardo %A Duijn, Cornelia van %A Scuteri, Angelo %A Homuth, Georg %A Mitchell, Braxton D %A Gudnason, Vilmundur %A O'Donnell, Christopher J %K Adult %K Aged %K Aging %K Atherosclerosis %K Carotid Intima-Media Thickness %K Cohort Studies %K Coronary Artery Disease %K European Continental Ancestry Group %K Genetic Loci %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Genotype %K Heart %K Humans %K Middle Aged %K Phenotype %K Plaque, Atherosclerotic %K Polymorphism, Single Nucleotide %K Risk Factors %X

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

%B Nat Genet %V 43 %P 940-7 %8 2011 Sep 11 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/21909108?dopt=Abstract %R 10.1038/ng.920 %0 Journal Article %J Circulation %D 2011 %T Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels. %A Dehghan, Abbas %A Dupuis, Josée %A Barbalic, Maja %A Bis, Joshua C %A Eiriksdottir, Gudny %A Lu, Chen %A Pellikka, Niina %A Wallaschofski, Henri %A Kettunen, Johannes %A Henneman, Peter %A Baumert, Jens %A Strachan, David P %A Fuchsberger, Christian %A Vitart, Veronique %A Wilson, James F %A Paré, Guillaume %A Naitza, Silvia %A Rudock, Megan E %A Surakka, Ida %A de Geus, Eco J C %A Alizadeh, Behrooz Z %A Guralnik, Jack %A Shuldiner, Alan %A Tanaka, Toshiko %A Zee, Robert Y L %A Schnabel, Renate B %A Nambi, Vijay %A Kavousi, Maryam %A Ripatti, Samuli %A Nauck, Matthias %A Smith, Nicholas L %A Smith, Albert V %A Sundvall, Jouko %A Scheet, Paul %A Liu, Yongmei %A Ruokonen, Aimo %A Rose, Lynda M %A Larson, Martin G %A Hoogeveen, Ron C %A Freimer, Nelson B %A Teumer, Alexander %A Tracy, Russell P %A Launer, Lenore J %A Buring, Julie E %A Yamamoto, Jennifer F %A Folsom, Aaron R %A Sijbrands, Eric J G %A Pankow, James %A Elliott, Paul %A Keaney, John F %A Sun, Wei %A Sarin, Antti-Pekka %A Fontes, João D %A Badola, Sunita %A Astor, Brad C %A Hofman, Albert %A Pouta, Anneli %A Werdan, Karl %A Greiser, Karin H %A Kuss, Oliver %A Meyer zu Schwabedissen, Henriette E %A Thiery, Joachim %A Jamshidi, Yalda %A Nolte, Ilja M %A Soranzo, Nicole %A Spector, Timothy D %A Völzke, Henry %A Parker, Alexander N %A Aspelund, Thor %A Bates, David %A Young, Lauren %A Tsui, Kim %A Siscovick, David S %A Guo, Xiuqing %A Rotter, Jerome I %A Uda, Manuela %A Schlessinger, David %A Rudan, Igor %A Hicks, Andrew A %A Penninx, Brenda W %A Thorand, Barbara %A Gieger, Christian %A Coresh, Joe %A Willemsen, Gonneke %A Harris, Tamara B %A Uitterlinden, André G %A Jarvelin, Marjo-Riitta %A Rice, Kenneth %A Radke, Dörte %A Salomaa, Veikko %A Willems van Dijk, Ko %A Boerwinkle, Eric %A Vasan, Ramachandran S %A Ferrucci, Luigi %A Gibson, Quince D %A Bandinelli, Stefania %A Snieder, Harold %A Boomsma, Dorret I %A Xiao, Xiangjun %A Campbell, Harry %A Hayward, Caroline %A Pramstaller, Peter P %A van Duijn, Cornelia M %A Peltonen, Leena %A Psaty, Bruce M %A Gudnason, Vilmundur %A Ridker, Paul M %A Homuth, Georg %A Koenig, Wolfgang %A Ballantyne, Christie M %A Witteman, Jacqueline C M %A Benjamin, Emelia J %A Perola, Markus %A Chasman, Daniel I %K Biomarkers %K C-Reactive Protein %K Cardiovascular Diseases %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Risk Factors %K Vasculitis %X

BACKGROUND: C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels.

METHODS AND RESULTS: We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P<2.9×10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ≈5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease.

CONCLUSIONS: We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.

%B Circulation %V 123 %P 731-8 %8 2011 Feb 22 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/21300955?dopt=Abstract %R 10.1161/CIRCULATIONAHA.110.948570 %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 PLoS Genet %D 2012 %T Genome-wide association and functional follow-up reveals new loci for kidney function. %A Pattaro, Cristian %A Köttgen, Anna %A Teumer, Alexander %A Garnaas, Maija %A Böger, Carsten A %A Fuchsberger, Christian %A Olden, Matthias %A Chen, Ming-Huei %A Tin, Adrienne %A Taliun, Daniel %A Li, Man %A Gao, Xiaoyi %A Gorski, Mathias %A Yang, Qiong %A Hundertmark, Claudia %A Foster, Meredith C %A O'Seaghdha, Conall M %A Glazer, Nicole %A Isaacs, Aaron %A Liu, Ching-Ti %A Smith, Albert V %A O'Connell, Jeffrey R %A Struchalin, Maksim %A Tanaka, Toshiko %A Li, Guo %A Johnson, Andrew D %A Gierman, Hinco J %A Feitosa, Mary %A Hwang, Shih-Jen %A Atkinson, Elizabeth J %A Lohman, Kurt %A Cornelis, Marilyn C %A Johansson, Asa %A Tönjes, Anke %A Dehghan, Abbas %A Chouraki, Vincent %A Holliday, Elizabeth G %A Sorice, Rossella %A Kutalik, Zoltán %A Lehtimäki, Terho %A Esko, Tõnu %A Deshmukh, Harshal %A Ulivi, Sheila %A Chu, Audrey Y %A Murgia, Federico %A Trompet, Stella %A Imboden, Medea %A Kollerits, Barbara %A Pistis, Giorgio %A Harris, Tamara B %A Launer, Lenore J %A Aspelund, Thor %A Eiriksdottir, Gudny %A Mitchell, Braxton D %A Boerwinkle, Eric %A Schmidt, Helena %A Cavalieri, Margherita %A Rao, Madhumathi %A Hu, Frank B %A Demirkan, Ayse %A Oostra, Ben A %A de Andrade, Mariza %A Turner, Stephen T %A Ding, Jingzhong %A Andrews, Jeanette S %A Freedman, Barry I %A Koenig, Wolfgang %A Illig, Thomas %A Döring, Angela %A Wichmann, H-Erich %A Kolcic, Ivana %A Zemunik, Tatijana %A Boban, Mladen %A Minelli, Cosetta %A Wheeler, Heather E %A Igl, Wilmar %A Zaboli, Ghazal %A Wild, Sarah H %A Wright, Alan F %A Campbell, Harry %A Ellinghaus, David %A Nöthlings, Ute %A Jacobs, Gunnar %A Biffar, Reiner %A Endlich, Karlhans %A Ernst, Florian %A Homuth, Georg %A Kroemer, Heyo K %A Nauck, Matthias %A Stracke, Sylvia %A Völker, Uwe %A Völzke, Henry %A Kovacs, Peter %A Stumvoll, Michael %A Mägi, Reedik %A Hofman, Albert %A Uitterlinden, André G %A Rivadeneira, Fernando %A Aulchenko, Yurii S %A Polasek, Ozren %A Hastie, Nick %A Vitart, Veronique %A Helmer, Catherine %A Wang, Jie Jin %A Ruggiero, Daniela %A Bergmann, Sven %A Kähönen, Mika %A Viikari, Jorma %A Nikopensius, Tiit %A Province, Michael %A Ketkar, Shamika %A Colhoun, Helen %A Doney, Alex %A Robino, Antonietta %A Giulianini, Franco %A Krämer, Bernhard K %A Portas, Laura %A Ford, Ian %A Buckley, Brendan M %A Adam, Martin %A Thun, Gian-Andri %A Paulweber, Bernhard %A Haun, Margot %A Sala, Cinzia %A Metzger, Marie %A Mitchell, Paul %A Ciullo, Marina %A Kim, Stuart K %A Vollenweider, Peter %A Raitakari, Olli %A Metspalu, Andres %A Palmer, Colin %A Gasparini, Paolo %A Pirastu, Mario %A Jukema, J Wouter %A Probst-Hensch, Nicole M %A Kronenberg, Florian %A Toniolo, Daniela %A Gudnason, Vilmundur %A Shuldiner, Alan R %A Coresh, Josef %A Schmidt, Reinhold %A Ferrucci, Luigi %A Siscovick, David S %A van Duijn, Cornelia M %A Borecki, Ingrid %A Kardia, Sharon L R %A Liu, Yongmei %A Curhan, Gary C %A Rudan, Igor %A Gyllensten, Ulf %A Wilson, James F %A Franke, Andre %A Pramstaller, Peter P %A Rettig, Rainer %A Prokopenko, Inga %A Witteman, Jacqueline C M %A Hayward, Caroline %A Ridker, Paul %A Parsa, Afshin %A Bochud, Murielle %A Heid, Iris M %A Goessling, Wolfram %A Chasman, Daniel I %A Kao, W H Linda %A Fox, Caroline S %K African Americans %K Aged %K Animals %K Caspase 9 %K Cyclin-Dependent Kinases %K DEAD-box RNA Helicases %K DNA Helicases %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Gene Knockdown Techniques %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Kidney %K Kidney Failure, Chronic %K Male %K Middle Aged %K Phosphoric Diester Hydrolases %K Zebrafish %X

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

%B PLoS Genet %V 8 %P e1002584 %8 2012 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22479191?dopt=Abstract %R 10.1371/journal.pgen.1002584 %0 Journal Article %J PLoS Genet %D 2012 %T Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function. %A Hancock, Dana B %A Soler Artigas, Maria %A Gharib, Sina A %A Henry, Amanda %A Manichaikul, Ani %A Ramasamy, Adaikalavan %A Loth, Daan W %A Imboden, Medea %A Koch, Beate %A McArdle, Wendy L %A Smith, Albert V %A Smolonska, Joanna %A Sood, Akshay %A Tang, Wenbo %A Wilk, Jemma B %A Zhai, Guangju %A Zhao, Jing Hua %A Aschard, Hugues %A Burkart, Kristin M %A Curjuric, Ivan %A Eijgelsheim, Mark %A Elliott, Paul %A Gu, Xiangjun %A Harris, Tamara B %A Janson, Christer %A Homuth, Georg %A Hysi, Pirro G %A Liu, Jason Z %A Loehr, Laura R %A Lohman, Kurt %A Loos, Ruth J F %A Manning, Alisa K %A Marciante, Kristin D %A Obeidat, Ma'en %A Postma, Dirkje S %A Aldrich, Melinda C %A Brusselle, Guy G %A Chen, Ting-Hsu %A Eiriksdottir, Gudny %A Franceschini, Nora %A Heinrich, Joachim %A Rotter, Jerome I %A Wijmenga, Cisca %A Williams, O Dale %A Bentley, Amy R %A Hofman, Albert %A Laurie, Cathy C %A Lumley, Thomas %A Morrison, Alanna C %A Joubert, Bonnie R %A Rivadeneira, Fernando %A Couper, David J %A Kritchevsky, Stephen B %A Liu, Yongmei %A Wjst, Matthias %A Wain, Louise V %A Vonk, Judith M %A Uitterlinden, André G %A Rochat, Thierry %A Rich, Stephen S %A Psaty, Bruce M %A O'Connor, George T %A North, Kari E %A Mirel, Daniel B %A Meibohm, Bernd %A Launer, Lenore J %A Khaw, Kay-Tee %A Hartikainen, Anna-Liisa %A Hammond, Christopher J %A Gläser, Sven %A Marchini, Jonathan %A Kraft, Peter %A Wareham, Nicholas J %A Völzke, Henry %A Stricker, Bruno H C %A Spector, Timothy D %A Probst-Hensch, Nicole M %A Jarvis, Deborah %A Jarvelin, Marjo-Riitta %A Heckbert, Susan R %A Gudnason, Vilmundur %A Boezen, H Marike %A Barr, R Graham %A Cassano, Patricia A %A Strachan, David P %A Fornage, Myriam %A Hall, Ian P %A Dupuis, Josée %A Tobin, Martin D %A London, Stephanie J %K Forced Expiratory Volume %K Gene Expression %K Genome, Human %K Genome-Wide Association Study %K HLA-DQ Antigens %K HLA-DQ beta-Chains %K Humans %K Lung %K Nerve Tissue Proteins %K Polymorphism, Single Nucleotide %K Potassium Channels, Inwardly Rectifying %K Pulmonary Disease, Chronic Obstructive %K Receptors, Cell Surface %K Smoking %K SOX9 Transcription Factor %K Vital Capacity %X

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

%B PLoS Genet %V 8 %P e1003098 %8 2012 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/23284291?dopt=Abstract %R 10.1371/journal.pgen.1003098 %0 Journal Article %J J Am Soc Nephrol %D 2013 %T Common variants in Mendelian kidney disease genes and their association with renal function. %A Parsa, Afshin %A Fuchsberger, Christian %A Köttgen, Anna %A O'Seaghdha, Conall M %A Pattaro, Cristian %A de Andrade, Mariza %A Chasman, Daniel I %A Teumer, Alexander %A Endlich, Karlhans %A Olden, Matthias %A Chen, Ming-Huei %A Tin, Adrienne %A Kim, Young J %A Taliun, Daniel %A Li, Man %A Feitosa, Mary %A Gorski, Mathias %A Yang, Qiong %A Hundertmark, Claudia %A Foster, Meredith C %A Glazer, Nicole %A Isaacs, Aaron %A Rao, Madhumathi %A Smith, Albert V %A O'Connell, Jeffrey R %A Struchalin, Maksim %A Tanaka, Toshiko %A Li, Guo %A Hwang, Shih-Jen %A Atkinson, Elizabeth J %A Lohman, Kurt %A Cornelis, Marilyn C %A Johansson, Asa %A Tönjes, Anke %A Dehghan, Abbas %A Couraki, Vincent %A Holliday, Elizabeth G %A Sorice, Rossella %A Kutalik, Zoltán %A Lehtimäki, Terho %A Esko, Tõnu %A Deshmukh, Harshal %A Ulivi, Sheila %A Chu, Audrey Y %A Murgia, Federico %A Trompet, Stella %A Imboden, Medea %A Kollerits, Barbara %A Pistis, Giorgio %A Harris, Tamara B %A Launer, Lenore J %A Aspelund, Thor %A Eiriksdottir, Gudny %A Mitchell, Braxton D %A Boerwinkle, Eric %A Schmidt, Helena %A Hofer, Edith %A Hu, Frank %A Demirkan, Ayse %A Oostra, Ben A %A Turner, Stephen T %A Ding, Jingzhong %A Andrews, Jeanette S %A Freedman, Barry I %A Giulianini, Franco %A Koenig, Wolfgang %A Illig, Thomas %A Döring, Angela %A Wichmann, H-Erich %A Zgaga, Lina %A Zemunik, Tatijana %A Boban, Mladen %A Minelli, Cosetta %A Wheeler, Heather E %A Igl, Wilmar %A Zaboli, Ghazal %A Wild, Sarah H %A Wright, Alan F %A Campbell, Harry %A Ellinghaus, David %A Nöthlings, Ute %A Jacobs, Gunnar %A Biffar, Reiner %A Ernst, Florian %A Homuth, Georg %A Kroemer, Heyo K %A Nauck, Matthias %A Stracke, Sylvia %A Völker, Uwe %A Völzke, Henry %A Kovacs, Peter %A Stumvoll, Michael %A Mägi, Reedik %A Hofman, Albert %A Uitterlinden, André G %A Rivadeneira, Fernando %A Aulchenko, Yurii S %A Polasek, Ozren %A Hastie, Nick %A Vitart, Veronique %A Helmer, Catherine %A Wang, Jie Jin %A Stengel, Bénédicte %A Ruggiero, Daniela %A Bergmann, Sven %A Kähönen, Mika %A Viikari, Jorma %A Nikopensius, Tiit %A Province, Michael %A Colhoun, Helen %A Doney, Alex %A Robino, Antonietta %A Krämer, Bernhard K %A Portas, Laura %A Ford, Ian %A Buckley, Brendan M %A Adam, Martin %A Thun, Gian-Andri %A Paulweber, Bernhard %A Haun, Margot %A Sala, Cinzia %A Mitchell, Paul %A Ciullo, Marina %A Vollenweider, Peter %A Raitakari, Olli %A Metspalu, Andres %A Palmer, Colin %A Gasparini, Paolo %A Pirastu, Mario %A Jukema, J Wouter %A Probst-Hensch, Nicole M %A Kronenberg, Florian %A Toniolo, Daniela %A Gudnason, Vilmundur %A Shuldiner, Alan R %A Coresh, Josef %A Schmidt, Reinhold %A Ferrucci, Luigi %A van Duijn, Cornelia M %A Borecki, Ingrid %A Kardia, Sharon L R %A Liu, Yongmei %A Curhan, Gary C %A Rudan, Igor %A Gyllensten, Ulf %A Wilson, James F %A Franke, Andre %A Pramstaller, Peter P %A Rettig, Rainer %A Prokopenko, Inga %A Witteman, Jacqueline %A Hayward, Caroline %A Ridker, Paul M %A Bochud, Murielle %A Heid, Iris M %A Siscovick, David S %A Fox, Caroline S %A Kao, W Linda %A Böger, Carsten A %K Databases, Genetic %K European Continental Ancestry Group %K Gene Frequency %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Kidney %K Mendelian Randomization Analysis %K Phenotype %K Polymorphism, Single Nucleotide %K Renal Insufficiency, Chronic %X

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

%B J Am Soc Nephrol %V 24 %P 2105-17 %8 2013 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/24029420?dopt=Abstract %R 10.1681/ASN.2012100983 %0 Journal Article %J Nat Genet %D 2013 %T 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 Circulation %D 2013 %T Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease. %A Sabater-Lleal, Maria %A Huang, Jie %A Chasman, Daniel %A Naitza, Silvia %A Dehghan, Abbas %A Johnson, Andrew D %A Teumer, Alexander %A Reiner, Alex P %A Folkersen, Lasse %A Basu, Saonli %A Rudnicka, Alicja R %A Trompet, Stella %A Mälarstig, Anders %A Baumert, Jens %A Bis, Joshua C %A Guo, Xiuqing %A Hottenga, Jouke J %A Shin, So-Youn %A Lopez, Lorna M %A Lahti, Jari %A Tanaka, Toshiko %A Yanek, Lisa R %A Oudot-Mellakh, Tiphaine %A Wilson, James F %A Navarro, Pau %A Huffman, Jennifer E %A Zemunik, Tatijana %A Redline, Susan %A Mehra, Reena %A Pulanic, Drazen %A Rudan, Igor %A Wright, Alan F %A Kolcic, Ivana %A Polasek, Ozren %A Wild, Sarah H %A Campbell, Harry %A Curb, J David %A Wallace, Robert %A Liu, Simin %A Eaton, Charles B %A Becker, Diane M %A Becker, Lewis C %A Bandinelli, Stefania %A Räikkönen, Katri %A Widen, Elisabeth %A Palotie, Aarno %A Fornage, Myriam %A Green, David %A Gross, Myron %A Davies, Gail %A Harris, Sarah E %A Liewald, David C %A Starr, John M %A Williams, Frances M K %A Grant, Peter J %A Spector, Timothy D %A Strawbridge, Rona J %A Silveira, Angela %A Sennblad, Bengt %A Rivadeneira, Fernando %A Uitterlinden, André G %A Franco, Oscar H %A Hofman, Albert %A van Dongen, Jenny %A Willemsen, Gonneke %A Boomsma, Dorret I %A Yao, Jie %A Swords Jenny, Nancy %A Haritunians, Talin %A McKnight, Barbara %A Lumley, Thomas %A Taylor, Kent D %A Rotter, Jerome I %A Psaty, Bruce M %A Peters, Annette %A Gieger, Christian %A Illig, Thomas %A Grotevendt, Anne %A Homuth, Georg %A Völzke, Henry %A Kocher, Thomas %A Goel, Anuj %A Franzosi, Maria Grazia %A Seedorf, Udo %A Clarke, Robert %A Steri, Maristella %A Tarasov, Kirill V %A Sanna, Serena %A Schlessinger, David %A Stott, David J %A Sattar, Naveed %A Buckley, Brendan M %A Rumley, Ann %A Lowe, Gordon D %A McArdle, Wendy L %A Chen, Ming-Huei %A Tofler, Geoffrey H %A Song, Jaejoon %A Boerwinkle, Eric %A Folsom, Aaron R %A Rose, Lynda M %A Franco-Cereceda, Anders %A Teichert, Martina %A Ikram, M Arfan %A Mosley, Thomas H %A Bevan, Steve %A Dichgans, Martin %A Rothwell, Peter M %A Sudlow, Cathie L M %A Hopewell, Jemma C %A Chambers, John C %A Saleheen, Danish %A Kooner, Jaspal S %A Danesh, John %A Nelson, Christopher P %A Erdmann, Jeanette %A Reilly, Muredach P %A Kathiresan, Sekar %A Schunkert, Heribert %A Morange, Pierre-Emmanuel %A Ferrucci, Luigi %A Eriksson, Johan G %A Jacobs, David %A Deary, Ian J %A Soranzo, Nicole %A Witteman, Jacqueline C M %A de Geus, Eco J C %A Tracy, Russell P %A Hayward, Caroline %A Koenig, Wolfgang %A Cucca, Francesco %A Jukema, J Wouter %A Eriksson, Per %A Seshadri, Sudha %A Markus, Hugh S %A Watkins, Hugh %A Samani, Nilesh J %A Wallaschofski, Henri %A Smith, Nicholas L %A Tregouet, David %A Ridker, Paul M %A Tang, Weihong %A Strachan, David P %A Hamsten, Anders %A O'Donnell, Christopher J %K Adolescent %K Adult %K African Continental Ancestry Group %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Coronary Artery Disease %K European Continental Ancestry Group %K Female %K Fibrinogen %K Genetic Loci %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Hispanic Americans %K Humans %K Male %K Middle Aged %K Myocardial Infarction %K Polymorphism, Single Nucleotide %K Risk Factors %K Stroke %K Venous Thromboembolism %K Young Adult %X

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

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

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

%B Circulation %V 128 %P 1310-24 %8 2013 Sep 17 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/23969696?dopt=Abstract %R 10.1161/CIRCULATIONAHA.113.002251 %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 PLoS Genet %D 2014 %T Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease. %A Medici, Marco %A Porcu, Eleonora %A Pistis, Giorgio %A Teumer, Alexander %A Brown, Suzanne J %A Jensen, Richard A %A Rawal, Rajesh %A Roef, Greet L %A Plantinga, Theo S %A Vermeulen, Sita H %A Lahti, Jari %A Simmonds, Matthew J %A Husemoen, Lise Lotte N %A Freathy, Rachel M %A Shields, Beverley M %A Pietzner, Diana %A Nagy, Rebecca %A Broer, Linda %A Chaker, Layal %A Korevaar, Tim I M %A Plia, Maria Grazia %A Sala, Cinzia %A Völker, Uwe %A Richards, J Brent %A Sweep, Fred C %A Gieger, Christian %A Corre, Tanguy %A Kajantie, Eero %A Thuesen, Betina %A Taes, Youri E %A Visser, W Edward %A Hattersley, Andrew T %A Kratzsch, Jürgen %A Hamilton, Alexander %A Li, Wei %A Homuth, Georg %A Lobina, Monia %A Mariotti, Stefano %A Soranzo, Nicole %A Cocca, Massimiliano %A Nauck, Matthias %A Spielhagen, Christin %A Ross, Alec %A Arnold, Alice %A van de Bunt, Martijn %A Liyanarachchi, Sandya %A Heier, Margit %A Grabe, Hans Jörgen %A Masciullo, Corrado %A Galesloot, Tessel E %A Lim, Ee M %A Reischl, Eva %A Leedman, Peter J %A Lai, Sandra %A Delitala, Alessandro %A Bremner, Alexandra P %A Philips, David I W %A Beilby, John P %A Mulas, Antonella %A Vocale, Matteo %A Abecasis, Goncalo %A Forsen, Tom %A James, Alan %A Widen, Elisabeth %A Hui, Jennie %A Prokisch, Holger %A Rietzschel, Ernst E %A Palotie, Aarno %A Feddema, Peter %A Fletcher, Stephen J %A Schramm, Katharina %A Rotter, Jerome I %A Kluttig, Alexander %A Radke, Dörte %A Traglia, Michela %A Surdulescu, Gabriela L %A He, Huiling %A Franklyn, Jayne A %A Tiller, Daniel %A Vaidya, Bijay %A De Meyer, Tim %A Jørgensen, Torben %A Eriksson, Johan G %A O'Leary, Peter C %A Wichmann, Eric %A Hermus, Ad R %A Psaty, Bruce M %A Ittermann, Till %A Hofman, Albert %A Bosi, Emanuele %A Schlessinger, David %A Wallaschofski, Henri %A Pirastu, Nicola %A Aulchenko, Yurii S %A de la Chapelle, Albert %A Netea-Maier, Romana T %A Gough, Stephen C L %A Meyer Zu Schwabedissen, Henriette %A Frayling, Timothy M %A Kaufman, Jean-Marc %A Linneberg, Allan %A Räikkönen, Katri %A Smit, Johannes W A %A Kiemeney, Lambertus A %A Rivadeneira, Fernando %A Uitterlinden, André G %A Walsh, John P %A Meisinger, Christa %A den Heijer, Martin %A Visser, Theo J %A Spector, Timothy D %A Wilson, Scott G %A Völzke, Henry %A Cappola, Anne %A Toniolo, Daniela %A Sanna, Serena %A Naitza, Silvia %A Peeters, Robin P %K Autoantibodies %K Genetic Loci %K Genome-Wide Association Study %K Graves Disease %K Hashimoto Disease %K Humans %K Iodide Peroxidase %K Risk Factors %K Thyroiditis, Autoimmune %K Thyrotropin %X

Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, P = 8.1×10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9×10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5×10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, P = 1.2×10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2×10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9×10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.

%B PLoS Genet %V 10 %P e1004123 %8 2014 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24586183?dopt=Abstract %R 10.1371/journal.pgen.1004123 %0 Journal Article %J PLoS One %D 2014 %T No evidence for genome-wide interactions on plasma fibrinogen by smoking, alcohol consumption and body mass index: results from meta-analyses of 80,607 subjects. %A Baumert, Jens %A Huang, Jie %A McKnight, Barbara %A Sabater-Lleal, Maria %A Steri, Maristella %A Chu, Audrey Y %A Trompet, Stella %A Lopez, Lorna M %A Fornage, Myriam %A Teumer, Alexander %A Tang, Weihong %A Rudnicka, Alicja R %A Mälarstig, Anders %A Hottenga, Jouke-Jan %A Kavousi, Maryam %A Lahti, Jari %A Tanaka, Toshiko %A Hayward, Caroline %A Huffman, Jennifer E %A Morange, Pierre-Emmanuel %A Rose, Lynda M %A Basu, Saonli %A Rumley, Ann %A Stott, David J %A Buckley, Brendan M %A de Craen, Anton J M %A Sanna, Serena %A Masala, Marco %A Biffar, Reiner %A Homuth, Georg %A Silveira, Angela %A Sennblad, Bengt %A Goel, Anuj %A Watkins, Hugh %A Müller-Nurasyid, Martina %A Rückerl, Regina %A Taylor, Kent %A Chen, Ming-Huei %A de Geus, Eco J C %A Hofman, Albert %A Witteman, Jacqueline C M %A de Maat, Moniek P M %A Palotie, Aarno %A Davies, Gail %A Siscovick, David S %A Kolcic, Ivana %A Wild, Sarah H %A Song, Jaejoon %A McArdle, Wendy L %A Ford, Ian %A Sattar, Naveed %A Schlessinger, David %A Grotevendt, Anne %A Franzosi, Maria Grazia %A Illig, Thomas %A Waldenberger, Melanie %A Lumley, Thomas %A Tofler, Geoffrey H %A Willemsen, Gonneke %A Uitterlinden, André G %A Rivadeneira, Fernando %A Räikkönen, Katri %A Chasman, Daniel I %A Folsom, Aaron R %A Lowe, Gordon D %A Westendorp, Rudi G J %A Slagboom, P Eline %A Cucca, Francesco %A Wallaschofski, Henri %A Strawbridge, Rona J %A Seedorf, Udo %A Koenig, Wolfgang %A Bis, Joshua C %A Mukamal, Kenneth J %A van Dongen, Jenny %A Widen, Elisabeth %A Franco, Oscar H %A Starr, John M %A Liu, Kiang %A Ferrucci, Luigi %A Polasek, Ozren %A Wilson, James F %A Oudot-Mellakh, Tiphaine %A Campbell, Harry %A Navarro, Pau %A Bandinelli, Stefania %A Eriksson, Johan %A Boomsma, Dorret I %A Dehghan, Abbas %A Clarke, Robert %A Hamsten, Anders %A Boerwinkle, Eric %A Jukema, J Wouter %A Naitza, Silvia %A Ridker, Paul M %A Völzke, Henry %A Deary, Ian J %A Reiner, Alexander P %A Trégouët, David-Alexandre %A O'Donnell, Christopher J %A Strachan, David P %A Peters, Annette %A Smith, Nicholas L %K Alcohol Drinking %K Body Mass Index %K Fibrinogen %K Gene-Environment Interaction %K Genomics %K Humans %K Smoking %X

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

%B PLoS One %V 9 %P e111156 %8 2014 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/25551457?dopt=Abstract %R 10.1371/journal.pone.0111156 %0 Journal Article %J J Am Soc Nephrol %D 2016 %T Genetic Variants Associated with Circulating Parathyroid Hormone. %A Robinson-Cohen, Cassianne %A Lutsey, Pamela L %A Kleber, Marcus E %A Nielson, Carrie M %A Mitchell, Braxton D %A Bis, Joshua C %A Eny, Karen M %A Portas, Laura %A Eriksson, Joel %A Lorentzon, Mattias %A Koller, Daniel L %A Milaneschi, Yuri %A Teumer, Alexander %A Pilz, Stefan %A Nethander, Maria %A Selvin, Elizabeth %A Tang, Weihong %A Weng, Lu-Chen %A Wong, Hoi Suen %A Lai, Dongbing %A Peacock, Munro %A Hannemann, Anke %A Völker, Uwe %A Homuth, Georg %A Nauk, Matthias %A Murgia, Federico %A Pattee, Jack W %A Orwoll, Eric %A Zmuda, Joseph M %A Riancho, Jose Antonio %A Wolf, Myles %A Williams, Frances %A Penninx, Brenda %A Econs, Michael J %A Ryan, Kathleen A %A Ohlsson, Claes %A Paterson, Andrew D %A Psaty, Bruce M %A Siscovick, David S %A Rotter, Jerome I %A Pirastu, Mario %A Streeten, Elizabeth %A März, Winfried %A Fox, Caroline %A Coresh, Josef %A Wallaschofski, Henri %A Pankow, James S %A de Boer, Ian H %A Kestenbaum, Bryan %X

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

%B J Am Soc Nephrol %8 2016 Dec 07 %G eng %R 10.1681/ASN.2016010069 %0 Journal Article %J 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 Nat Commun %D 2016 %T A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape. %A Ried, Janina S %A Jeff M, Janina %A Chu, Audrey Y %A Bragg-Gresham, Jennifer L %A van Dongen, Jenny %A Huffman, Jennifer E %A Ahluwalia, Tarunveer S %A Cadby, Gemma %A Eklund, Niina %A Eriksson, Joel %A Esko, Tõnu %A Feitosa, Mary F %A Goel, Anuj %A Gorski, Mathias %A Hayward, Caroline %A Heard-Costa, Nancy L %A Jackson, Anne U %A Jokinen, Eero %A Kanoni, Stavroula %A Kristiansson, Kati %A Kutalik, Zoltán %A Lahti, Jari %A Luan, Jian'an %A Mägi, Reedik %A Mahajan, Anubha %A Mangino, Massimo %A Medina-Gómez, Carolina %A Monda, Keri L %A Nolte, Ilja M %A Perusse, Louis %A Prokopenko, Inga %A Qi, Lu %A Rose, Lynda M %A Salvi, Erika %A Smith, Megan T %A Snieder, Harold %A Stančáková, Alena %A Ju Sung, Yun %A Tachmazidou, Ioanna %A Teumer, Alexander %A Thorleifsson, Gudmar %A van der Harst, Pim %A Walker, Ryan W %A Wang, Sophie R %A Wild, Sarah H %A Willems, Sara M %A Wong, Andrew %A Zhang, Weihua %A Albrecht, Eva %A Couto Alves, Alexessander %A Bakker, Stephan J L %A Barlassina, Cristina %A Bartz, Traci M %A Beilby, John %A Bellis, Claire %A Bergman, Richard N %A Bergmann, Sven %A Blangero, John %A Blüher, Matthias %A Boerwinkle, Eric %A Bonnycastle, Lori L %A Bornstein, Stefan R %A Bruinenberg, Marcel %A Campbell, Harry %A Chen, Yii-Der Ida %A Chiang, Charleston W K %A Chines, Peter S %A Collins, Francis S %A Cucca, Fracensco %A Cupples, L Adrienne %A D'Avila, Francesca %A de Geus, Eco J C %A Dedoussis, George %A Dimitriou, Maria %A Döring, Angela %A Eriksson, Johan G %A Farmaki, Aliki-Eleni %A Farrall, Martin %A Ferreira, Teresa %A Fischer, Krista %A Forouhi, Nita G %A Friedrich, Nele %A Gjesing, Anette Prior %A Glorioso, Nicola %A Graff, Mariaelisa %A Grallert, Harald %A Grarup, Niels %A Gräßler, Jürgen %A Grewal, Jagvir %A Hamsten, Anders %A Harder, Marie Neergaard %A Hartman, Catharina A %A Hassinen, Maija %A Hastie, Nicholas %A Hattersley, Andrew Tym %A Havulinna, Aki S %A Heliövaara, Markku %A Hillege, Hans %A Hofman, Albert %A Holmen, Oddgeir %A Homuth, Georg %A Hottenga, Jouke-Jan %A Hui, Jennie %A Husemoen, Lise Lotte %A Hysi, Pirro G %A Isaacs, Aaron %A Ittermann, Till %A Jalilzadeh, Shapour %A James, Alan L %A Jørgensen, Torben %A Jousilahti, Pekka %A Jula, Antti %A Marie Justesen, Johanne %A Justice, Anne E %A Kähönen, Mika %A Karaleftheri, Maria %A Tee Khaw, Kay %A Keinanen-Kiukaanniemi, Sirkka M %A Kinnunen, Leena %A Knekt, Paul B %A Koistinen, Heikki A %A Kolcic, Ivana %A Kooner, Ishminder K %A Koskinen, Seppo %A Kovacs, Peter %A Kyriakou, Theodosios %A Laitinen, Tomi %A Langenberg, Claudia %A Lewin, Alexandra M %A Lichtner, Peter %A Lindgren, Cecilia M %A Lindström, Jaana %A Linneberg, Allan %A Lorbeer, Roberto %A Lorentzon, Mattias %A Luben, Robert %A Lyssenko, Valeriya %A Männistö, Satu %A Manunta, Paolo %A Leach, Irene Mateo %A McArdle, Wendy L %A McKnight, Barbara %A Mohlke, Karen L %A Mihailov, Evelin %A Milani, Lili %A Mills, Rebecca %A Montasser, May E %A Morris, Andrew P %A Müller, Gabriele %A Musk, Arthur W %A Narisu, Narisu %A Ong, Ken K %A Oostra, Ben A %A Osmond, Clive %A Palotie, Aarno %A Pankow, James S %A Paternoster, Lavinia %A Penninx, Brenda W %A Pichler, Irene %A Pilia, Maria G %A Polasek, Ozren %A Pramstaller, Peter P %A Raitakari, Olli T %A Rankinen, Tuomo %A Rao, D C %A Rayner, Nigel W %A Ribel-Madsen, Rasmus %A Rice, Treva K %A Richards, Marcus %A Ridker, Paul M %A Rivadeneira, Fernando %A Ryan, Kathy A %A Sanna, Serena %A Sarzynski, Mark A %A Scholtens, Salome %A Scott, Robert A %A Sebert, Sylvain %A Southam, Lorraine %A Sparsø, Thomas Hempel %A Steinthorsdottir, Valgerdur %A Stirrups, Kathleen %A Stolk, Ronald P %A Strauch, Konstantin %A Stringham, Heather M %A Swertz, Morris A %A Swift, Amy J %A Tönjes, Anke %A Tsafantakis, Emmanouil %A van der Most, Peter J %A van Vliet-Ostaptchouk, Jana V %A Vandenput, Liesbeth %A Vartiainen, Erkki %A Venturini, Cristina %A Verweij, Niek %A Viikari, Jorma S %A Vitart, Veronique %A Vohl, Marie-Claude %A Vonk, Judith M %A Waeber, Gérard %A Widen, Elisabeth %A Willemsen, Gonneke %A Wilsgaard, Tom %A Winkler, Thomas W %A Wright, Alan F %A Yerges-Armstrong, Laura M %A Hua Zhao, Jing %A Zillikens, M Carola %A Boomsma, Dorret I %A Bouchard, Claude %A Chambers, John C %A Chasman, Daniel I %A Cusi, Daniele %A Gansevoort, Ron T %A Gieger, Christian %A Hansen, Torben %A Hicks, Andrew A %A Hu, Frank %A Hveem, Kristian %A Jarvelin, Marjo-Riitta %A Kajantie, Eero %A Kooner, Jaspal S %A Kuh, Diana %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo A %A Lehtimäki, Terho %A Metspalu, Andres %A Njølstad, Inger %A Ohlsson, Claes %A Oldehinkel, Albertine J %A Palmer, Lyle J %A Pedersen, Oluf %A Perola, Markus %A Peters, Annette %A Psaty, Bruce M %A Puolijoki, Hannu %A Rauramaa, Rainer %A Rudan, Igor %A Salomaa, Veikko %A Schwarz, Peter E H %A Shudiner, Alan R %A Smit, Jan H %A Sørensen, Thorkild I A %A Spector, Timothy D %A Stefansson, Kari %A Stumvoll, Michael %A Tremblay, Angelo %A Tuomilehto, Jaakko %A Uitterlinden, André G %A Uusitupa, Matti %A Völker, Uwe %A Vollenweider, Peter %A Wareham, Nicholas J %A Watkins, Hugh %A Wilson, James F %A Zeggini, Eleftheria %A Abecasis, Goncalo R %A Boehnke, Michael %A Borecki, Ingrid B %A Deloukas, Panos %A van Duijn, Cornelia M %A Fox, Caroline %A Groop, Leif C %A Heid, Iris M %A Hunter, David J %A Kaplan, Robert C %A McCarthy, Mark I %A North, Kari E %A O'Connell, Jeffrey R %A Schlessinger, David %A Thorsteinsdottir, Unnur %A Strachan, David P %A Frayling, Timothy %A Hirschhorn, Joel N %A Müller-Nurasyid, Martina %A Loos, Ruth J F %K Anthropometry %K Body Size %K Genome-Wide Association Study %K Genotype %K Humans %K Models, Genetic %K Principal Component Analysis %X

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

%B Nat Commun %V 7 %P 13357 %8 2016 11 23 %G eng %R 10.1038/ncomms13357 %0 Journal Article %J Nat Commun %D 2017 %T Large meta-analysis of genome-wide association studies identifies five loci for lean body mass. %A Zillikens, M Carola %A Demissie, Serkalem %A Hsu, Yi-Hsiang %A Yerges-Armstrong, Laura M %A Chou, Wen-Chi %A Stolk, Lisette %A Livshits, Gregory %A Broer, Linda %A Johnson, Toby %A Koller, Daniel L %A Kutalik, Zoltán %A Luan, Jian'an %A Malkin, Ida %A Ried, Janina S %A Smith, Albert V %A Thorleifsson, Gudmar %A Vandenput, Liesbeth %A Hua Zhao, Jing %A Zhang, Weihua %A Aghdassi, Ali %A Åkesson, Kristina %A Amin, Najaf %A Baier, Leslie J %A Barroso, Inês %A Bennett, David A %A Bertram, Lars %A Biffar, Rainer %A Bochud, Murielle %A Boehnke, Michael %A Borecki, Ingrid B %A Buchman, Aron S %A Byberg, Liisa %A Campbell, Harry %A Campos Obanda, Natalia %A Cauley, Jane A %A Cawthon, Peggy M %A Cederberg, Henna %A Chen, Zhao %A Cho, Nam H %A Jin Choi, Hyung %A Claussnitzer, Melina %A Collins, Francis %A Cummings, Steven R %A De Jager, Philip L %A Demuth, Ilja %A Dhonukshe-Rutten, Rosalie A M %A Diatchenko, Luda %A Eiriksdottir, Gudny %A Enneman, Anke W %A Erdos, Mike %A Eriksson, Johan G %A Eriksson, Joel %A Estrada, Karol %A Evans, Daniel S %A Feitosa, Mary F %A Fu, Mao %A Garcia, Melissa %A Gieger, Christian %A Girke, Thomas %A Glazer, Nicole L %A Grallert, Harald %A Grewal, Jagvir %A Han, Bok-Ghee %A Hanson, Robert L %A Hayward, Caroline %A Hofman, Albert %A Hoffman, Eric P %A Homuth, Georg %A Hsueh, Wen-Chi %A Hubal, Monica J %A Hubbard, Alan %A Huffman, Kim M %A Husted, Lise B %A Illig, Thomas %A Ingelsson, Erik %A Ittermann, Till %A Jansson, John-Olov %A Jordan, Joanne M %A Jula, Antti %A Karlsson, Magnus %A Khaw, Kay-Tee %A Kilpeläinen, Tuomas O %A Klopp, Norman %A Kloth, Jacqueline S L %A Koistinen, Heikki A %A Kraus, William E %A Kritchevsky, Stephen %A Kuulasmaa, Teemu %A Kuusisto, Johanna %A Laakso, Markku %A Lahti, Jari %A Lang, Thomas %A Langdahl, Bente L %A Launer, Lenore J %A Lee, Jong-Young %A Lerch, Markus M %A Lewis, Joshua R %A Lind, Lars %A Lindgren, Cecilia %A Liu, Yongmei %A Liu, Tian %A Liu, Youfang %A Ljunggren, Osten %A Lorentzon, Mattias %A Luben, Robert N %A Maixner, William %A McGuigan, Fiona E %A Medina-Gómez, Carolina %A Meitinger, Thomas %A Melhus, Håkan %A Mellström, Dan %A Melov, Simon %A Michaëlsson, Karl %A Mitchell, Braxton D %A Morris, Andrew P %A Mosekilde, Leif %A Newman, Anne %A Nielson, Carrie M %A O'Connell, Jeffrey R %A Oostra, Ben A %A Orwoll, Eric S %A Palotie, Aarno %A Parker, Stephen C J %A Peacock, Munro %A Perola, Markus %A Peters, Annette %A Polasek, Ozren %A Prince, Richard L %A Räikkönen, Katri %A Ralston, Stuart H %A Ripatti, Samuli %A Robbins, John A %A Rotter, Jerome I %A Rudan, Igor %A Salomaa, Veikko %A Satterfield, Suzanne %A Schadt, Eric E %A Schipf, Sabine %A Scott, Laura %A Sehmi, Joban %A Shen, Jian %A Soo Shin, Chan %A Sigurdsson, Gunnar %A Smith, Shad %A Soranzo, Nicole %A Stančáková, Alena %A Steinhagen-Thiessen, Elisabeth %A Streeten, Elizabeth A %A Styrkarsdottir, Unnur %A Swart, Karin M A %A Tan, Sian-Tsung %A Tarnopolsky, Mark A %A Thompson, Patricia %A Thomson, Cynthia A %A Thorsteinsdottir, Unnur %A Tikkanen, Emmi %A Tranah, Gregory J %A Tuomilehto, Jaakko %A van Schoor, Natasja M %A Verma, Arjun %A Vollenweider, Peter %A Völzke, Henry %A Wactawski-Wende, Jean %A Walker, Mark %A Weedon, Michael N %A Welch, Ryan %A Wichmann, H-Erich %A Widen, Elisabeth %A Williams, Frances M K %A Wilson, James F %A Wright, Nicole C %A Xie, Weijia %A Yu, Lei %A Zhou, Yanhua %A Chambers, John C %A Döring, Angela %A van Duijn, Cornelia M %A Econs, Michael J %A Gudnason, Vilmundur %A Kooner, Jaspal S %A Psaty, Bruce M %A Spector, Timothy D %A Stefansson, Kari %A Rivadeneira, Fernando %A Uitterlinden, André G %A Wareham, Nicholas J %A Ossowski, Vicky %A Waterworth, Dawn %A Loos, Ruth J F %A Karasik, David %A Harris, Tamara B %A Ohlsson, Claes %A Kiel, Douglas P %X

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

%B Nat Commun %V 8 %P 80 %8 2017 Jul 19 %G eng %N 1 %R 10.1038/s41467-017-00031-7 %0 Journal Article %J Circ Genom Precis Med %D 2018 %T Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval. %A Lin, Honghuang %A van Setten, Jessica %A Smith, Albert V %A Bihlmeyer, Nathan A %A Warren, Helen R %A Brody, Jennifer A %A Radmanesh, Farid %A Hall, Leanne %A Grarup, Niels %A Müller-Nurasyid, Martina %A Boutin, Thibaud %A Verweij, Niek %A Lin, Henry J %A Li-Gao, Ruifang %A van den Berg, Marten E %A Marten, Jonathan %A Weiss, Stefan %A Prins, Bram P %A Haessler, Jeffrey %A Lyytikäinen, Leo-Pekka %A Mei, Hao %A Harris, Tamara B %A Launer, Lenore J %A Li, Man %A Alonso, Alvaro %A Soliman, Elsayed Z %A Connell, John M %A Huang, Paul L %A Weng, Lu-Chen %A Jameson, Heather S %A Hucker, William %A Hanley, Alan %A Tucker, Nathan R %A Chen, Yii-Der Ida %A Bis, Joshua C %A Rice, Kenneth M %A Sitlani, Colleen M %A Kors, Jan A %A Xie, Zhijun %A Wen, Chengping %A Magnani, Jared W %A Nelson, Christopher P %A Kanters, Jørgen K %A Sinner, Moritz F %A Strauch, Konstantin %A Peters, Annette %A Waldenberger, Melanie %A Meitinger, Thomas %A Bork-Jensen, Jette %A Pedersen, Oluf %A Linneberg, Allan %A Rudan, Igor %A de Boer, Rudolf A %A van der Meer, Peter %A Yao, Jie %A Guo, Xiuqing %A Taylor, Kent D %A Sotoodehnia, Nona %A Rotter, Jerome I %A Mook-Kanamori, Dennis O %A Trompet, Stella %A Rivadeneira, Fernando %A Uitterlinden, Andre %A Eijgelsheim, Mark %A Padmanabhan, Sandosh %A Smith, Blair H %A Völzke, Henry %A Felix, Stephan B %A Homuth, Georg %A Völker, Uwe %A Mangino, Massimo %A Spector, Timothy D %A Bots, Michiel L %A Perez, Marco %A Kähönen, Mika %A Raitakari, Olli T %A Gudnason, Vilmundur %A Arking, Dan E %A Munroe, Patricia B %A Psaty, Bruce M %A van Duijn, Cornelia M %A Benjamin, Emelia J %A Rosand, Jonathan %A Samani, Nilesh J %A Hansen, Torben %A Kääb, Stefan %A Polasek, Ozren %A van der Harst, Pim %A Heckbert, Susan R %A Jukema, J Wouter %A Stricker, Bruno H %A Hayward, Caroline %A Dörr, Marcus %A Jamshidi, Yalda %A Asselbergs, Folkert W %A Kooperberg, Charles %A Lehtimäki, Terho %A Wilson, James G %A Ellinor, Patrick T %A Lubitz, Steven A %A Isaacs, Aaron %X

BACKGROUND: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability.

METHODS: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval.

RESULTS: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (<1.2×10), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at (=5.9×10) and (=1.1×10) were associated with PR interval. locus also was implicated in the common variant analysis, whereas was a novel locus.

CONCLUSIONS: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health.

%B Circ Genom Precis Med %V 11 %P e002037 %8 2018 May %G eng %N 5 %R 10.1161/CIRCGEN.117.002037 %0 Journal Article %J Stroke %D 2018 %T Exome Chip Analysis Identifies Low-Frequency and Rare Variants in for White Matter Hyperintensities on Brain Magnetic Resonance Imaging. %A Jian, Xueqiu %A Satizabal, Claudia L %A Smith, Albert V %A Wittfeld, Katharina %A Bis, Joshua C %A Smith, Jennifer A %A Hsu, Fang-Chi %A Nho, Kwangsik %A Hofer, Edith %A Hagenaars, Saskia P %A Nyquist, Paul A %A Mishra, Aniket %A Adams, Hieab H H %A Li, Shuo %A Teumer, Alexander %A Zhao, Wei %A Freedman, Barry I %A Saba, Yasaman %A Yanek, Lisa R %A Chauhan, Ganesh %A van Buchem, Mark A %A Cushman, Mary %A Royle, Natalie A %A Bryan, R Nick %A Niessen, Wiro J %A Windham, Beverly G %A DeStefano, Anita L %A Habes, Mohamad %A Heckbert, Susan R %A Palmer, Nicholette D %A Lewis, Cora E %A Eiriksdottir, Gudny %A Maillard, Pauline %A Mathias, Rasika A %A Homuth, Georg %A Valdés-Hernández, Maria Del C %A Divers, Jasmin %A Beiser, Alexa S %A Langner, Sönke %A Rice, Kenneth M %A Bastin, Mark E %A Yang, Qiong %A Maldjian, Joseph A %A Starr, John M %A Sidney, Stephen %A Risacher, Shannon L %A Uitterlinden, André G %A Gudnason, Vilmundur G %A Nauck, Matthias %A Rotter, Jerome I %A Schreiner, Pamela J %A Boerwinkle, Eric %A van Duijn, Cornelia M %A Mazoyer, Bernard %A von Sarnowski, Bettina %A Gottesman, Rebecca F %A Levy, Daniel %A Sigurdsson, Sigurdur %A Vernooij, Meike W %A Turner, Stephen T %A Schmidt, Reinhold %A Wardlaw, Joanna M %A Psaty, Bruce M %A Mosley, Thomas H %A DeCarli, Charles S %A Saykin, Andrew J %A Bowden, Donald W %A Becker, Diane M %A Deary, Ian J %A Schmidt, Helena %A Kardia, Sharon L R %A Ikram, M Arfan %A Debette, Stephanie %A Grabe, Hans J %A Longstreth, W T %A Seshadri, Sudha %A Launer, Lenore J %A Fornage, Myriam %X

BACKGROUND AND PURPOSE: White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored.

METHODS: In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies.

RESULTS: At 17q25, we confirmed the association of multiple common variants in , , and (<6×10). We also identified a novel association with 2 low-frequency nonsynonymous variants in (lead, rs34136221; =4.5×10) partially independent of known common signal (=1.4×10). We further identified a locus at 2q33 containing common variants in , , and (lead, rs2351524; =1.9×10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency variants (=2.8×10).

CONCLUSIONS: Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.

%B Stroke %8 2018 Jul 12 %G eng %R 10.1161/STROKEAHA.118.020689 %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 analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation. %A Teumer, Alexander %A Chaker, Layal %A Groeneweg, Stefan %A Li, Yong %A Di Munno, Celia %A Barbieri, Caterina %A Schultheiss, Ulla T %A Traglia, Michela %A Ahluwalia, Tarunveer S %A Akiyama, Masato %A Appel, Emil Vincent R %A Arking, Dan E %A Arnold, Alice %A Astrup, Arne %A Beekman, Marian %A Beilby, John P %A Bekaert, Sofie %A Boerwinkle, Eric %A Brown, Suzanne J %A De Buyzere, Marc %A Campbell, Purdey J %A Ceresini, Graziano %A Cerqueira, Charlotte %A Cucca, Francesco %A Deary, Ian J %A Deelen, Joris %A Eckardt, Kai-Uwe %A Ekici, Arif B %A Eriksson, Johan G %A Ferrrucci, Luigi %A Fiers, Tom %A Fiorillo, Edoardo %A Ford, Ian %A Fox, Caroline S %A Fuchsberger, Christian %A Galesloot, Tessel E %A Gieger, Christian %A Gögele, Martin %A De Grandi, Alessandro %A Grarup, Niels %A Greiser, Karin Halina %A Haljas, Kadri %A Hansen, Torben %A Harris, Sarah E %A van Heemst, Diana %A den Heijer, Martin %A Hicks, Andrew A %A den Hollander, Wouter %A Homuth, Georg %A Hui, Jennie %A Ikram, M Arfan %A Ittermann, Till %A Jensen, Richard A %A Jing, Jiaojiao %A Jukema, J Wouter %A Kajantie, Eero %A Kamatani, Yoichiro %A Kasbohm, Elisa %A Kaufman, Jean-Marc %A Kiemeney, Lambertus A %A Kloppenburg, Margreet %A Kronenberg, Florian %A Kubo, Michiaki %A Lahti, Jari %A Lapauw, Bruno %A Li, Shuo %A Liewald, David C M %A Lim, Ee Mun %A Linneberg, Allan %A Marina, Michela %A Mascalzoni, Deborah %A Matsuda, Koichi %A Medenwald, Daniel %A Meisinger, Christa %A Meulenbelt, Ingrid %A De Meyer, Tim %A Meyer zu Schwabedissen, Henriette E %A Mikolajczyk, Rafael %A Moed, Matthijs %A Netea-Maier, Romana T %A Nolte, Ilja M %A Okada, Yukinori %A Pala, Mauro %A Pattaro, Cristian %A Pedersen, Oluf %A Petersmann, Astrid %A Porcu, Eleonora %A Postmus, Iris %A Pramstaller, Peter P %A Psaty, Bruce M %A Ramos, Yolande F M %A Rawal, Rajesh %A Redmond, Paul %A Richards, J Brent %A Rietzschel, Ernst R %A Rivadeneira, Fernando %A Roef, Greet %A Rotter, Jerome I %A Sala, Cinzia F %A Schlessinger, David %A Selvin, Elizabeth %A Slagboom, P Eline %A Soranzo, Nicole %A Sørensen, Thorkild I A %A Spector, Timothy D %A Starr, John M %A Stott, David J %A Taes, Youri %A Taliun, Daniel %A Tanaka, Toshiko %A Thuesen, Betina %A Tiller, Daniel %A Toniolo, Daniela %A Uitterlinden, André G %A Visser, W Edward %A Walsh, John P %A Wilson, Scott G %A Wolffenbuttel, Bruce H R %A Yang, Qiong %A Zheng, Hou-Feng %A Cappola, Anne %A Peeters, Robin P %A Naitza, Silvia %A Völzke, Henry %A Sanna, Serena %A Köttgen, Anna %A Visser, Theo J %A Medici, Marco %X

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

%B Nat Commun %V 9 %P 4455 %8 2018 10 26 %G eng %N 1 %R 10.1038/s41467-018-06356-1 %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 JAMA Cardiol %D 2019 %T Assessment of the Relationship Between Genetic Determinants of Thyroid Function and Atrial Fibrillation: A Mendelian Randomization Study. %A Ellervik, Christina %A Roselli, Carolina %A Christophersen, Ingrid E %A Alonso, Alvaro %A Pietzner, Maik %A Sitlani, Collen M %A Trompet, Stella %A Arking, Dan E %A Geelhoed, Bastiaan %A Guo, Xiuqing %A Kleber, Marcus E %A Lin, Henry J %A Lin, Honghuang %A Macfarlane, Peter %A Selvin, Elizabeth %A Shaffer, Christian %A Smith, Albert V %A Verweij, Niek %A Weiss, Stefan %A Cappola, Anne R %A Dörr, Marcus %A Gudnason, Vilmundur %A Heckbert, Susan %A Mooijaart, Simon %A März, Winfried %A Psaty, Bruce M %A Ridker, Paul M %A Roden, Dan %A Stott, David J %A Völzke, Henry %A Benjamin, Emelia J %A Delgado, Graciela %A Ellinor, Patrick %A Homuth, Georg %A Köttgen, Anna %A Jukema, Johan W %A Lubitz, Steven A %A Mora, Samia %A Rienstra, Michiel %A Rotter, Jerome I %A Shoemaker, M Benjamin %A Sotoodehnia, Nona %A Taylor, Kent D %A van der Harst, Pim %A Albert, Christine M %A Chasman, Daniel I %X

Importance: Increased free thyroxine (FT4) and decreased thyrotropin are associated with increased risk of atrial fibrillation (AF) in observational studies, but direct involvement is unclear.

Objective: To evaluate the potential direct involvement of thyroid traits on AF.

Design, Setting, and Participants: Study-level mendelian randomization (MR) included 11 studies, and summary-level MR included 55 114 AF cases and 482 295 referents, all of European ancestry.

Exposures: Genomewide significant variants were used as instruments for standardized FT4 and thyrotropin levels within the reference range, standardized triiodothyronine (FT3):FT4 ratio, hypothyroidism, standardized thyroid peroxidase antibody levels, and hyperthyroidism. Mendelian randomization used genetic risk scores in study-level analysis or individual single-nucleotide polymorphisms in 2-sample MR for the summary-level data.

Main Outcomes and Measures: Prevalent and incident AF.

Results: The study-level analysis included 7679 individuals with AF and 49 233 referents (mean age [standard error], 62 [3] years; 15 859 men [29.7%]). In study-level random-effects meta-analysis, the pooled hazard ratio of FT4 levels (nanograms per deciliter) for incident AF was 1.55 (95% CI, 1.09-2.20; P = .02; I2 = 76%) and the pooled odds ratio (OR) for prevalent AF was 2.80 (95% CI, 1.41-5.54; P = .003; I2 = 64%) in multivariable-adjusted analyses. The FT4 genetic risk score was associated with an increase in FT4 by 0.082 SD (standard error, 0.007; P < .001) but not with incident AF (risk ratio, 0.84; 95% CI, 0.62-1.14; P = .27) or prevalent AF (OR, 1.32; 95% CI, 0.64-2.73; P = .46). Similarly, in summary-level inverse-variance weighted random-effects MR, gene-based FT4 within the reference range was not associated with AF (OR, 1.01; 95% CI, 0.89-1.14; P = .88). However, gene-based increased FT3:FT4 ratio, increased thyrotropin within the reference range, and hypothyroidism were associated with AF with inverse-variance weighted random-effects OR of 1.33 (95% CI, 1.08-1.63; P = .006), 0.88 (95% CI, 0.84-0.92; P < .001), and 0.94 (95% CI, 0.90-0.99; P = .009), respectively, and robust to tests of horizontal pleiotropy. However, the subset of hypothyroidism single-nucleotide polymorphisms involved in autoimmunity and thyroid peroxidase antibodies levels were not associated with AF. Gene-based hyperthyroidism was associated with AF with MR-Egger OR of 1.31 (95% CI, 1.05-1.63; P = .02) with evidence of horizontal pleiotropy (P = .045).

Conclusions and Relevance: Genetically increased FT3:FT4 ratio and hyperthyroidism, but not FT4 within the reference range, were associated with increased AF, and increased thyrotropin within the reference range and hypothyroidism were associated with decreased AF, supporting a pathway involving the pituitary-thyroid-cardiac axis.

%B JAMA Cardiol %8 2019 Jan 23 %G eng %R 10.1001/jamacardio.2018.4635 %0 Journal Article %J Am J Clin Nutr %D 2019 %T Disentangling the genetics of lean mass. %A Karasik, David %A Zillikens, M Carola %A Hsu, Yi-Hsiang %A Aghdassi, Ali %A Åkesson, Kristina %A Amin, Najaf %A Barroso, Inês %A Bennett, David A %A Bertram, Lars %A Bochud, Murielle %A Borecki, Ingrid B %A Broer, Linda %A Buchman, Aron S %A Byberg, Liisa %A Campbell, Harry %A Campos-Obando, Natalia %A Cauley, Jane A %A Cawthon, Peggy M %A Chambers, John C %A Chen, Zhao %A Cho, Nam H %A Choi, Hyung Jin %A Chou, Wen-Chi %A Cummings, Steven R %A de Groot, Lisette C P G M %A De Jager, Phillip L %A Demuth, Ilja %A Diatchenko, Luda %A Econs, Michael J %A Eiriksdottir, Gudny %A Enneman, Anke W %A Eriksson, Joel %A Eriksson, Johan G %A Estrada, Karol %A Evans, Daniel S %A Feitosa, Mary F %A Fu, Mao %A Gieger, Christian %A Grallert, Harald %A Gudnason, Vilmundur %A Lenore, Launer J %A Hayward, Caroline %A Hofman, Albert %A Homuth, Georg %A Huffman, Kim M %A Husted, Lise B %A Illig, Thomas %A Ingelsson, Erik %A Ittermann, Till %A Jansson, John-Olov %A Johnson, Toby %A Biffar, Reiner %A Jordan, Joanne M %A Jula, Antti %A Karlsson, Magnus %A Khaw, Kay-Tee %A Kilpeläinen, Tuomas O %A Klopp, Norman %A Kloth, Jacqueline S L %A Koller, Daniel L %A Kooner, Jaspal S %A Kraus, William E %A Kritchevsky, Stephen %A Kutalik, Zoltán %A Kuulasmaa, Teemu %A Kuusisto, Johanna %A Laakso, Markku %A Lahti, Jari %A Lang, Thomas %A Langdahl, Bente L %A Lerch, Markus M %A Lewis, Joshua R %A Lill, Christina %A Lind, Lars %A Lindgren, Cecilia %A Liu, Yongmei %A Livshits, Gregory %A Ljunggren, Osten %A Loos, Ruth J F %A Lorentzon, Mattias %A Luan, Jian'an %A Luben, Robert N %A Malkin, Ida %A McGuigan, Fiona E %A Medina-Gómez, Carolina %A Meitinger, Thomas %A Melhus, Håkan %A Mellström, Dan %A Michaëlsson, Karl %A Mitchell, Braxton D %A Morris, Andrew P %A Mosekilde, Leif %A Nethander, Maria %A Newman, Anne B %A O'Connell, Jeffery R %A Oostra, Ben A %A Orwoll, Eric S %A Palotie, Aarno %A Peacock, Munro %A Perola, Markus %A Peters, Annette %A Prince, Richard L %A Psaty, Bruce M %A Räikkönen, Katri %A Ralston, Stuart H %A Ripatti, Samuli %A Rivadeneira, Fernando %A Robbins, John A %A Rotter, Jerome I %A Rudan, Igor %A Salomaa, Veikko %A Satterfield, Suzanne %A Schipf, Sabine %A Shin, Chan Soo %A Smith, Albert V %A Smith, Shad B %A Soranzo, Nicole %A Spector, Timothy D %A Stančáková, Alena %A Stefansson, Kari %A Steinhagen-Thiessen, Elisabeth %A Stolk, Lisette %A Streeten, Elizabeth A %A Styrkarsdottir, Unnur %A Swart, Karin M A %A Thompson, Patricia %A Thomson, Cynthia A %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tikkanen, Emmi %A Tranah, Gregory J %A Uitterlinden, André G %A van Duijn, Cornelia M %A van Schoor, Natasja M %A Vandenput, Liesbeth %A Vollenweider, Peter %A Völzke, Henry %A Wactawski-Wende, Jean %A Walker, Mark %A J Wareham, Nicholas %A Waterworth, Dawn %A Weedon, Michael N %A Wichmann, H-Erich %A Widen, Elisabeth %A Williams, Frances M K %A Wilson, James F %A Wright, Nicole C %A Yerges-Armstrong, Laura M %A Yu, Lei %A Zhang, Weihua %A Zhao, Jing Hua %A Zhou, Yanhua %A Nielson, Carrie M %A Harris, Tamara B %A Demissie, Serkalem %A Kiel, Douglas P %A Ohlsson, Claes %X

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

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

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

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

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

%B Am J Clin Nutr %V 109 %P 276-287 %8 2019 Feb 01 %G eng %N 2 %R 10.1093/ajcn/nqy272 %0 Journal Article %J Nat Genet %D 2019 %T Genetic architecture of subcortical brain structures in 38,851 individuals. %A Satizabal, Claudia L %A Adams, Hieab H H %A Hibar, Derrek P %A White, Charles C %A Knol, Maria J %A Stein, Jason L %A Scholz, Markus %A Sargurupremraj, Muralidharan %A Jahanshad, Neda %A Roshchupkin, Gennady V %A Smith, Albert V %A Bis, Joshua C %A Jian, Xueqiu %A Luciano, Michelle %A Hofer, Edith %A Teumer, Alexander %A van der Lee, Sven J %A Yang, Jingyun %A Yanek, Lisa R %A Lee, Tom V %A Li, Shuo %A Hu, Yanhui %A Koh, Jia Yu %A Eicher, John D %A Desrivières, Sylvane %A Arias-Vasquez, Alejandro %A Chauhan, Ganesh %A Athanasiu, Lavinia %A Rentería, Miguel E %A Kim, Sungeun %A Hoehn, David %A Armstrong, Nicola J %A Chen, Qiang %A Holmes, Avram J %A den Braber, Anouk %A Kloszewska, Iwona %A Andersson, Micael %A Espeseth, Thomas %A Grimm, Oliver %A Abramovic, Lucija %A Alhusaini, Saud %A Milaneschi, Yuri %A Papmeyer, Martina %A Axelsson, Tomas %A Ehrlich, Stefan %A Roiz-Santiañez, Roberto %A Kraemer, Bernd %A Håberg, Asta K %A Jones, Hannah J %A Pike, G Bruce %A Stein, Dan J %A Stevens, Allison %A Bralten, Janita %A Vernooij, Meike W %A Harris, Tamara B %A Filippi, Irina %A Witte, A Veronica %A Guadalupe, Tulio %A Wittfeld, Katharina %A Mosley, Thomas H %A Becker, James T %A Doan, Nhat Trung %A Hagenaars, Saskia P %A Saba, Yasaman %A Cuellar-Partida, Gabriel %A Amin, Najaf %A Hilal, Saima %A Nho, Kwangsik %A Mirza-Schreiber, Nazanin %A Arfanakis, Konstantinos %A Becker, Diane M %A Ames, David %A Goldman, Aaron L %A Lee, Phil H %A Boomsma, Dorret I %A Lovestone, Simon %A Giddaluru, Sudheer %A Le Hellard, Stephanie %A Mattheisen, Manuel %A Bohlken, Marc M %A Kasperaviciute, Dalia %A Schmaal, Lianne %A Lawrie, Stephen M %A Agartz, Ingrid %A Walton, Esther %A Tordesillas-Gutierrez, Diana %A Davies, Gareth E %A Shin, Jean %A Ipser, Jonathan C %A Vinke, Louis N %A Hoogman, Martine %A Jia, Tianye %A Burkhardt, Ralph %A Klein, Marieke %A Crivello, Fabrice %A Janowitz, Deborah %A Carmichael, Owen %A Haukvik, Unn K %A Aribisala, Benjamin S %A Schmidt, Helena %A Strike, Lachlan T %A Cheng, Ching-Yu %A Risacher, Shannon L %A Pütz, Benno %A Fleischman, Debra A %A Assareh, Amelia A %A Mattay, Venkata S %A Buckner, Randy L %A Mecocci, Patrizia %A Dale, Anders M %A Cichon, Sven %A Boks, Marco P %A Matarin, Mar %A Penninx, Brenda W J H %A Calhoun, Vince D %A Chakravarty, M Mallar %A Marquand, Andre F %A Macare, Christine %A Kharabian Masouleh, Shahrzad %A Oosterlaan, Jaap %A Amouyel, Philippe %A Hegenscheid, Katrin %A Rotter, Jerome I %A Schork, Andrew J %A Liewald, David C M %A de Zubicaray, Greig I %A Wong, Tien Yin %A Shen, Li %A Sämann, Philipp G %A Brodaty, Henry %A Roffman, Joshua L %A de Geus, Eco J C %A Tsolaki, Magda %A Erk, Susanne %A van Eijk, Kristel R %A Cavalleri, Gianpiero L %A van der Wee, Nic J A %A McIntosh, Andrew M %A Gollub, Randy L %A Bulayeva, Kazima B %A Bernard, Manon %A Richards, Jennifer S %A Himali, Jayandra J %A Loeffler, Markus %A Rommelse, Nanda %A Hoffmann, Wolfgang %A Westlye, Lars T %A Valdés Hernández, Maria C %A Hansell, Narelle K %A van Erp, Theo G M %A Wolf, Christiane %A Kwok, John B J %A Vellas, Bruno %A Heinz, Andreas %A Olde Loohuis, Loes M %A Delanty, Norman %A Ho, Beng-Choon %A Ching, Christopher R K %A Shumskaya, Elena %A Singh, Baljeet %A Hofman, Albert %A van der Meer, Dennis %A Homuth, Georg %A Psaty, Bruce M %A Bastin, Mark E %A Montgomery, Grant W %A Foroud, Tatiana M %A Reppermund, Simone %A Hottenga, Jouke-Jan %A Simmons, Andrew %A Meyer-Lindenberg, Andreas %A Cahn, Wiepke %A Whelan, Christopher D %A van Donkelaar, Marjolein M J %A Yang, Qiong %A Hosten, Norbert %A Green, Robert C %A Thalamuthu, Anbupalam %A Mohnke, Sebastian %A Hulshoff Pol, Hilleke E %A Lin, Honghuang %A Jack, Clifford R %A Schofield, Peter R %A Mühleisen, Thomas W %A Maillard, Pauline %A Potkin, Steven G %A Wen, Wei %A Fletcher, Evan %A Toga, Arthur W %A Gruber, Oliver %A Huentelman, Matthew %A Davey Smith, George %A Launer, Lenore J %A Nyberg, Lars %A Jönsson, Erik G %A Crespo-Facorro, Benedicto %A Koen, Nastassja %A Greve, Douglas N %A Uitterlinden, André G %A Weinberger, Daniel R %A Steen, Vidar M %A Fedko, Iryna O %A Groenewold, Nynke A %A Niessen, Wiro J %A Toro, Roberto %A Tzourio, Christophe %A Longstreth, William T %A Ikram, M Kamran %A Smoller, Jordan W %A van Tol, Marie-Jose %A Sussmann, Jessika E %A Paus, Tomáš %A Lemaître, Hervé %A Schroeter, Matthias L %A Mazoyer, Bernard %A Andreassen, Ole A %A Holsboer, Florian %A Depondt, Chantal %A Veltman, Dick J %A Turner, Jessica A %A Pausova, Zdenka %A Schumann, Gunter %A van Rooij, Daan %A Djurovic, Srdjan %A Deary, Ian J %A McMahon, Katie L %A Müller-Myhsok, Bertram %A Brouwer, Rachel M %A Soininen, Hilkka %A Pandolfo, Massimo %A Wassink, Thomas H %A Cheung, Joshua W %A Wolfers, Thomas %A Martinot, Jean-Luc %A Zwiers, Marcel P %A Nauck, Matthias %A Melle, Ingrid %A Martin, Nicholas G %A Kanai, Ryota %A Westman, Eric %A Kahn, René S %A Sisodiya, Sanjay M %A White, Tonya %A Saremi, Arvin %A van Bokhoven, Hans %A Brunner, Han G %A Völzke, Henry %A Wright, Margaret J %A van 't Ent, Dennis %A Nöthen, Markus M %A Ophoff, Roel A %A Buitelaar, Jan K %A Fernández, Guillén %A Sachdev, Perminder S %A Rietschel, Marcella %A van Haren, Neeltje E M %A Fisher, Simon E %A Beiser, Alexa S %A Francks, Clyde %A Saykin, Andrew J %A Mather, Karen A %A Romanczuk-Seiferth, Nina %A Hartman, Catharina A %A DeStefano, Anita L %A Heslenfeld, Dirk J %A Weiner, Michael W %A Walter, Henrik %A Hoekstra, Pieter J %A Nyquist, Paul A %A Franke, Barbara %A Bennett, David A %A Grabe, Hans J %A Johnson, Andrew D %A Chen, Christopher %A van Duijn, Cornelia M %A Lopez, Oscar L %A Fornage, Myriam %A Wardlaw, Joanna M %A Schmidt, Reinhold %A DeCarli, Charles %A De Jager, Philip L %A Villringer, Arno %A Debette, Stephanie %A Gudnason, Vilmundur %A Medland, Sarah E %A Shulman, Joshua M %A Thompson, Paul M %A Seshadri, Sudha %A Ikram, M Arfan %X

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

%B Nat Genet %V 51 %P 1624-1636 %8 2019 Nov %G eng %N 11 %R 10.1038/s41588-019-0511-y %0 Journal Article %J Nat Commun %D 2019 %T Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration. %A Noordam, Raymond %A Bos, Maxime M %A Wang, Heming %A Winkler, Thomas W %A Bentley, Amy R %A Kilpeläinen, Tuomas O %A de Vries, Paul S %A Sung, Yun Ju %A Schwander, Karen %A Cade, Brian E %A Manning, Alisa %A Aschard, Hugues %A Brown, Michael R %A Chen, Han %A Franceschini, Nora %A Musani, Solomon K %A Richard, Melissa %A Vojinovic, Dina %A Aslibekyan, Stella %A Bartz, Traci M %A de Las Fuentes, Lisa %A Feitosa, Mary %A Horimoto, Andrea R %A Ilkov, Marjan %A Kho, Minjung %A Kraja, Aldi %A Li, Changwei %A Lim, Elise %A Liu, Yongmei %A Mook-Kanamori, Dennis O %A Rankinen, Tuomo %A Tajuddin, Salman M %A van der Spek, Ashley %A Wang, Zhe %A Marten, Jonathan %A Laville, Vincent %A Alver, Maris %A Evangelou, Evangelos %A Graff, Maria E %A He, Meian %A Kuhnel, Brigitte %A Lyytikäinen, Leo-Pekka %A Marques-Vidal, Pedro %A Nolte, Ilja M %A Palmer, Nicholette D %A Rauramaa, Rainer %A Shu, Xiao-Ou %A Snieder, Harold %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Adolfo, Correa %A Ballantyne, Christie %A Bielak, Larry %A Biermasz, Nienke R %A Boerwinkle, Eric %A Dimou, Niki %A Eiriksdottir, Gudny %A Gao, Chuan %A Gharib, Sina A %A Gottlieb, Daniel J %A Haba-Rubio, José %A Harris, Tamara B %A Heikkinen, Sami %A Heinzer, Raphael %A Hixson, James E %A Homuth, Georg %A Ikram, M Arfan %A Komulainen, Pirjo %A Krieger, Jose E %A Lee, Jiwon %A Liu, Jingmin %A Lohman, Kurt K %A Luik, Annemarie I %A Mägi, Reedik %A Martin, Lisa W %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Nalls, Mike A %A O'Connell, Jeff %A Peters, Annette %A Peyser, Patricia %A Raitakari, Olli T %A Reiner, Alex P %A Rensen, Patrick C N %A Rice, Treva K %A Rich, Stephen S %A Roenneberg, Till %A Rotter, Jerome I %A Schreiner, Pamela J %A Shikany, James %A Sidney, Stephen S %A Sims, Mario %A Sitlani, Colleen M %A Sofer, Tamar %A Strauch, Konstantin %A Swertz, Morris A %A Taylor, Kent D %A Uitterlinden, André G %A van Duijn, Cornelia M %A Völzke, Henry %A Waldenberger, Melanie %A Wallance, Robert B %A van Dijk, Ko Willems %A Yu, Caizheng %A Zonderman, Alan B %A Becker, Diane M %A Elliott, Paul %A Esko, Tõnu %A Gieger, Christian %A Grabe, Hans J %A Lakka, Timo A %A Lehtimäki, Terho %A North, Kari E %A Penninx, Brenda W J H %A Vollenweider, Peter %A Wagenknecht, Lynne E %A Wu, Tangchun %A Xiang, Yong-Bing %A Zheng, Wei %A Arnett, Donna K %A Bouchard, Claude %A Evans, Michele K %A Gudnason, Vilmundur %A Kardia, Sharon %A Kelly, Tanika N %A Kritchevsky, Stephen B %A Loos, Ruth J F %A Pereira, Alexandre C %A Province, Mike %A Psaty, Bruce M %A Rotimi, Charles %A Zhu, Xiaofeng %A Amin, Najaf %A Cupples, L Adrienne %A Fornage, Myriam %A Fox, Ervin F %A Guo, Xiuqing %A Gauderman, W James %A Rice, Kenneth %A Kooperberg, Charles %A Munroe, Patricia B %A Liu, Ching-Ti %A Morrison, Alanna C %A Rao, Dabeeru C %A van Heemst, Diana %A Redline, Susan %X

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

%B Nat Commun %V 10 %P 5121 %8 2019 Nov 12 %G eng %N 1 %R 10.1038/s41467-019-12958-0 %0 Journal Article %J Science %D 2020 %T The genetic architecture of the human cerebral cortex %A Grasby, Katrina L. %A Jahanshad, Neda %A Painter, Jodie N. %A Colodro-Conde, Lucía %A Bralten, Janita %A Hibar, Derrek P. %A Lind, Penelope A. %A Pizzagalli, Fabrizio %A Ching, Christopher R. K. %A McMahon, Mary Agnes B. %A Shatokhina, Natalia %A Zsembik, Leo C. P. %A Thomopoulos, Sophia I. %A Zhu, Alyssa H. %A Strike, Lachlan T. %A Agartz, Ingrid %A Alhusaini, Saud %A Almeida, Marcio A. A. %A Alnæs, Dag %A Amlien, Inge K. %A Andersson, Micael %A Ard, Tyler %A Armstrong, Nicola J. %A Ashley-Koch, Allison %A Atkins, Joshua R. %A Bernard, Manon %A Brouwer, Rachel M. %A Buimer, Elizabeth E. L. %A Bülow, Robin %A Bürger, Christian %A Cannon, Dara M. %A Chakravarty, Mallar %A Chen, Qiang %A Cheung, Joshua W. %A Couvy-Duchesne, Baptiste %A Dale, Anders M. %A Dalvie, Shareefa %A de Araujo, Tânia K. %A de Zubicaray, Greig I. %A de Zwarte, Sonja M. C. %A den Braber, Anouk %A Doan, Nhat Trung %A Dohm, Katharina %A Ehrlich, Stefan %A Engelbrecht, Hannah-Ruth %A Erk, Susanne %A Fan, Chun Chieh %A Fedko, Iryna O. %A Foley, Sonya F. %A Ford, Judith M. %A Fukunaga, Masaki %A Garrett, Melanie E. %A Ge, Tian %A Giddaluru, Sudheer %A Goldman, Aaron L. %A Green, Melissa J. %A Groenewold, Nynke A. %A Grotegerd, Dominik %A Gurholt, Tiril P. %A Gutman, Boris A. %A Hansell, Narelle K. %A Harris, Mathew A. %A Harrison, Marc B. %A Haswell, Courtney C. %A Hauser, Michael %A Herms, Stefan %A Heslenfeld, Dirk J. %A Ho, New Fei %A Hoehn, David %A Hoffmann, Per %A Holleran, Laurena %A Hoogman, Martine %A Hottenga, Jouke-Jan %A Ikeda, Masashi %A Janowitz, Deborah %A Jansen, Iris E. %A Jia, Tianye %A Jockwitz, Christiane %A Kanai, Ryota %A Karama, Sherif %A Kasperaviciute, Dalia %A Kaufmann, Tobias %A Kelly, Sinead %A Kikuchi, Masataka %A Klein, Marieke %A Knapp, Michael %A Knodt, Annchen R. %A Krämer, Bernd %A Lam, Max %A Lancaster, Thomas M. %A Lee, Phil H. %A Lett, Tristram A. %A Lewis, Lindsay B. %A Lopes-Cendes, Iscia %A Luciano, Michelle %A Macciardi, Fabio %A Marquand, Andre F. %A Mathias, Samuel R. %A Melzer, Tracy R. %A Milaneschi, Yuri %A Mirza-Schreiber, Nazanin %A Moreira, Jose C. V. %A Mühleisen, Thomas W. %A Müller-Myhsok, Bertram %A Najt, Pablo %A Nakahara, Soichiro %A Nho, Kwangsik %A Olde Loohuis, Loes M. %A Orfanos, Dimitri Papadopoulos %A Pearson, John F. %A Pitcher, Toni L. %A Pütz, Benno %A Quidé, Yann %A Ragothaman, Anjanibhargavi %A Rashid, Faisal M. %A Reay, William R. %A Redlich, Ronny %A Reinbold, Céline S. %A Repple, Jonathan %A Richard, Geneviève %A Riedel, Brandalyn C. %A Risacher, Shannon L. %A Rocha, Cristiane S. %A Mota, Nina Roth %A Salminen, Lauren %A Saremi, Arvin %A Saykin, Andrew J. %A Schlag, Fenja %A Schmaal, Lianne %A Schofield, Peter R. %A Secolin, Rodrigo %A Shapland, Chin Yang %A Shen, Li %A Shin, Jean %A Shumskaya, Elena %A Sønderby, Ida E. %A Sprooten, Emma %A Tansey, Katherine E. %A Teumer, Alexander %A Thalamuthu, Anbupalam %A Tordesillas-Gutierrez, Diana %A Turner, Jessica A. %A Uhlmann, Anne %A Vallerga, Costanza Ludovica %A van der Meer, Dennis %A van Donkelaar, Marjolein M. J. %A van Eijk, Liza %A van Erp, Theo G. M. %A van Haren, Neeltje E. M. %A van Rooij, Daan %A van Tol, Marie-Jose %A Veldink, Jan H. %A Verhoef, Ellen %A Walton, Esther %A Wang, Mingyuan %A Wang, Yunpeng %A Wardlaw, Joanna M. %A Wen, Wei %A Westlye, Lars T. %A Whelan, Christopher D. %A Witt, Stephanie H. %A Wittfeld, Katharina %A Wolf, Christiane %A Wolfers, Thomas %A Wu, Jing Qin %A Yasuda, Clarissa L. %A Zaremba, Dario %A Zhang, Zuo %A Zwiers, Marcel P. %A Artiges, Eric %A Assareh, Amelia A. %A Ayesa-Arriola, Rosa %A Belger, Aysenil %A Brandt, Christine L. %A Brown, Gregory G. %A Cichon, Sven %A Curran, Joanne E. %A Davies, Gareth E. %A Degenhardt, Franziska %A Dennis, Michelle F. %A Dietsche, Bruno %A Djurovic, Srdjan %A Doherty, Colin P. %A Espiritu, Ryan %A Garijo, Daniel %A Gil, Yolanda %A Gowland, Penny A. %A Green, Robert C. %A Häusler, Alexander N. %A Heindel, Walter %A Ho, Beng-Choon %A Hoffmann, Wolfgang U. %A Holsboer, Florian %A Homuth, Georg %A Hosten, Norbert %A Jack, Clifford R. %A Jang, MiHyun %A Jansen, Andreas %A Kimbrel, Nathan A. %A Kolskår, Knut %A Koops, Sanne %A Krug, Axel %A Lim, Kelvin O. %A Luykx, Jurjen J. %A Mathalon, Daniel H. %A Mather, Karen A. %A Mattay, Venkata S. %A Matthews, Sarah %A Mayoral Van Son, Jaqueline %A McEwen, Sarah C. %A Melle, Ingrid %A Morris, Derek W. %A Mueller, Bryon A. %A Nauck, Matthias %A Nordvik, Jan E. %A Nöthen, Markus M. %A O’Leary, Daniel S. %A Opel, Nils %A Martinot, Marie-Laure Paillère %A Pike, G. Bruce %A Preda, Adrian %A Quinlan, Erin B. %A Rasser, Paul E. %A Ratnakar, Varun %A Reppermund, Simone %A Steen, Vidar M. %A Tooney, Paul A. %A Torres, Fábio R. %A Veltman, Dick J. %A Voyvodic, James T. %A Whelan, Robert %A White, Tonya %A Yamamori, Hidenaga %A Adams, Hieab H. H. %A Bis, Joshua C. %A Debette, Stephanie %A DeCarli, Charles %A Fornage, Myriam %A Gudnason, Vilmundur %A Hofer, Edith %A Ikram, M. Arfan %A Launer, Lenore %A Longstreth, W. T. %A Lopez, Oscar L. %A Mazoyer, Bernard %A Mosley, Thomas H. %A Roshchupkin, Gennady V. %A Satizabal, Claudia L. %A Schmidt, Reinhold %A Seshadri, Sudha %A Yang, Qiong %A Alvim, Marina K. M. %A Ames, David %A Anderson, Tim J. %A Andreassen, Ole A. %A Arias-Vasquez, Alejandro %A Bastin, Mark E. %A Baune, Bernhard T. %A Beckham, Jean C. %A Blangero, John %A Boomsma, Dorret I. %A Brodaty, Henry %A Brunner, Han G. %A Buckner, Randy L. %A Buitelaar, Jan K. %A Bustillo, Juan R. %A Cahn, Wiepke %A Cairns, Murray J. %A Calhoun, Vince %A Carr, Vaughan J. %A Caseras, Xavier %A Caspers, Svenja %A Cavalleri, Gianpiero L. %A Cendes, Fernando %A Corvin, Aiden %A Crespo-Facorro, Benedicto %A Dalrymple-Alford, John C. %A Dannlowski, Udo %A de Geus, Eco J. C. %A Deary, Ian J. %A Delanty, Norman %A Depondt, Chantal %A Desrivières, Sylvane %A Donohoe, Gary %A Espeseth, Thomas %A Fernández, Guillén %A Fisher, Simon E. %A Flor, Herta %A Forstner, Andreas J. %A Francks, Clyde %A Franke, Barbara %A Glahn, David C. %A Gollub, Randy L. %A Grabe, Hans J. %A Gruber, Oliver %A Håberg, Asta K. %A Hariri, Ahmad R. %A Hartman, Catharina A. %A Hashimoto, Ryota %A Heinz, Andreas %A Henskens, Frans A. %A Hillegers, Manon H. J. %A Hoekstra, Pieter J. %A Holmes, Avram J. %A Hong, L. Elliot %A Hopkins, William D. %A Hulshoff Pol, Hilleke E. %A Jernigan, Terry L. %A Jönsson, Erik G. %A Kahn, René S. %A Kennedy, Martin A. %A Kircher, Tilo T. J. %A Kochunov, Peter %A Kwok, John B. J. %A Le Hellard, Stephanie %A Loughland, Carmel M. %A Martin, Nicholas G. %A Martinot, Jean-Luc %A McDonald, Colm %A McMahon, Katie L. %A Meyer-Lindenberg, Andreas %A Michie, Patricia T. %A Morey, Rajendra A. %A Mowry, Bryan %A Nyberg, Lars %A Oosterlaan, Jaap %A Ophoff, Roel A. %A Pantelis, Christos %A Paus, Tomáš %A Pausova, Zdenka %A Penninx, Brenda W. J. H. %A Polderman, Tinca J. C. %A Posthuma, Danielle %A Rietschel, Marcella %A Roffman, Joshua L. %A Rowland, Laura M. %A Sachdev, Perminder S. %A Sämann, Philipp G. %A Schall, Ulrich %A Schumann, Gunter %A Scott, Rodney J. %A Sim, Kang %A Sisodiya, Sanjay M. %A Smoller, Jordan W. %A Sommer, Iris E. %A St Pourcain, Beate %A Stein, Dan J. %A Toga, Arthur W. %A Trollor, Julian N. %A Van der Wee, Nic J. A. %A van ’t Ent, Dennis %A Völzke, Henry %A Walter, Henrik %A Weber, Bernd %A Weinberger, Daniel R. %A Wright, Margaret J. %A Zhou, Juan %A Stein, Jason L. %A Thompson, Paul M. %A Medland, Sarah E. %B Science %V 367 %P eaay6690 %8 Aug-03-2021 %G eng %U https://www.sciencemag.org/lookup/doi/10.1126/science.aay6690https://syndication.highwire.org/content/doi/10.1126/science.aay6690https://syndication.highwire.org/content/doi/10.1126/science.aay6690 %N 6484 %! Science %R 10.1126/science.aay6690 %0 Journal Article %J Diabetes %D 2020 %T Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity. %A Yaghootkar, Hanieh %A Zhang, Yiying %A Spracklen, Cassandra N %A Karaderi, Tugce %A Huang, Lam Opal %A Bradfield, Jonathan %A Schurmann, Claudia %A Fine, Rebecca S %A Preuss, Michael H %A Kutalik, Zoltán %A Wittemans, Laura Bl %A Lu, Yingchang %A Metz, Sophia %A Willems, Sara M %A Li-Gao, Ruifang %A Grarup, Niels %A Wang, Shuai %A Molnos, Sophie %A Sandoval-Zárate, América A %A Nalls, Mike A %A Lange, Leslie A %A Haesser, Jeffrey %A Guo, Xiuqing %A Lyytikäinen, Leo-Pekka %A Feitosa, Mary F %A Sitlani, Colleen M %A Venturini, Cristina %A Mahajan, Anubha %A Kacprowski, Tim %A Wang, Carol A %A Chasman, Daniel I %A Amin, Najaf %A Broer, Linda %A Robertson, Neil %A Young, Kristin L %A Allison, Matthew %A Auer, Paul L %A Blüher, Matthias %A Borja, Judith B %A Bork-Jensen, Jette %A Carrasquilla, Germán D %A Christofidou, Paraskevi %A Demirkan, Ayse %A Doege, Claudia A %A Garcia, Melissa E %A Graff, Mariaelisa %A Guo, Kaiying %A Hakonarson, Hakon %A Hong, Jaeyoung %A Ida Chen, Yii-Der %A Jackson, Rebecca %A Jakupović, Hermina %A Jousilahti, Pekka %A Justice, Anne E %A Kähönen, Mika %A Kizer, Jorge R %A Kriebel, Jennifer %A LeDuc, Charles A %A Li, Jin %A Lind, Lars %A Luan, Jian'an %A Mackey, David %A Mangino, Massimo %A Männistö, Satu %A Martin Carli, Jayne F %A Medina-Gómez, Carolina %A Mook-Kanamori, Dennis O %A Morris, Andrew P %A de Mutsert, Renée %A Nauck, Matthias %A Nedeljkovic, Ivana %A Pennell, Craig E %A Pradhan, Arund D %A Psaty, Bruce M %A Raitakari, Olli T %A Scott, Robert A %A Skaaby, Tea %A Strauch, Konstantin %A Taylor, Kent D %A Teumer, Alexander %A Uitterlinden, André G %A Wu, Ying %A Yao, Jie %A Walker, Mark %A North, Kari E %A Kovacs, Peter %A Ikram, M Arfan %A van Duijn, Cornelia M %A Ridker, Paul M %A Lye, Stephen %A Homuth, Georg %A Ingelsson, Erik %A Spector, Tim D %A McKnight, Barbara %A Province, Michael A %A Lehtimäki, Terho %A Adair, Linda S %A Rotter, Jerome I %A Reiner, Alexander P %A Wilson, James G %A Harris, Tamara B %A Ripatti, Samuli %A Grallert, Harald %A Meigs, James B %A Salomaa, Veikko %A Hansen, Torben %A Willems van Dijk, Ko %A Wareham, Nicholas J %A Grant, Struan Fa %A Langenberg, Claudia %A Frayling, Timothy M %A Lindgren, Cecilia M %A Mohlke, Karen L %A Leibel, Rudolph L %A Loos, Ruth Jf %A Kilpeläinen, Tuomas O %X

Leptin influences food intake by informing the brain about the status of body fat stores. Rare mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in , and , and one intergenic variant near The missense variant Val94Met (rs17151919) in was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10, n=3,901). Using analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.

%B Diabetes %8 2020 Sep 11 %G eng %R 10.2337/db20-0070 %0 Journal Article %J Front Genet %D 2023 %T Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci. %A de Las Fuentes, Lisa %A Schwander, Karen L %A Brown, Michael R %A Bentley, Amy R %A Winkler, Thomas W %A Sung, Yun Ju %A Munroe, Patricia B %A Miller, Clint L %A Aschard, Hugo %A Aslibekyan, Stella %A Bartz, Traci M %A Bielak, Lawrence F %A Chai, Jin Fang %A Cheng, Ching-Yu %A Dorajoo, Rajkumar %A Feitosa, Mary F %A Guo, Xiuqing %A Hartwig, Fernando P %A Horimoto, Andrea %A Kolcic, Ivana %A Lim, Elise %A Liu, Yongmei %A Manning, Alisa K %A Marten, Jonathan %A Musani, Solomon K %A Noordam, Raymond %A Padmanabhan, Sandosh %A Rankinen, Tuomo %A Richard, Melissa A %A Ridker, Paul M %A Smith, Albert V %A Vojinovic, Dina %A Zonderman, Alan B %A Alver, Maris %A Boissel, Mathilde %A Christensen, Kaare %A Freedman, Barry I %A Gao, Chuan %A Giulianini, Franco %A Harris, Sarah E %A He, Meian %A Hsu, Fang-Chi %A Kuhnel, Brigitte %A Laguzzi, Federica %A Li, Xiaoyin %A Lyytikäinen, Leo-Pekka %A Nolte, Ilja M %A Poveda, Alaitz %A Rauramaa, Rainer %A Riaz, Muhammad %A Robino, Antonietta %A Sofer, Tamar %A Takeuchi, Fumihiko %A Tayo, Bamidele O %A van der Most, Peter J %A Verweij, Niek %A Ware, Erin B %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Zhan, Yiqiang %A Amin, Najaf %A Arking, Dan E %A Ballantyne, Christie %A Boerwinkle, Eric %A Brody, Jennifer A %A Broeckel, Ulrich %A Campbell, Archie %A Canouil, Mickaël %A Chai, Xiaoran %A Chen, Yii-Der Ida %A Chen, Xu %A Chitrala, Kumaraswamy Naidu %A Concas, Maria Pina %A de Faire, Ulf %A de Mutsert, Renée %A de Silva, H Janaka %A de Vries, Paul S %A Do, Ahn %A Faul, Jessica D %A Fisher, Virginia %A Floyd, James S %A Forrester, Terrence %A Friedlander, Yechiel %A Girotto, Giorgia %A Gu, C Charles %A Hallmans, Göran %A Heikkinen, Sami %A Heng, Chew-Kiat %A Homuth, Georg %A Hunt, Steven %A Ikram, M Arfan %A Jacobs, David R %A Kavousi, Maryam %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Komulainen, Pirjo %A Langefeld, Carl D %A Liang, Jingjing %A Liu, Kiang %A Liu, Jianjun %A Lohman, Kurt %A Mägi, Reedik %A Manichaikul, Ani W %A McKenzie, Colin A %A Meitinger, Thomas %A Milaneschi, Yuri %A Nauck, Matthias %A Nelson, Christopher P %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Pereira, Alexandre C %A Perls, Thomas %A Peters, Annette %A Polasek, Ozren %A Raitakari, Olli T %A Rice, Kenneth %A Rice, Treva K %A Rich, Stephen S %A Sabanayagam, Charumathi %A Schreiner, Pamela J %A Shu, Xiao-Ou %A Sidney, Stephen %A Sims, Mario %A Smith, Jennifer A %A Starr, John M %A Strauch, Konstantin %A Tai, E Shyong %A Taylor, Kent D %A Tsai, Michael Y %A Uitterlinden, André G %A van Heemst, Diana %A Waldenberger, Melanie %A Wang, Ya-Xing %A Wei, Wen-Bin %A Wilson, Gregory %A Xuan, Deng %A Yao, Jie %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Becker, Diane M %A Bonnefond, Amélie %A Bowden, Donald W %A Cooper, Richard S %A Deary, Ian J %A Divers, Jasmin %A Esko, Tõnu %A Franks, Paul W %A Froguel, Philippe %A Gieger, Christian %A Jonas, Jost B %A Kato, Norihiro %A Lakka, Timo A %A Leander, Karin %A Lehtimäki, Terho %A Magnusson, Patrik K E %A North, Kari E %A Ntalla, Ioanna %A Penninx, Brenda %A Samani, Nilesh J %A Snieder, Harold %A Spedicati, Beatrice %A van der Harst, Pim %A Völzke, Henry %A Wagenknecht, Lynne E %A Weir, David R %A Wojczynski, Mary K %A Wu, Tangchun %A Zheng, Wei %A Zhu, Xiaofeng %A Bouchard, Claude %A Chasman, Daniel I %A Evans, Michele K %A Fox, Ervin R %A Gudnason, Vilmundur %A Hayward, Caroline %A Horta, Bernardo L %A Kardia, Sharon L R %A Krieger, Jose Eduardo %A Mook-Kanamori, Dennis O %A Peyser, Patricia A %A Province, Michael M %A Psaty, Bruce M %A Rudan, Igor %A Sim, Xueling %A Smith, Blair H %A van Dam, Rob M %A van Duijn, Cornelia M %A Wong, Tien Yin %A Arnett, Donna K %A Rao, Dabeeru C %A Gauderman, James %A Liu, Ching-Ti %A Morrison, Alanna C %A Rotter, Jerome I %A Fornage, Myriam %X

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

%B Front Genet %V 14 %P 1235337 %8 2023 %G eng %R 10.3389/fgene.2023.1235337 %0 Journal Article %J Alzheimers Res Ther %D 2024 %T Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance. %A Mei, Hao %A Simino, Jeannette %A Li, Lianna %A Jiang, Fan %A Bis, Joshua C %A Davies, Gail %A Hill, W David %A Xia, Charley %A Gudnason, Vilmundur %A Yang, Qiong %A Lahti, Jari %A Smith, Jennifer A %A Kirin, Mirna %A De Jager, Philip %A Armstrong, Nicola J %A Ghanbari, Mohsen %A Kolcic, Ivana %A Moran, Christopher %A Teumer, Alexander %A Sargurupremraj, Murali %A Mahmud, Shamsed %A Fornage, Myriam %A Zhao, Wei %A Satizabal, Claudia L %A Polasek, Ozren %A Räikkönen, Katri %A Liewald, David C %A Homuth, Georg %A Callisaya, Michele %A Mather, Karen A %A Windham, B Gwen %A Zemunik, Tatijana %A Palotie, Aarno %A Pattie, Alison %A van der Auwera, Sandra %A Thalamuthu, Anbupalam %A Knopman, David S %A Rudan, Igor %A Starr, John M %A Wittfeld, Katharina %A Kochan, Nicole A %A Griswold, Michael E %A Vitart, Veronique %A Brodaty, Henry %A Gottesman, Rebecca %A Cox, Simon R %A Psaty, Bruce M %A Boerwinkle, Eric %A Chasman, Daniel I %A Grodstein, Francine %A Sachdev, Perminder S %A Srikanth, Velandai %A Hayward, Caroline %A Wilson, James F %A Eriksson, Johan G %A Kardia, Sharon L R %A Grabe, Hans J %A Bennett, David A %A Ikram, M Arfan %A Deary, Ian J %A van Duijn, Cornelia M %A Launer, Lenore %A Fitzpatrick, Annette L %A Seshadri, Sudha %A Bressler, Jan %A Debette, Stephanie %A Mosley, Thomas H %K Aged %K Cognition %K Genome-Wide Association Study %K Humans %K Memory %K MicroRNAs %K Multiomics %K Polymorphism, Single Nucleotide %X

BACKGROUND: Uncovering the functional relevance underlying verbal declarative memory (VDM) genome-wide association study (GWAS) results may facilitate the development of interventions to reduce age-related memory decline and dementia.

METHODS: We performed multi-omics and pathway enrichment analyses of paragraph (PAR-dr) and word list (WL-dr) delayed recall GWAS from 29,076 older non-demented individuals of European descent. We assessed the relationship between single-variant associations and expression quantitative trait loci (eQTLs) in 44 tissues and methylation quantitative trait loci (meQTLs) in the hippocampus. We determined the relationship between gene associations and transcript levels in 53 tissues, annotation as immune genes, and regulation by transcription factors (TFs) and microRNAs. To identify significant pathways, gene set enrichment was tested in each cohort and meta-analyzed across cohorts. Analyses of differential expression in brain tissues were conducted for pathway component genes.

RESULTS: The single-variant associations of VDM showed significant linkage disequilibrium (LD) with eQTLs across all tissues and meQTLs within the hippocampus. Stronger WL-dr gene associations correlated with reduced expression in four brain tissues, including the hippocampus. More robust PAR-dr and/or WL-dr gene associations were intricately linked with immunity and were influenced by 31 TFs and 2 microRNAs. Six pathways, including type I diabetes, exhibited significant associations with both PAR-dr and WL-dr. These pathways included fifteen MHC genes intricately linked to VDM performance, showing diverse expression patterns based on cognitive status in brain tissues.

CONCLUSIONS: VDM genetic associations influence expression regulation via eQTLs and meQTLs. The involvement of TFs, microRNAs, MHC genes, and immune-related pathways contributes to VDM performance in older individuals.

%B Alzheimers Res Ther %V 16 %P 14 %8 2024 Jan 20 %G eng %N 1 %R 10.1186/s13195-023-01376-6