%0 Journal Article %J Nat Genet %D 2012 %T Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. %A Scott, Robert A %A Lagou, Vasiliki %A Welch, Ryan P %A Wheeler, Eleanor %A Montasser, May E %A Luan, Jian'an %A Mägi, Reedik %A Strawbridge, Rona J %A Rehnberg, Emil %A Gustafsson, Stefan %A Kanoni, Stavroula %A Rasmussen-Torvik, Laura J %A Yengo, Loic %A Lecoeur, Cécile %A Shungin, Dmitry %A Sanna, Serena %A Sidore, Carlo %A Johnson, Paul C D %A Jukema, J Wouter %A Johnson, Toby %A Mahajan, Anubha %A Verweij, Niek %A Thorleifsson, Gudmar %A Hottenga, Jouke-Jan %A Shah, Sonia %A Smith, Albert V %A Sennblad, Bengt %A Gieger, Christian %A Salo, Perttu %A Perola, Markus %A Timpson, Nicholas J %A Evans, David M %A Pourcain, Beate St %A Wu, Ying %A Andrews, Jeanette S %A Hui, Jennie %A Bielak, Lawrence F %A Zhao, Wei %A Horikoshi, Momoko %A Navarro, Pau %A Isaacs, Aaron %A O'Connell, Jeffrey R %A Stirrups, Kathleen %A Vitart, Veronique %A Hayward, Caroline %A Esko, Tõnu %A Mihailov, Evelin %A Fraser, Ross M %A Fall, Tove %A Voight, Benjamin F %A Raychaudhuri, Soumya %A Chen, Han %A Lindgren, Cecilia M %A Morris, Andrew P %A Rayner, Nigel W %A Robertson, Neil %A Rybin, Denis %A Liu, Ching-Ti %A Beckmann, Jacques S %A Willems, Sara M %A Chines, Peter S %A Jackson, Anne U %A Kang, Hyun Min %A Stringham, Heather M %A Song, Kijoung %A Tanaka, Toshiko %A Peden, John F %A Goel, Anuj %A Hicks, Andrew A %A An, Ping %A Müller-Nurasyid, Martina %A Franco-Cereceda, Anders %A Folkersen, Lasse %A Marullo, Letizia %A Jansen, Hanneke %A Oldehinkel, Albertine J %A Bruinenberg, Marcel %A Pankow, James S %A North, Kari E %A Forouhi, Nita G %A Loos, Ruth J F %A Edkins, Sarah %A Varga, Tibor V %A Hallmans, Göran %A Oksa, Heikki %A Antonella, Mulas %A Nagaraja, Ramaiah %A Trompet, Stella %A Ford, Ian %A Bakker, Stephan J L %A Kong, Augustine %A Kumari, Meena %A Gigante, Bruna %A Herder, Christian %A Munroe, Patricia B %A Caulfield, Mark %A Antti, Jula %A Mangino, Massimo %A Small, Kerrin %A Miljkovic, Iva %A Liu, Yongmei %A Atalay, Mustafa %A Kiess, Wieland %A James, Alan L %A Rivadeneira, Fernando %A Uitterlinden, André G %A Palmer, Colin N A %A Doney, Alex S F %A Willemsen, Gonneke %A Smit, Johannes H %A Campbell, Susan %A Polasek, Ozren %A Bonnycastle, Lori L %A Hercberg, Serge %A Dimitriou, Maria %A Bolton, Jennifer L %A Fowkes, Gerard R %A Kovacs, Peter %A Lindström, Jaana %A Zemunik, Tatijana %A Bandinelli, Stefania %A Wild, Sarah H %A Basart, Hanneke V %A Rathmann, Wolfgang %A Grallert, Harald %A Maerz, Winfried %A Kleber, Marcus E %A Boehm, Bernhard O %A Peters, Annette %A Pramstaller, Peter P %A Province, Michael A %A Borecki, Ingrid B %A Hastie, Nicholas D %A Rudan, Igor %A Campbell, Harry %A Watkins, Hugh %A Farrall, Martin %A Stumvoll, Michael %A Ferrucci, Luigi %A Waterworth, Dawn M %A Bergman, Richard N %A Collins, Francis S %A Tuomilehto, Jaakko %A Watanabe, Richard M %A de Geus, Eco J C %A Penninx, Brenda W %A Hofman, Albert %A Oostra, Ben A %A Psaty, Bruce M %A Vollenweider, Peter %A Wilson, James F %A Wright, Alan F %A Hovingh, G Kees %A Metspalu, Andres %A Uusitupa, Matti %A Magnusson, Patrik K E %A Kyvik, Kirsten O %A Kaprio, Jaakko %A Price, Jackie F %A Dedoussis, George V %A Deloukas, Panos %A Meneton, Pierre %A Lind, Lars %A Boehnke, Michael %A Shuldiner, Alan R %A van Duijn, Cornelia M %A Morris, Andrew D %A Toenjes, Anke %A Peyser, Patricia A %A Beilby, John P %A Körner, Antje %A Kuusisto, Johanna %A Laakso, Markku %A Bornstein, Stefan R %A Schwarz, Peter E H %A Lakka, Timo A %A Rauramaa, Rainer %A Adair, Linda S %A Smith, George Davey %A Spector, Tim D %A Illig, Thomas %A de Faire, Ulf %A Hamsten, Anders %A Gudnason, Vilmundur %A Kivimaki, Mika %A Hingorani, Aroon %A Keinanen-Kiukaanniemi, Sirkka M %A Saaristo, Timo E %A Boomsma, Dorret I %A Stefansson, Kari %A van der Harst, Pim %A Dupuis, Josée %A Pedersen, Nancy L %A Sattar, Naveed %A Harris, Tamara B %A Cucca, Francesco %A Ripatti, Samuli %A Salomaa, Veikko %A Mohlke, Karen L %A Balkau, Beverley %A Froguel, Philippe %A Pouta, Anneli %A Jarvelin, Marjo-Riitta %A Wareham, Nicholas J %A Bouatia-Naji, Nabila %A McCarthy, Mark I %A Franks, Paul W %A Meigs, James B %A Teslovich, Tanya M %A Florez, Jose C %A Langenberg, Claudia %A Ingelsson, Erik %A Prokopenko, Inga %A Barroso, Inês %K Adult %K Animals %K Blood Glucose %K Fasting %K Female %K Gene Frequency %K Genome-Wide Association Study %K Humans %K Insulin %K Male %K Metabolic Networks and Pathways %K Mice %K Osmolar Concentration %K Quantitative Trait Loci %X

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

%B Nat Genet %V 44 %P 991-1005 %8 2012 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/22885924?dopt=Abstract %R 10.1038/ng.2385 %0 Journal Article %J Nat Genet %D 2013 %T Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. %A Köttgen, Anna %A Albrecht, Eva %A Teumer, Alexander %A Vitart, Veronique %A Krumsiek, Jan %A Hundertmark, Claudia %A Pistis, Giorgio %A Ruggiero, Daniela %A O'Seaghdha, Conall M %A Haller, Toomas %A Yang, Qiong %A Tanaka, Toshiko %A Johnson, Andrew D %A Kutalik, Zoltán %A Smith, Albert V %A Shi, Julia %A Struchalin, Maksim %A Middelberg, Rita P S %A Brown, Morris J %A Gaffo, Angelo L %A Pirastu, Nicola %A Li, Guo %A Hayward, Caroline %A Zemunik, Tatijana %A Huffman, Jennifer %A Yengo, Loic %A Zhao, Jing Hua %A Demirkan, Ayse %A Feitosa, Mary F %A Liu, Xuan %A Malerba, Giovanni %A Lopez, Lorna M %A van der Harst, Pim %A Li, Xinzhong %A Kleber, Marcus E %A Hicks, Andrew A %A Nolte, Ilja M %A Johansson, Asa %A Murgia, Federico %A Wild, Sarah H %A Bakker, Stephan J L %A Peden, John F %A Dehghan, Abbas %A Steri, Maristella %A Tenesa, Albert %A Lagou, Vasiliki %A Salo, Perttu %A Mangino, Massimo %A Rose, Lynda M %A Lehtimäki, Terho %A Woodward, Owen M %A Okada, Yukinori %A Tin, Adrienne %A Müller, Christian %A Oldmeadow, Christopher %A Putku, Margus %A Czamara, Darina %A Kraft, Peter %A Frogheri, Laura %A Thun, Gian Andri %A Grotevendt, Anne %A Gislason, Gauti Kjartan %A Harris, Tamara B %A Launer, Lenore J %A McArdle, Patrick %A Shuldiner, Alan R %A Boerwinkle, Eric %A Coresh, Josef %A Schmidt, Helena %A Schallert, Michael %A Martin, Nicholas G %A Montgomery, Grant W %A Kubo, Michiaki %A Nakamura, Yusuke %A Tanaka, Toshihiro %A Munroe, Patricia B %A Samani, Nilesh J %A Jacobs, David R %A Liu, Kiang %A D'Adamo, Pio %A Ulivi, Sheila %A Rotter, Jerome I %A Psaty, Bruce M %A Vollenweider, Peter %A Waeber, Gérard %A Campbell, Susan %A Devuyst, Olivier %A Navarro, Pau %A Kolcic, Ivana %A Hastie, Nicholas %A Balkau, Beverley %A Froguel, Philippe %A Esko, Tõnu %A Salumets, Andres %A Khaw, Kay Tee %A Langenberg, Claudia %A Wareham, Nicholas J %A Isaacs, Aaron %A Kraja, Aldi %A Zhang, Qunyuan %A Wild, Philipp S %A Scott, Rodney J %A Holliday, Elizabeth G %A Org, Elin %A Viigimaa, Margus %A Bandinelli, Stefania %A Metter, Jeffrey E %A Lupo, Antonio %A Trabetti, Elisabetta %A Sorice, Rossella %A Döring, Angela %A Lattka, Eva %A Strauch, Konstantin %A Theis, Fabian %A Waldenberger, Melanie %A Wichmann, H-Erich %A Davies, Gail %A Gow, Alan J %A Bruinenberg, Marcel %A Stolk, Ronald P %A Kooner, Jaspal S %A Zhang, Weihua %A Winkelmann, Bernhard R %A Boehm, Bernhard O %A Lucae, Susanne %A Penninx, Brenda W %A Smit, Johannes H %A Curhan, Gary %A Mudgal, Poorva %A Plenge, Robert M %A Portas, Laura %A Persico, Ivana %A Kirin, Mirna %A Wilson, James F %A Mateo Leach, Irene %A van Gilst, Wiek H %A Goel, Anuj %A Ongen, Halit %A Hofman, Albert %A Rivadeneira, Fernando %A Uitterlinden, André G %A Imboden, Medea %A von Eckardstein, Arnold %A Cucca, Francesco %A Nagaraja, Ramaiah %A Piras, Maria Grazia %A Nauck, Matthias %A Schurmann, Claudia %A Budde, Kathrin %A Ernst, Florian %A Farrington, Susan M %A Theodoratou, Evropi %A Prokopenko, Inga %A Stumvoll, Michael %A Jula, Antti %A Perola, Markus %A Salomaa, Veikko %A Shin, So-Youn %A Spector, Tim D %A Sala, Cinzia %A Ridker, Paul M %A Kähönen, Mika %A Viikari, Jorma %A Hengstenberg, Christian %A Nelson, Christopher P %A Meschia, James F %A Nalls, Michael A %A Sharma, Pankaj %A Singleton, Andrew B %A Kamatani, Naoyuki %A Zeller, Tanja %A Burnier, Michel %A Attia, John %A Laan, Maris %A Klopp, Norman %A Hillege, Hans L %A Kloiber, Stefan %A Choi, Hyon %A Pirastu, Mario %A Tore, Silvia %A Probst-Hensch, Nicole M %A Völzke, Henry %A Gudnason, Vilmundur %A Parsa, Afshin %A Schmidt, Reinhold %A Whitfield, John B %A Fornage, Myriam %A Gasparini, Paolo %A Siscovick, David S %A Polasek, Ozren %A Campbell, Harry %A Rudan, Igor %A Bouatia-Naji, Nabila %A Metspalu, Andres %A Loos, Ruth J F %A van Duijn, Cornelia M %A Borecki, Ingrid B %A Ferrucci, Luigi %A Gambaro, Giovanni %A Deary, Ian J %A Wolffenbuttel, Bruce H R %A Chambers, John C %A März, Winfried %A Pramstaller, Peter P %A Snieder, Harold %A Gyllensten, Ulf %A Wright, Alan F %A Navis, Gerjan %A Watkins, Hugh %A Witteman, Jacqueline C M %A Sanna, Serena %A Schipf, Sabine %A Dunlop, Malcolm G %A Tönjes, Anke %A Ripatti, Samuli %A Soranzo, Nicole %A Toniolo, Daniela %A Chasman, Daniel I %A Raitakari, Olli %A Kao, W H Linda %A Ciullo, Marina %A Fox, Caroline S %A Caulfield, Mark %A Bochud, Murielle %A Gieger, Christian %K Analysis of Variance %K European Continental Ancestry Group %K Gene Frequency %K Genetic Loci %K Genome-Wide Association Study %K Glucose %K Gout %K Humans %K Inhibins %K Polymorphism, Single Nucleotide %K Signal Transduction %K Uric Acid %X

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

%B Nat Genet %V 45 %P 145-54 %8 2013 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23263486?dopt=Abstract %R 10.1038/ng.2500 %0 Journal Article %J Nat Genet %D 2013 %T Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. %A den Hoed, Marcel %A Eijgelsheim, Mark %A Esko, Tõnu %A Brundel, Bianca J J M %A Peal, David S %A Evans, David M %A Nolte, Ilja M %A Segrè, Ayellet V %A Holm, Hilma %A Handsaker, Robert E %A Westra, Harm-Jan %A Johnson, Toby %A Isaacs, Aaron %A Yang, Jian %A Lundby, Alicia %A Zhao, Jing Hua %A Kim, Young Jin %A Go, Min Jin %A Almgren, Peter %A Bochud, Murielle %A Boucher, Gabrielle %A Cornelis, Marilyn C %A Gudbjartsson, Daniel %A Hadley, David %A van der Harst, Pim %A Hayward, Caroline %A den Heijer, Martin %A Igl, Wilmar %A Jackson, Anne U %A Kutalik, Zoltán %A Luan, Jian'an %A Kemp, John P %A Kristiansson, Kati %A Ladenvall, Claes %A Lorentzon, Mattias %A Montasser, May E %A Njajou, Omer T %A O'Reilly, Paul F %A Padmanabhan, Sandosh %A St Pourcain, Beate %A Rankinen, Tuomo %A Salo, Perttu %A Tanaka, Toshiko %A Timpson, Nicholas J %A Vitart, Veronique %A Waite, Lindsay %A Wheeler, William %A Zhang, Weihua %A Draisma, Harmen H M %A Feitosa, Mary F %A Kerr, Kathleen F %A Lind, Penelope A %A Mihailov, Evelin %A Onland-Moret, N Charlotte %A Song, Ci %A Weedon, Michael N %A Xie, Weijia %A Yengo, Loic %A Absher, Devin %A Albert, Christine M %A Alonso, Alvaro %A Arking, Dan E %A de Bakker, Paul I W %A Balkau, Beverley %A Barlassina, Cristina %A Benaglio, Paola %A Bis, Joshua C %A Bouatia-Naji, Nabila %A Brage, Søren %A Chanock, Stephen J %A Chines, Peter S %A Chung, Mina %A Darbar, Dawood %A Dina, Christian %A Dörr, Marcus %A Elliott, Paul %A Felix, Stephan B %A Fischer, Krista %A Fuchsberger, Christian %A de Geus, Eco J C %A Goyette, Philippe %A Gudnason, Vilmundur %A Harris, Tamara B %A Hartikainen, Anna-Liisa %A Havulinna, Aki S %A Heckbert, Susan R %A Hicks, Andrew A %A Hofman, Albert %A Holewijn, Suzanne %A Hoogstra-Berends, Femke %A Hottenga, Jouke-Jan %A Jensen, Majken K %A Johansson, Asa %A Junttila, Juhani %A Kääb, Stefan %A Kanon, Bart %A Ketkar, Shamika %A Khaw, Kay-Tee %A Knowles, Joshua W %A Kooner, Angrad S %A Kors, Jan A %A Kumari, Meena %A Milani, Lili %A Laiho, Päivi %A Lakatta, Edward G %A Langenberg, Claudia %A Leusink, Maarten %A Liu, Yongmei %A Luben, Robert N %A Lunetta, Kathryn L %A Lynch, Stacey N %A Markus, Marcello R P %A Marques-Vidal, Pedro %A Mateo Leach, Irene %A McArdle, Wendy L %A McCarroll, Steven A %A Medland, Sarah E %A Miller, Kathryn A %A Montgomery, Grant W %A Morrison, Alanna C %A Müller-Nurasyid, Martina %A Navarro, Pau %A Nelis, Mari %A O'Connell, Jeffrey R %A O'Donnell, Christopher J %A Ong, Ken K %A Newman, Anne B %A Peters, Annette %A Polasek, Ozren %A Pouta, Anneli %A Pramstaller, Peter P %A Psaty, Bruce M %A Rao, Dabeeru C %A Ring, Susan M %A Rossin, Elizabeth J %A Rudan, Diana %A Sanna, Serena %A Scott, Robert A %A Sehmi, Jaban S %A Sharp, Stephen %A Shin, Jordan T %A Singleton, Andrew B %A Smith, Albert V %A Soranzo, Nicole %A Spector, Tim D %A Stewart, Chip %A Stringham, Heather M %A Tarasov, Kirill V %A Uitterlinden, André G %A Vandenput, Liesbeth %A Hwang, Shih-Jen %A Whitfield, John B %A Wijmenga, Cisca %A Wild, Sarah H %A Willemsen, Gonneke %A Wilson, James F %A Witteman, Jacqueline C M %A Wong, Andrew %A Wong, Quenna %A Jamshidi, Yalda %A Zitting, Paavo %A Boer, Jolanda M A %A Boomsma, Dorret I %A Borecki, Ingrid B %A van Duijn, Cornelia M %A Ekelund, Ulf %A Forouhi, Nita G %A Froguel, Philippe %A Hingorani, Aroon %A Ingelsson, Erik %A Kivimaki, Mika %A Kronmal, Richard A %A Kuh, Diana %A Lind, Lars %A Martin, Nicholas G %A Oostra, Ben A %A Pedersen, Nancy L %A Quertermous, Thomas %A Rotter, Jerome I %A van der Schouw, Yvonne T %A Verschuren, W M Monique %A Walker, Mark %A Albanes, Demetrius %A Arnar, David O %A Assimes, Themistocles L %A Bandinelli, Stefania %A Boehnke, Michael %A de Boer, Rudolf A %A Bouchard, Claude %A Caulfield, W L Mark %A Chambers, John C %A Curhan, Gary %A Cusi, Daniele %A Eriksson, Johan %A Ferrucci, Luigi %A van Gilst, Wiek H %A Glorioso, Nicola %A de Graaf, Jacqueline %A Groop, Leif %A Gyllensten, Ulf %A Hsueh, Wen-Chi %A Hu, Frank B %A Huikuri, Heikki V %A Hunter, David J %A Iribarren, Carlos %A Isomaa, Bo %A Jarvelin, Marjo-Riitta %A Jula, Antti %A Kähönen, Mika %A Kiemeney, Lambertus A %A van der Klauw, Melanie M %A Kooner, Jaspal S %A Kraft, Peter %A Iacoviello, Licia %A Lehtimäki, Terho %A Lokki, Marja-Liisa L %A Mitchell, Braxton D %A Navis, Gerjan %A Nieminen, Markku S %A Ohlsson, Claes %A Poulter, Neil R %A Qi, Lu %A Raitakari, Olli T %A Rimm, Eric B %A Rioux, John D %A Rizzi, Federica %A Rudan, Igor %A Salomaa, Veikko %A Sever, Peter S %A Shields, Denis C %A Shuldiner, Alan R %A Sinisalo, Juha %A Stanton, Alice V %A Stolk, Ronald P %A Strachan, David P %A Tardif, Jean-Claude %A Thorsteinsdottir, Unnur %A Tuomilehto, Jaako %A van Veldhuisen, Dirk J %A Virtamo, Jarmo %A Viikari, Jorma %A Vollenweider, Peter %A Waeber, Gérard %A Widen, Elisabeth %A Cho, Yoon Shin %A Olsen, Jesper V %A Visscher, Peter M %A Willer, Cristen %A Franke, Lude %A Erdmann, Jeanette %A Thompson, John R %A Pfeufer, Arne %A Sotoodehnia, Nona %A Newton-Cheh, Christopher %A Ellinor, Patrick T %A Stricker, Bruno H Ch %A Metspalu, Andres %A Perola, Markus %A Beckmann, Jacques S %A Smith, George Davey %A Stefansson, Kari %A Wareham, Nicholas J %A Munroe, Patricia B %A Sibon, Ody C M %A Milan, David J %A Snieder, Harold %A Samani, Nilesh J %A Loos, Ruth J F %K Animals %K Arrhythmias, Cardiac %K Gene Frequency %K Genetic Loci %K Genome-Wide Association Study %K Heart Conduction System %K Heart Rate %K Humans %K Metabolic Networks and Pathways %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

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

%B Nat Genet %V 45 %P 621-31 %8 2013 Jun %G eng %N 6 %R 10.1038/ng.2610 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2016 %T KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference. %A Schumann, Gunter %A Liu, Chunyu %A O'Reilly, Paul %A Gao, He %A Song, Parkyong %A Xu, Bing %A Ruggeri, Barbara %A Amin, Najaf %A Jia, Tianye %A Preis, Sarah %A Segura Lepe, Marcelo %A Akira, Shizuo %A Barbieri, Caterina %A Baumeister, Sebastian %A Cauchi, Stephane %A Clarke, Toni-Kim %A Enroth, Stefan %A Fischer, Krista %A Hällfors, Jenni %A Harris, Sarah E %A Hieber, Saskia %A Hofer, Edith %A Hottenga, Jouke-Jan %A Johansson, Asa %A Joshi, Peter K %A Kaartinen, Niina %A Laitinen, Jaana %A Lemaitre, Rozenn %A Loukola, Anu %A Luan, Jian'an %A Lyytikäinen, Leo-Pekka %A Mangino, Massimo %A Manichaikul, Ani %A Mbarek, Hamdi %A Milaneschi, Yuri %A Moayyeri, Alireza %A Mukamal, Kenneth %A Nelson, Christopher %A Nettleton, Jennifer %A Partinen, Eemil %A Rawal, Rajesh %A Robino, Antonietta %A Rose, Lynda %A Sala, Cinzia %A Satoh, Takashi %A Schmidt, Reinhold %A Schraut, Katharina %A Scott, Robert %A Smith, Albert Vernon %A Starr, John M %A Teumer, Alexander %A Trompet, Stella %A Uitterlinden, André G %A Venturini, Cristina %A Vergnaud, Anne-Claire %A Verweij, Niek %A Vitart, Veronique %A Vuckovic, Dragana %A Wedenoja, Juho %A Yengo, Loic %A Yu, Bing %A Zhang, Weihua %A Zhao, Jing Hua %A Boomsma, Dorret I %A Chambers, John %A Chasman, Daniel I %A Daniela, Toniolo %A de Geus, Eco %A Deary, Ian %A Eriksson, Johan G %A Esko, Tõnu %A Eulenburg, Volker %A Franco, Oscar H %A Froguel, Philippe %A Gieger, Christian %A Grabe, Hans J %A Gudnason, Vilmundur %A Gyllensten, Ulf %A Harris, Tamara B %A Hartikainen, Anna-Liisa %A Heath, Andrew C %A Hocking, Lynne %A Hofman, Albert %A Huth, Cornelia %A Jarvelin, Marjo-Riitta %A Jukema, J Wouter %A Kaprio, Jaakko %A Kooner, Jaspal S %A Kutalik, Zoltán %A Lahti, Jari %A Langenberg, Claudia %A Lehtimäki, Terho %A Liu, Yongmei %A Madden, Pamela A F %A Martin, Nicholas %A Morrison, Alanna %A Penninx, Brenda %A Pirastu, Nicola %A Psaty, Bruce %A Raitakari, Olli %A Ridker, Paul %A Rose, Richard %A Rotter, Jerome I %A Samani, Nilesh J %A Schmidt, Helena %A Spector, Tim D %A Stott, David %A Strachan, David %A Tzoulaki, Ioanna %A van der Harst, Pim %A van Duijn, Cornelia M %A Marques-Vidal, Pedro %A Vollenweider, Peter %A Wareham, Nicholas J %A Whitfield, John B %A Wilson, James %A Wolffenbuttel, Bruce %A Bakalkin, Georgy %A Evangelou, Evangelos %A Liu, Yun %A Rice, Kenneth M %A Desrivières, Sylvane %A Kliewer, Steven A %A Mangelsdorf, David J %A Müller, Christian P %A Levy, Daniel %A Elliott, Paul %X

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

%B Proc Natl Acad Sci U S A %V 113 %P 14372-14377 %8 2016 Dec 13 %G eng %N 50 %R 10.1073/pnas.1611243113 %0 Journal Article %J PLoS Med %D 2017 %T Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis. %A Wheeler, Eleanor %A Leong, Aaron %A Liu, Ching-Ti %A Hivert, Marie-France %A Strawbridge, Rona J %A Podmore, Clara %A Li, Man %A Yao, Jie %A Sim, Xueling %A Hong, Jaeyoung %A Chu, Audrey Y %A Zhang, Weihua %A Wang, Xu %A Chen, Peng %A Maruthur, Nisa M %A Porneala, Bianca C %A Sharp, Stephen J %A Jia, Yucheng %A Kabagambe, Edmond K %A Chang, Li-Ching %A Chen, Wei-Min %A Elks, Cathy E %A Evans, Daniel S %A Fan, Qiao %A Giulianini, Franco %A Go, Min Jin %A Hottenga, Jouke-Jan %A Hu, Yao %A Jackson, Anne U %A Kanoni, Stavroula %A Kim, Young Jin %A Kleber, Marcus E %A Ladenvall, Claes %A Lecoeur, Cécile %A Lim, Sing-Hui %A Lu, Yingchang %A Mahajan, Anubha %A Marzi, Carola %A Nalls, Mike A %A Navarro, Pau %A Nolte, Ilja M %A Rose, Lynda M %A Rybin, Denis V %A Sanna, Serena %A Shi, Yuan %A Stram, Daniel O %A Takeuchi, Fumihiko %A Tan, Shu Pei %A van der Most, Peter J %A van Vliet-Ostaptchouk, Jana V %A Wong, Andrew %A Yengo, Loic %A Zhao, Wanting %A Goel, Anuj %A Martinez Larrad, Maria Teresa %A Radke, Dörte %A Salo, Perttu %A Tanaka, Toshiko %A van Iperen, Erik P A %A Abecasis, Goncalo %A Afaq, Saima %A Alizadeh, Behrooz Z %A Bertoni, Alain G %A Bonnefond, Amélie %A Böttcher, Yvonne %A Bottinger, Erwin P %A Campbell, Harry %A Carlson, Olga D %A Chen, Chien-Hsiun %A Cho, Yoon Shin %A Garvey, W Timothy %A Gieger, Christian %A Goodarzi, Mark O %A Grallert, Harald %A Hamsten, Anders %A Hartman, Catharina A %A Herder, Christian %A Hsiung, Chao Agnes %A Huang, Jie %A Igase, Michiya %A Isono, Masato %A Katsuya, Tomohiro %A Khor, Chiea-Chuen %A Kiess, Wieland %A Kohara, Katsuhiko %A Kovacs, Peter %A Lee, Juyoung %A Lee, Wen-Jane %A Lehne, Benjamin %A Li, Huaixing %A Liu, Jianjun %A Lobbens, Stephane %A Luan, Jian'an %A Lyssenko, Valeriya %A Meitinger, Thomas %A Miki, Tetsuro %A Miljkovic, Iva %A Moon, Sanghoon %A Mulas, Antonella %A Müller, Gabriele %A Müller-Nurasyid, Martina %A Nagaraja, Ramaiah %A Nauck, Matthias %A Pankow, James S %A Polasek, Ozren %A Prokopenko, Inga %A Ramos, Paula S %A Rasmussen-Torvik, Laura %A Rathmann, Wolfgang %A Rich, Stephen S %A Robertson, Neil R %A Roden, Michael %A Roussel, Ronan %A Rudan, Igor %A Scott, Robert A %A Scott, William R %A Sennblad, Bengt %A Siscovick, David S %A Strauch, Konstantin %A Sun, Liang %A Swertz, Morris %A Tajuddin, Salman M %A Taylor, Kent D %A Teo, Yik-Ying %A Tham, Yih Chung %A Tönjes, Anke %A Wareham, Nicholas J %A Willemsen, Gonneke %A Wilsgaard, Tom %A Hingorani, Aroon D %A Egan, Josephine %A Ferrucci, Luigi %A Hovingh, G Kees %A Jula, Antti %A Kivimaki, Mika %A Kumari, Meena %A Njølstad, Inger %A Palmer, Colin N A %A Serrano Ríos, Manuel %A Stumvoll, Michael %A Watkins, Hugh %A Aung, Tin %A Blüher, Matthias %A Boehnke, Michael %A Boomsma, Dorret I %A Bornstein, Stefan R %A Chambers, John C %A Chasman, Daniel I %A Chen, Yii-Der Ida %A Chen, Yduan-Tsong %A Cheng, Ching-Yu %A Cucca, Francesco %A de Geus, Eco J C %A Deloukas, Panos %A Evans, Michele K %A Fornage, Myriam %A Friedlander, Yechiel %A Froguel, Philippe %A Groop, Leif %A Gross, Myron D %A Harris, Tamara B %A Hayward, Caroline %A Heng, Chew-Kiat %A Ingelsson, Erik %A Kato, Norihiro %A Kim, Bong-Jo %A Koh, Woon-Puay %A Kooner, Jaspal S %A Körner, Antje %A Kuh, Diana %A Kuusisto, Johanna %A Laakso, Markku %A Lin, Xu %A Liu, Yongmei %A Loos, Ruth J F %A Magnusson, Patrik K E %A März, Winfried %A McCarthy, Mark I %A Oldehinkel, Albertine J %A Ong, Ken K %A Pedersen, Nancy L %A Pereira, Mark A %A Peters, Annette %A Ridker, Paul M %A Sabanayagam, Charumathi %A Sale, Michele %A Saleheen, Danish %A Saltevo, Juha %A Schwarz, Peter Eh %A Sheu, Wayne H H %A Snieder, Harold %A Spector, Timothy D %A Tabara, Yasuharu %A Tuomilehto, Jaakko %A van Dam, Rob M %A Wilson, James G %A Wilson, James F %A Wolffenbuttel, Bruce H R %A Wong, Tien Yin %A Wu, Jer-Yuarn %A Yuan, Jian-Min %A Zonderman, Alan B %A Soranzo, Nicole %A Guo, Xiuqing %A Roberts, David J %A Florez, Jose C %A Sladek, Robert %A Dupuis, Josée %A Morris, Andrew P %A Tai, E-Shyong %A Selvin, Elizabeth %A Rotter, Jerome I %A Langenberg, Claudia %A Barroso, Inês %A Meigs, James B %K Diabetes Mellitus, Type 2 %K Genetic Variation %K Genome-Wide Association Study %K Glycated Hemoglobin A %K Humans %K Phenotype %K Risk %X

BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.

METHODS & FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.

CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

%B PLoS Med %V 14 %P e1002383 %8 2017 Sep %G eng %N 9 %R 10.1371/journal.pmed.1002383 %0 Journal Article %J Am J Hum Genet %D 2018 %T Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. %A Ligthart, Symen %A Vaez, Ahmad %A Võsa, Urmo %A Stathopoulou, Maria G %A de Vries, Paul S %A Prins, Bram P %A van der Most, Peter J %A Tanaka, Toshiko %A Naderi, Elnaz %A Rose, Lynda M %A Wu, Ying %A Karlsson, Robert %A Barbalic, Maja %A Lin, Honghuang %A Pool, Rene %A Zhu, Gu %A Mace, Aurelien %A Sidore, Carlo %A Trompet, Stella %A Mangino, Massimo %A Sabater-Lleal, Maria %A Kemp, John P %A Abbasi, Ali %A Kacprowski, Tim %A Verweij, Niek %A Smith, Albert V %A Huang, Tao %A Marzi, Carola %A Feitosa, Mary F %A Lohman, Kurt K %A Kleber, Marcus E %A Milaneschi, Yuri %A Mueller, Christian %A Huq, Mahmudul %A Vlachopoulou, Efthymia %A Lyytikäinen, Leo-Pekka %A Oldmeadow, Christopher %A Deelen, Joris %A Perola, Markus %A Zhao, Jing Hua %A Feenstra, Bjarke %A Amini, Marzyeh %A Lahti, Jari %A Schraut, Katharina E %A Fornage, Myriam %A Suktitipat, Bhoom %A Chen, Wei-Min %A Li, Xiaohui %A Nutile, Teresa %A Malerba, Giovanni %A Luan, Jian'an %A Bak, Tom %A Schork, Nicholas %A del Greco M, Fabiola %A Thiering, Elisabeth %A Mahajan, Anubha %A Marioni, Riccardo E %A Mihailov, Evelin %A Eriksson, Joel %A Ozel, Ayse Bilge %A Zhang, Weihua %A Nethander, Maria %A Cheng, Yu-Ching %A Aslibekyan, Stella %A Ang, Wei %A Gandin, Ilaria %A Yengo, Loic %A Portas, Laura %A Kooperberg, Charles %A Hofer, Edith %A Rajan, Kumar B %A Schurmann, Claudia %A den Hollander, Wouter %A Ahluwalia, Tarunveer S %A Zhao, Jing %A Draisma, Harmen H M %A Ford, Ian %A Timpson, Nicholas %A Teumer, Alexander %A Huang, Hongyan %A Wahl, Simone %A Liu, Yongmei %A Huang, Jie %A Uh, Hae-Won %A Geller, Frank %A Joshi, Peter K %A Yanek, Lisa R %A Trabetti, Elisabetta %A Lehne, Benjamin %A Vozzi, Diego %A Verbanck, Marie %A Biino, Ginevra %A Saba, Yasaman %A Meulenbelt, Ingrid %A O'Connell, Jeff R %A Laakso, Markku %A Giulianini, Franco %A Magnusson, Patrik K E %A Ballantyne, Christie M %A Hottenga, Jouke Jan %A Montgomery, Grant W %A Rivadineira, Fernando %A Rueedi, Rico %A Steri, Maristella %A Herzig, Karl-Heinz %A Stott, David J %A Menni, Cristina %A Frånberg, Mattias %A St Pourcain, Beate %A Felix, Stephan B %A Pers, Tune H %A Bakker, Stephan J L %A Kraft, Peter %A Peters, Annette %A Vaidya, Dhananjay %A Delgado, Graciela %A Smit, Johannes H %A Großmann, Vera %A Sinisalo, Juha %A Seppälä, Ilkka %A Williams, Stephen R %A Holliday, Elizabeth G %A Moed, Matthijs %A Langenberg, Claudia %A Räikkönen, Katri %A Ding, Jingzhong %A Campbell, Harry %A Sale, Michèle M %A Chen, Yii-der I %A James, Alan L %A Ruggiero, Daniela %A Soranzo, Nicole %A Hartman, Catharina A %A Smith, Erin N %A Berenson, Gerald S %A Fuchsberger, Christian %A Hernandez, Dena %A Tiesler, Carla M T %A Giedraitis, Vilmantas %A Liewald, David %A Fischer, Krista %A Mellström, Dan %A Larsson, Anders %A Wang, Yunmei %A Scott, William R %A Lorentzon, Matthias %A Beilby, John %A Ryan, Kathleen A %A Pennell, Craig E %A Vuckovic, Dragana %A Balkau, Beverly %A Concas, Maria Pina %A Schmidt, Reinhold %A Mendes de Leon, Carlos F %A Bottinger, Erwin P %A Kloppenburg, Margreet %A Paternoster, Lavinia %A Boehnke, Michael %A Musk, A W %A Willemsen, Gonneke %A Evans, David M %A Madden, Pamela A F %A Kähönen, Mika %A Kutalik, Zoltán %A Zoledziewska, Magdalena %A Karhunen, Ville %A Kritchevsky, Stephen B %A Sattar, Naveed %A Lachance, Genevieve %A Clarke, Robert %A Harris, Tamara B %A Raitakari, Olli T %A Attia, John R %A van Heemst, Diana %A Kajantie, Eero %A Sorice, Rossella %A Gambaro, Giovanni %A Scott, Robert A %A Hicks, Andrew A %A Ferrucci, Luigi %A Standl, Marie %A Lindgren, Cecilia M %A Starr, John M %A Karlsson, Magnus %A Lind, Lars %A Li, Jun Z %A Chambers, John C %A Mori, Trevor A %A de Geus, Eco J C N %A Heath, Andrew C %A Martin, Nicholas G %A Auvinen, Juha %A Buckley, Brendan M %A de Craen, Anton J M %A Waldenberger, Melanie %A Strauch, Konstantin %A Meitinger, Thomas %A Scott, Rodney J %A McEvoy, Mark %A Beekman, Marian %A Bombieri, Cristina %A Ridker, Paul M %A Mohlke, Karen L %A Pedersen, Nancy L %A Morrison, Alanna C %A Boomsma, Dorret I %A Whitfield, John B %A Strachan, David P %A Hofman, Albert %A Vollenweider, Peter %A Cucca, Francesco %A Jarvelin, Marjo-Riitta %A Jukema, J Wouter %A Spector, Tim D %A Hamsten, Anders %A Zeller, Tanja %A Uitterlinden, André G %A Nauck, Matthias %A Gudnason, Vilmundur %A Qi, Lu %A Grallert, Harald %A Borecki, Ingrid B %A Rotter, Jerome I %A März, Winfried %A Wild, Philipp S %A Lokki, Marja-Liisa %A Boyle, Michael %A Salomaa, Veikko %A Melbye, Mads %A Eriksson, Johan G %A Wilson, James F %A Penninx, Brenda W J H %A Becker, Diane M %A Worrall, Bradford B %A Gibson, Greg %A Krauss, Ronald M %A Ciullo, Marina %A Zaza, Gianluigi %A Wareham, Nicholas J %A Oldehinkel, Albertine J %A Palmer, Lyle J %A Murray, Sarah S %A Pramstaller, Peter P %A Bandinelli, Stefania %A Heinrich, Joachim %A Ingelsson, Erik %A Deary, Ian J %A Mägi, Reedik %A Vandenput, Liesbeth %A van der Harst, Pim %A Desch, Karl C %A Kooner, Jaspal S %A Ohlsson, Claes %A Hayward, Caroline %A Lehtimäki, Terho %A Shuldiner, Alan R %A Arnett, Donna K %A Beilin, Lawrence J %A Robino, Antonietta %A Froguel, Philippe %A Pirastu, Mario %A Jess, Tine %A Koenig, Wolfgang %A Loos, Ruth J F %A Evans, Denis A %A Schmidt, Helena %A Smith, George Davey %A Slagboom, P Eline %A Eiriksdottir, Gudny %A Morris, Andrew P %A Psaty, Bruce M %A Tracy, Russell P %A Nolte, Ilja M %A Boerwinkle, Eric %A Visvikis-Siest, Sophie %A Reiner, Alex P %A Gross, Myron %A Bis, Joshua C %A Franke, Lude %A Franco, Oscar H %A Benjamin, Emelia J %A Chasman, Daniel I %A Dupuis, Josée %A Snieder, Harold %A Dehghan, Abbas %A Alizadeh, Behrooz Z %X

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

%B Am J Hum Genet %V 103 %P 691-706 %8 2018 Nov 01 %G eng %N 5 %R 10.1016/j.ajhg.2018.09.009 %0 Journal Article %J Nat Genet %D 2018 %T Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. %A Mahajan, Anubha %A Wessel, Jennifer %A Willems, Sara M %A Zhao, Wei %A Robertson, Neil R %A Chu, Audrey Y %A Gan, Wei %A Kitajima, Hidetoshi %A Taliun, Daniel %A Rayner, N William %A Guo, Xiuqing %A Lu, Yingchang %A Li, Man %A Jensen, Richard A %A Hu, Yao %A Huo, Shaofeng %A Lohman, Kurt K %A Zhang, Weihua %A Cook, James P %A Prins, Bram Peter %A Flannick, Jason %A Grarup, Niels %A Trubetskoy, Vassily Vladimirovich %A Kravic, Jasmina %A Kim, Young Jin %A Rybin, Denis V %A Yaghootkar, Hanieh %A Müller-Nurasyid, Martina %A Meidtner, Karina %A Li-Gao, Ruifang %A Varga, Tibor V %A Marten, Jonathan %A Li, Jin %A Smith, Albert Vernon %A An, Ping %A Ligthart, Symen %A Gustafsson, Stefan %A Malerba, Giovanni %A Demirkan, Ayse %A Tajes, Juan Fernandez %A Steinthorsdottir, Valgerdur %A Wuttke, Matthias %A Lecoeur, Cécile %A Preuss, Michael %A Bielak, Lawrence F %A Graff, Marielisa %A Highland, Heather M %A Justice, Anne E %A Liu, Dajiang J %A Marouli, Eirini %A Peloso, Gina Marie %A Warren, Helen R %A Afaq, Saima %A Afzal, Shoaib %A Ahlqvist, Emma %A Almgren, Peter %A Amin, Najaf %A Bang, Lia B %A Bertoni, Alain G %A Bombieri, Cristina %A Bork-Jensen, Jette %A Brandslund, Ivan %A Brody, Jennifer A %A Burtt, Noel P %A Canouil, Mickaël %A Chen, Yii-Der Ida %A Cho, Yoon Shin %A Christensen, Cramer %A Eastwood, Sophie V %A Eckardt, Kai-Uwe %A Fischer, Krista %A Gambaro, Giovanni %A Giedraitis, Vilmantas %A Grove, Megan L %A de Haan, Hugoline G %A Hackinger, Sophie %A Hai, Yang %A Han, Sohee %A Tybjærg-Hansen, Anne %A Hivert, Marie-France %A Isomaa, Bo %A Jäger, Susanne %A Jørgensen, Marit E %A Jørgensen, Torben %A Käräjämäki, AnneMari %A Kim, Bong-Jo %A Kim, Sung Soo %A Koistinen, Heikki A %A Kovacs, Peter %A Kriebel, Jennifer %A Kronenberg, Florian %A Läll, Kristi %A Lange, Leslie A %A Lee, Jung-Jin %A Lehne, Benjamin %A Li, Huaixing %A Lin, Keng-Hung %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Jun %A Loh, Marie %A Mägi, Reedik %A Mamakou, Vasiliki %A McKean-Cowdin, Roberta %A Nadkarni, Girish %A Neville, Matt %A Nielsen, Sune F %A Ntalla, Ioanna %A Peyser, Patricia A %A Rathmann, Wolfgang %A Rice, Kenneth %A Rich, Stephen S %A Rode, Line %A Rolandsson, Olov %A Schönherr, Sebastian %A Selvin, Elizabeth %A Small, Kerrin S %A Stančáková, Alena %A Surendran, Praveen %A Taylor, Kent D %A Teslovich, Tanya M %A Thorand, Barbara %A Thorleifsson, Gudmar %A Tin, Adrienne %A Tönjes, Anke %A Varbo, Anette %A Witte, Daniel R %A Wood, Andrew R %A Yajnik, Pranav %A Yao, Jie %A Yengo, Loic %A Young, Robin %A Amouyel, Philippe %A Boeing, Heiner %A Boerwinkle, Eric %A Bottinger, Erwin P %A Chowdhury, Rajiv %A Collins, Francis S %A Dedoussis, George %A Dehghan, Abbas %A Deloukas, Panos %A Ferrario, Marco M %A Ferrieres, Jean %A Florez, Jose C %A Frossard, Philippe %A Gudnason, Vilmundur %A Harris, Tamara B %A Heckbert, Susan R %A Howson, Joanna M M %A Ingelsson, Martin %A Kathiresan, Sekar %A Kee, Frank %A Kuusisto, Johanna %A Langenberg, Claudia %A Launer, Lenore J %A Lindgren, Cecilia M %A Männistö, Satu %A Meitinger, Thomas %A Melander, Olle %A Mohlke, Karen L %A Moitry, Marie %A Morris, Andrew D %A Murray, Alison D %A de Mutsert, Renée %A Orho-Melander, Marju %A Owen, Katharine R %A Perola, Markus %A Peters, Annette %A Province, Michael A %A Rasheed, Asif %A Ridker, Paul M %A Rivadineira, Fernando %A Rosendaal, Frits R %A Rosengren, Anders H %A Salomaa, Veikko %A Sheu, Wayne H-H %A Sladek, Rob %A Smith, Blair H %A Strauch, Konstantin %A Uitterlinden, André G %A Varma, Rohit %A Willer, Cristen J %A Blüher, Matthias %A Butterworth, Adam S %A Chambers, John Campbell %A Chasman, Daniel I %A Danesh, John %A van Duijn, Cornelia %A Dupuis, Josée %A Franco, Oscar H %A Franks, Paul W %A Froguel, Philippe %A Grallert, Harald %A Groop, Leif %A Han, Bok-Ghee %A Hansen, Torben %A Hattersley, Andrew T %A Hayward, Caroline %A Ingelsson, Erik %A Kardia, Sharon L R %A Karpe, Fredrik %A Kooner, Jaspal Singh %A Köttgen, Anna %A Kuulasmaa, Kari %A Laakso, Markku %A Lin, Xu %A Lind, Lars %A Liu, Yongmei %A Loos, Ruth J F %A Marchini, Jonathan %A Metspalu, Andres %A Mook-Kanamori, Dennis %A Nordestgaard, Børge G %A Palmer, Colin N A %A Pankow, James S %A Pedersen, Oluf %A Psaty, Bruce M %A Rauramaa, Rainer %A Sattar, Naveed %A Schulze, Matthias B %A Soranzo, Nicole %A Spector, Timothy D %A Stefansson, Kari %A Stumvoll, Michael %A Thorsteinsdottir, Unnur %A Tuomi, Tiinamaija %A Tuomilehto, Jaakko %A Wareham, Nicholas J %A Wilson, James G %A Zeggini, Eleftheria %A Scott, Robert A %A Barroso, Inês %A Frayling, Timothy M %A Goodarzi, Mark O %A Meigs, James B %A Boehnke, Michael %A Saleheen, Danish %A Morris, Andrew P %A Rotter, Jerome I %A McCarthy, Mark I %X

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

%B Nat Genet %V 50 %P 559-571 %8 2018 Apr %G eng %N 4 %R 10.1038/s41588-018-0084-1 %0 Journal Article %J Nat Genet %D 2022 %T Assessing the contribution of rare variants to complex trait heritability from whole-genome sequence data. %A Wainschtein, Pierrick %A Jain, Deepti %A Zheng, Zhili %A Cupples, L Adrienne %A Shadyab, Aladdin H %A McKnight, Barbara %A Shoemaker, Benjamin M %A Mitchell, Braxton D %A Psaty, Bruce M %A Kooperberg, Charles %A Liu, Ching-Ti %A Albert, Christine M %A Roden, Dan %A Chasman, Daniel I %A Darbar, Dawood %A Lloyd-Jones, Donald M %A Arnett, Donna K %A Regan, Elizabeth A %A Boerwinkle, Eric %A Rotter, Jerome I %A O'Connell, Jeffrey R %A Yanek, Lisa R %A de Andrade, Mariza %A Allison, Matthew A %A McDonald, Merry-Lynn N %A Chung, Mina K %A Fornage, Myriam %A Chami, Nathalie %A Smith, Nicholas L %A Ellinor, Patrick T %A Vasan, Ramachandran S %A Mathias, Rasika A %A Loos, Ruth J F %A Rich, Stephen S %A Lubitz, Steven A %A Heckbert, Susan R %A Redline, Susan %A Guo, Xiuqing %A Chen, Y -D Ida %A Laurie, Cecelia A %A Hernandez, Ryan D %A McGarvey, Stephen T %A Goddard, Michael E %A Laurie, Cathy C %A North, Kari E %A Lange, Leslie A %A Weir, Bruce S %A Yengo, Loic %A Yang, Jian %A Visscher, Peter M %X

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

%B Nat Genet %V 54 %P 263-273 %8 2022 Mar %G eng %N 3 %R 10.1038/s41588-021-00997-7 %0 Journal Article %J Nat Genet %D 2022 %T Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation. %A Mahajan, Anubha %A Spracklen, Cassandra N %A Zhang, Weihua %A Ng, Maggie C Y %A Petty, Lauren E %A Kitajima, Hidetoshi %A Yu, Grace Z %A Rüeger, Sina %A Speidel, Leo %A Kim, Young Jin %A Horikoshi, Momoko %A Mercader, Josep M %A Taliun, Daniel %A Moon, Sanghoon %A Kwak, Soo-Heon %A Robertson, Neil R %A Rayner, Nigel W %A Loh, Marie %A Kim, Bong-Jo %A Chiou, Joshua %A Miguel-Escalada, Irene %A Della Briotta Parolo, Pietro %A Lin, Kuang %A Bragg, Fiona %A Preuss, Michael H %A Takeuchi, Fumihiko %A Nano, Jana %A Guo, Xiuqing %A Lamri, Amel %A Nakatochi, Masahiro %A Scott, Robert A %A Lee, Jung-Jin %A Huerta-Chagoya, Alicia %A Graff, Mariaelisa %A Chai, Jin-Fang %A Parra, Esteban J %A Yao, Jie %A Bielak, Lawrence F %A Tabara, Yasuharu %A Hai, Yang %A Steinthorsdottir, Valgerdur %A Cook, James P %A Kals, Mart %A Grarup, Niels %A Schmidt, Ellen M %A Pan, Ian %A Sofer, Tamar %A Wuttke, Matthias %A Sarnowski, Chloe %A Gieger, Christian %A Nousome, Darryl %A Trompet, Stella %A Long, Jirong %A Sun, Meng %A Tong, Lin %A Chen, Wei-Min %A Ahmad, Meraj %A Noordam, Raymond %A Lim, Victor J Y %A Tam, Claudia H T %A Joo, Yoonjung Yoonie %A Chen, Chien-Hsiun %A Raffield, Laura M %A Lecoeur, Cécile %A Prins, Bram Peter %A Nicolas, Aude %A Yanek, Lisa R %A Chen, Guanjie %A Jensen, Richard A %A Tajuddin, Salman %A Kabagambe, Edmond K %A An, Ping %A Xiang, Anny H %A Choi, Hyeok Sun %A Cade, Brian E %A Tan, Jingyi %A Flanagan, Jack %A Abaitua, Fernando %A Adair, Linda S %A Adeyemo, Adebowale %A Aguilar-Salinas, Carlos A %A Akiyama, Masato %A Anand, Sonia S %A Bertoni, Alain %A Bian, Zheng %A Bork-Jensen, Jette %A Brandslund, Ivan %A Brody, Jennifer A %A Brummett, Chad M %A Buchanan, Thomas A %A Canouil, Mickaël %A Chan, Juliana C N %A Chang, Li-Ching %A Chee, Miao-Li %A Chen, Ji %A Chen, Shyh-Huei %A Chen, Yuan-Tsong %A Chen, Zhengming %A Chuang, Lee-Ming %A Cushman, Mary %A Das, Swapan K %A de Silva, H Janaka %A Dedoussis, George %A Dimitrov, Latchezar %A Doumatey, Ayo P %A Du, Shufa %A Duan, Qing %A Eckardt, Kai-Uwe %A Emery, Leslie S %A Evans, Daniel S %A Evans, Michele K %A Fischer, Krista %A Floyd, James S %A Ford, Ian %A Fornage, Myriam %A Franco, Oscar H %A Frayling, Timothy M %A Freedman, Barry I %A Fuchsberger, Christian %A Genter, Pauline %A Gerstein, Hertzel C %A Giedraitis, Vilmantas %A González-Villalpando, Clicerio %A Gonzalez-Villalpando, Maria Elena %A Goodarzi, Mark O %A Gordon-Larsen, Penny %A Gorkin, David %A Gross, Myron %A Guo, Yu %A Hackinger, Sophie %A Han, Sohee %A Hattersley, Andrew T %A Herder, Christian %A Howard, Annie-Green %A Hsueh, Willa %A Huang, Mengna %A Huang, Wei %A Hung, Yi-Jen %A Hwang, Mi Yeong %A Hwu, Chii-Min %A Ichihara, Sahoko %A Ikram, Mohammad Arfan %A Ingelsson, Martin %A Islam, Md Tariqul %A Isono, Masato %A Jang, Hye-Mi %A Jasmine, Farzana %A Jiang, Guozhi %A Jonas, Jost B %A Jørgensen, Marit E %A Jørgensen, Torben %A Kamatani, Yoichiro %A Kandeel, Fouad R %A Kasturiratne, Anuradhani %A Katsuya, Tomohiro %A Kaur, Varinderpal %A Kawaguchi, Takahisa %A Keaton, Jacob M %A Kho, Abel N %A Khor, Chiea-Chuen %A Kibriya, Muhammad G %A Kim, Duk-Hwan %A Kohara, Katsuhiko %A Kriebel, Jennifer %A Kronenberg, Florian %A Kuusisto, Johanna %A Läll, Kristi %A Lange, Leslie A %A Lee, Myung-Shik %A Lee, Nanette R %A Leong, Aaron %A Li, Liming %A Li, Yun %A Li-Gao, Ruifang %A Ligthart, Symen %A Lindgren, Cecilia M %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Jianjun %A Locke, Adam E %A Louie, Tin %A Luan, Jian'an %A Luk, Andrea O %A Luo, Xi %A Lv, Jun %A Lyssenko, Valeriya %A Mamakou, Vasiliki %A Mani, K Radha %A Meitinger, Thomas %A Metspalu, Andres %A Morris, Andrew D %A Nadkarni, Girish N %A Nadler, Jerry L %A Nalls, Michael A %A Nayak, Uma %A Nongmaithem, Suraj S %A Ntalla, Ioanna %A Okada, Yukinori %A Orozco, Lorena %A Patel, Sanjay R %A Pereira, Mark A %A Peters, Annette %A Pirie, Fraser J %A Porneala, Bianca %A Prasad, Gauri %A Preissl, Sebastian %A Rasmussen-Torvik, Laura J %A Reiner, Alexander P %A Roden, Michael %A Rohde, Rebecca %A Roll, Kathryn %A Sabanayagam, Charumathi %A Sander, Maike %A Sandow, Kevin %A Sattar, Naveed %A Schönherr, Sebastian %A Schurmann, Claudia %A Shahriar, Mohammad %A Shi, Jinxiu %A Shin, Dong Mun %A Shriner, Daniel %A Smith, Jennifer A %A So, Wing Yee %A Stančáková, Alena %A Stilp, Adrienne M %A Strauch, Konstantin %A Suzuki, Ken %A Takahashi, Atsushi %A Taylor, Kent D %A Thorand, Barbara %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tomlinson, Brian %A Torres, Jason M %A Tsai, Fuu-Jen %A Tuomilehto, Jaakko %A Tusié-Luna, Teresa %A Udler, Miriam S %A Valladares-Salgado, Adan %A van Dam, Rob M %A van Klinken, Jan B %A Varma, Rohit %A Vujkovic, Marijana %A Wacher-Rodarte, Niels %A Wheeler, Eleanor %A Whitsel, Eric A %A Wickremasinghe, Ananda R %A van Dijk, Ko Willems %A Witte, Daniel R %A Yajnik, Chittaranjan S %A Yamamoto, Ken %A Yamauchi, Toshimasa %A Yengo, Loic %A Yoon, Kyungheon %A Yu, Canqing %A Yuan, Jian-Min %A Yusuf, Salim %A Zhang, Liang %A Zheng, Wei %A Raffel, Leslie J %A Igase, Michiya %A Ipp, Eli %A Redline, Susan %A Cho, Yoon Shin %A Lind, Lars %A Province, Michael A %A Hanis, Craig L %A Peyser, Patricia A %A Ingelsson, Erik %A Zonderman, Alan B %A Psaty, Bruce M %A Wang, Ya-Xing %A Rotimi, Charles N %A Becker, Diane M %A Matsuda, Fumihiko %A Liu, Yongmei %A Zeggini, Eleftheria %A Yokota, Mitsuhiro %A Rich, Stephen S %A Kooperberg, Charles %A Pankow, James S %A Engert, James C %A Chen, Yii-Der Ida %A Froguel, Philippe %A Wilson, James G %A Sheu, Wayne H H %A Kardia, Sharon L R %A Wu, Jer-Yuarn %A Hayes, M Geoffrey %A Ma, Ronald C W %A Wong, Tien-Yin %A Groop, Leif %A Mook-Kanamori, Dennis O %A Chandak, Giriraj R %A Collins, Francis S %A Bharadwaj, Dwaipayan %A Paré, Guillaume %A Sale, Michèle M %A Ahsan, Habibul %A Motala, Ayesha A %A Shu, Xiao-Ou %A Park, Kyong-Soo %A Jukema, J Wouter %A Cruz, Miguel %A McKean-Cowdin, Roberta %A Grallert, Harald %A Cheng, Ching-Yu %A Bottinger, Erwin P %A Dehghan, Abbas %A Tai, E-Shyong %A Dupuis, Josée %A Kato, Norihiro %A Laakso, Markku %A Köttgen, Anna %A Koh, Woon-Puay %A Palmer, Colin N A %A Liu, Simin %A Abecasis, Goncalo %A Kooner, Jaspal S %A Loos, Ruth J F %A North, Kari E %A Haiman, Christopher A %A Florez, Jose C %A Saleheen, Danish %A Hansen, Torben %A Pedersen, Oluf %A Mägi, Reedik %A Langenberg, Claudia %A Wareham, Nicholas J %A Maeda, Shiro %A Kadowaki, Takashi %A Lee, Juyoung %A Millwood, Iona Y %A Walters, Robin G %A Stefansson, Kari %A Myers, Simon R %A Ferrer, Jorge %A Gaulton, Kyle J %A Meigs, James B %A Mohlke, Karen L %A Gloyn, Anna L %A Bowden, Donald W %A Below, Jennifer E %A Chambers, John C %A Sim, Xueling %A Boehnke, Michael %A Rotter, Jerome I %A McCarthy, Mark I %A Morris, Andrew P %K Diabetes Mellitus, Type 2 %K Ethnicity %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Polymorphism, Single Nucleotide %K Risk Factors %X

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.

%B Nat Genet %V 54 %P 560-572 %8 2022 May %G eng %N 5 %R 10.1038/s41588-022-01058-3