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

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

%B Nature %V 590 %P 290-299 %8 2021 02 %G eng %N 7845 %R 10.1038/s41586-021-03205-y %0 Journal Article %J 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 %0 Journal Article %J medRxiv %D 2023 %T Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications. %A Suzuki, Ken %A Hatzikotoulas, Konstantinos %A Southam, Lorraine %A Taylor, Henry J %A Yin, Xianyong %A Lorenz, Kim M %A Mandla, Ravi %A Huerta-Chagoya, Alicia %A Rayner, Nigel W %A Bocher, Ozvan %A Ana Luiza de, S V Arruda %A Sonehara, Kyuto %A Namba, Shinichi %A Lee, Simon S K %A Preuss, Michael H %A Petty, Lauren E %A Schroeder, Philip %A Vanderwerff, Brett %A Kals, Mart %A Bragg, Fiona %A Lin, Kuang %A Guo, Xiuqing %A Zhang, Weihua %A Yao, Jie %A Kim, Young Jin %A Graff, Mariaelisa %A Takeuchi, Fumihiko %A Nano, Jana %A Lamri, Amel %A Nakatochi, Masahiro %A Moon, Sanghoon %A Scott, Robert A %A Cook, James P %A Lee, Jung-Jin %A Pan, Ian %A Taliun, Daniel %A Parra, Esteban J %A Chai, Jin-Fang %A Bielak, Lawrence F %A Tabara, Yasuharu %A Hai, Yang %A Thorleifsson, Gudmar %A Grarup, Niels %A Sofer, Tamar %A Wuttke, Matthias %A Sarnowski, Chloe %A Gieger, Christian %A Nousome, Darryl %A Trompet, Stella %A Kwak, Soo-Heon %A Long, Jirong %A Sun, Meng %A Tong, Lin %A Chen, Wei-Min %A Nongmaithem, Suraj S %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 Prins, Bram Peter %A Nicolas, Aude %A Yanek, Lisa R %A Chen, Guanjie %A Brody, Jennifer A %A Kabagambe, Edmond %A An, Ping %A Xiang, Anny H %A Choi, Hyeok Sun %A Cade, Brian E %A Tan, Jingyi %A Alaine Broadaway, K %A Williamson, Alice %A Kamali, Zoha %A Cui, Jinrui %A Adair, Linda S %A Adeyemo, Adebowale %A Aguilar-Salinas, Carlos A %A Ahluwalia, Tarunveer S %A Anand, Sonia S %A Bertoni, Alain %A Bork-Jensen, Jette %A Brandslund, Ivan %A Buchanan, Thomas A %A Burant, Charles F %A Butterworth, Adam S %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 Danesh, John %A Das, Swapan K %A Janaka de Silva, H %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 Franco, Oscar H %A Frayling, Timothy M %A Freedman, Barry I %A Genter, Pauline %A Gerstein, Hertzel C %A Giedraitis, Vilmantas %A González-Villalpando, Clicerio %A Gonzalez-Villalpando, Maria Elena %A Gordon-Larsen, Penny %A Gross, Myron %A Guare, Lindsay A %A Hackinger, Sophie %A Han, Sohee %A Hattersley, Andrew T %A Herder, Christian %A Horikoshi, Momoko %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, Torben %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 Kronenberg, Florian %A Kuusisto, Johanna %A Läll, Kristi %A Lange, Leslie A %A Lee, Kyung Min %A Lee, Myung-Shik %A Lee, Nanette R %A Leong, Aaron %A Li, Liming %A Li, Yun %A Li-Gao, Ruifang %A Lithgart, 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 Lynch, Julie A %A Lyssenko, Valeriya %A Maeda, Shiro %A Mamakou, Vasiliki %A Mansuri, Sohail Rafik %A Matsuda, Koichi %A Meitinger, Thomas %A Metspalu, Andres %A Mo, Huan %A Morris, Andrew D %A Nadler, Jerry L %A Nalls, Michael A %A Nayak, Uma %A Ntalla, Ioanna %A Okada, Yukinori %A Orozco, Lorena %A Patel, Sanjay R %A Patil, Snehal %A Pei, Pei %A Pereira, Mark A %A Peters, Annette %A Pirie, Fraser J %A Polikowsky, Hannah G %A Porneala, Bianca %A Prasad, Gauri %A Rasmussen-Torvik, Laura J %A Reiner, Alexander P %A Roden, Michael %A Rohde, Rebecca %A Roll, Katheryn %A Sabanayagam, Charumathi %A Sandow, Kevin %A Sankareswaran, Alagu %A Sattar, Naveed %A Schönherr, Sebastian %A Shahriar, Mohammad %A Shen, Botong %A Shi, Jinxiu %A Shin, Dong Mun %A Shojima, Nobuhiro %A Smith, Jennifer A %A So, Wing Yee %A Stančáková, Alena %A Steinthorsdottir, Valgerdur %A Stilp, Adrienne M %A Strauch, Konstantin %A Taylor, Kent D %A Thorand, Barbara %A Thorsteinsdottir, Unnur %A Tomlinson, Brian %A Tran, Tam C %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 Wacher-Rodarte, Niels %A Wheeler, Eleanor %A Wickremasinghe, Ananda R %A van Dijk, Ko Willems %A Witte, Daniel R %A Yajnik, Chittaranjan S %A Yamamoto, Ken %A Yamamoto, Kenichi %A Yoon, Kyungheon %A Yu, Canqing %A Yuan, Jian-Min %A Yusuf, Salim %A Zawistowski, Matthew %A Zhang, Liang %A Zheng, Wei %A Project, Biobank Japan %A BioBank, Penn Medicine %A Center, Regeneron Genetics %A Consortium, eMERGE %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 Fornage, Myriam %A Hanis, Craig L %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 Yokota, Mitsuhiro %A Kardia, Sharon L R %A Peyser, Patricia A %A Pankow, James S %A Engert, James C %A Bonnefond, Amélie %A Froguel, Philippe %A Wilson, James G %A Sheu, Wayne H H %A Wu, Jer-Yuarn %A Geoffrey Hayes, M %A Ma, Ronald C W %A Wong, Tien-Yin %A Mook-Kanamori, Dennis O %A Tuomi, Tiinamaija %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 Chen, Yii-Der Ida %A Rich, Stephen S %A McKean-Cowdin, Roberta %A Grallert, Harald %A Cheng, Ching-Yu %A Ghanbari, Mohsen %A Tai, E-Shyong %A Dupuis, Josée %A Kato, Norihiro %A Laakso, Markku %A Köttgen, Anna %A Koh, Woon-Puay %A Bowden, Donald W %A Palmer, Colin N A %A Kooner, Jaspal S %A Kooperberg, Charles %A Liu, Simin %A North, Kari E %A Saleheen, Danish %A Hansen, Torben %A Pedersen, Oluf %A Wareham, Nicholas J %A Lee, Juyoung %A Kim, Bong-Jo %A Millwood, Iona Y %A Walters, Robin G %A Stefansson, Kari %A Goodarzi, Mark O %A Mohlke, Karen L %A Langenberg, Claudia %A Haiman, Christopher A %A Loos, Ruth J F %A Florez, Jose C %A Rader, Daniel J %A Ritchie, Marylyn D %A Zöllner, Sebastian %A Mägi, Reedik %A Denny, Joshua C %A Yamauchi, Toshimasa %A Kadowaki, Takashi %A Chambers, John C %A Ng, Maggie C Y %A Sim, Xueling %A Below, Jennifer E %A Tsao, Philip S %A Chang, Kyong-Mi %A McCarthy, Mark I %A Meigs, James B %A Mahajan, Anubha %A Spracklen, Cassandra N %A Mercader, Josep M %A Boehnke, Michael %A Rotter, Jerome I %A Vujkovic, Marijana %A Voight, Benjamin F %A Morris, Andrew P %A Zeggini, Eleftheria %X

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P<5×10 ) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.

%B medRxiv %8 2023 Mar 31 %G eng %R 10.1101/2023.03.31.23287839 %0 Journal Article %J Nature %D 2024 %T Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. %A Suzuki, Ken %A Hatzikotoulas, Konstantinos %A Southam, Lorraine %A Taylor, Henry J %A Yin, Xianyong %A Lorenz, Kim M %A Mandla, Ravi %A Huerta-Chagoya, Alicia %A Melloni, Giorgio E M %A Kanoni, Stavroula %A Rayner, Nigel W %A Bocher, Ozvan %A Arruda, Ana Luiza %A Sonehara, Kyuto %A Namba, Shinichi %A Lee, Simon S K %A Preuss, Michael H %A Petty, Lauren E %A Schroeder, Philip %A Vanderwerff, Brett %A Kals, Mart %A Bragg, Fiona %A Lin, Kuang %A Guo, Xiuqing %A Zhang, Weihua %A Yao, Jie %A Kim, Young Jin %A Graff, Mariaelisa %A Takeuchi, Fumihiko %A Nano, Jana %A Lamri, Amel %A Nakatochi, Masahiro %A Moon, Sanghoon %A Scott, Robert A %A Cook, James P %A Lee, Jung-Jin %A Pan, Ian %A Taliun, Daniel %A Parra, Esteban J %A Chai, Jin-Fang %A Bielak, Lawrence F %A Tabara, Yasuharu %A Hai, Yang %A Thorleifsson, Gudmar %A Grarup, Niels %A Sofer, Tamar %A Wuttke, Matthias %A Sarnowski, Chloe %A Gieger, Christian %A Nousome, Darryl %A Trompet, Stella %A Kwak, Soo-Heon %A Long, Jirong %A Sun, Meng %A Tong, Lin %A Chen, Wei-Min %A Nongmaithem, Suraj S %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 Prins, Bram Peter %A Nicolas, Aude %A Yanek, Lisa R %A Chen, Guanjie %A Brody, Jennifer A %A Kabagambe, Edmond %A An, Ping %A Xiang, Anny H %A Choi, Hyeok Sun %A Cade, Brian E %A Tan, Jingyi %A Broadaway, K Alaine %A Williamson, Alice %A Kamali, Zoha %A Cui, Jinrui %A Thangam, Manonanthini %A Adair, Linda S %A Adeyemo, Adebowale %A Aguilar-Salinas, Carlos A %A Ahluwalia, Tarunveer S %A Anand, Sonia S %A Bertoni, Alain %A Bork-Jensen, Jette %A Brandslund, Ivan %A Buchanan, Thomas A %A Burant, Charles F %A Butterworth, Adam S %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 Danesh, John %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 Franco, Oscar H %A Frayling, Timothy M %A Freedman, Barry I %A Genter, Pauline %A Gerstein, Hertzel C %A Giedraitis, Vilmantas %A González-Villalpando, Clicerio %A Gonzalez-Villalpando, Maria Elena %A Gordon-Larsen, Penny %A Gross, Myron %A Guare, Lindsay A %A Hackinger, Sophie %A Hakaste, Liisa %A Han, Sohee %A Hattersley, Andrew T %A Herder, Christian %A Horikoshi, Momoko %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, Torben %A Kamanu, Frederick K %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 Kronenberg, Florian %A Kuusisto, Johanna %A Läll, Kristi %A Lange, Leslie A %A Lee, Kyung Min %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 Lynch, Julie A %A Lyssenko, Valeriya %A Maeda, Shiro %A Mamakou, Vasiliki %A Mansuri, Sohail Rafik %A Matsuda, Koichi %A Meitinger, Thomas %A Melander, Olle %A Metspalu, Andres %A Mo, Huan %A Morris, Andrew D %A Moura, Filipe A %A Nadler, Jerry L %A Nalls, Michael A %A Nayak, Uma %A Ntalla, Ioanna %A Okada, Yukinori %A Orozco, Lorena %A Patel, Sanjay R %A Patil, Snehal %A Pei, Pei %A Pereira, Mark A %A Peters, Annette %A Pirie, Fraser J %A Polikowsky, Hannah G %A Porneala, Bianca %A Prasad, Gauri %A Rasmussen-Torvik, Laura J %A Reiner, Alexander P %A Roden, Michael %A Rohde, Rebecca %A Roll, Katheryn %A Sabanayagam, Charumathi %A Sandow, Kevin %A Sankareswaran, Alagu %A Sattar, Naveed %A Schönherr, Sebastian %A Shahriar, Mohammad %A Shen, Botong %A Shi, Jinxiu %A Shin, Dong Mun %A Shojima, Nobuhiro %A Smith, Jennifer A %A So, Wing Yee %A Stančáková, Alena %A Steinthorsdottir, Valgerdur %A Stilp, Adrienne M %A Strauch, Konstantin %A Taylor, Kent D %A Thorand, Barbara %A Thorsteinsdottir, Unnur %A Tomlinson, Brian %A Tran, Tam C %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 Wacher-Rodarte, Niels %A Wheeler, Eleanor %A Wickremasinghe, Ananda R %A van Dijk, Ko Willems %A Witte, Daniel R %A Yajnik, Chittaranjan S %A Yamamoto, Ken %A Yamamoto, Kenichi %A Yoon, Kyungheon %A Yu, Canqing %A Yuan, Jian-Min %A Yusuf, Salim %A Zawistowski, Matthew %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 Fornage, Myriam %A Hanis, Craig L %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 Yokota, Mitsuhiro %A Kardia, Sharon L R %A Peyser, Patricia A %A Pankow, James S %A Engert, James C %A Bonnefond, Amélie %A Froguel, Philippe %A Wilson, James G %A Sheu, Wayne H H %A Wu, Jer-Yuarn %A Hayes, M Geoffrey %A Ma, Ronald C W %A Wong, Tien-Yin %A Mook-Kanamori, Dennis O %A Tuomi, Tiinamaija %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 Chen, Yii-Der Ida %A Rich, Stephen S %A McKean-Cowdin, Roberta %A Grallert, Harald %A Cheng, Ching-Yu %A Ghanbari, Mohsen %A Tai, E-Shyong %A Dupuis, Josée %A Kato, Norihiro %A Laakso, Markku %A Köttgen, Anna %A Koh, Woon-Puay %A Bowden, Donald W %A Palmer, Colin N A %A Kooner, Jaspal S %A Kooperberg, Charles %A Liu, Simin %A North, Kari E %A Saleheen, Danish %A Hansen, Torben %A Pedersen, Oluf %A Wareham, Nicholas J %A Lee, Juyoung %A Kim, Bong-Jo %A Millwood, Iona Y %A Walters, Robin G %A Stefansson, Kari %A Ahlqvist, Emma %A Goodarzi, Mark O %A Mohlke, Karen L %A Langenberg, Claudia %A Haiman, Christopher A %A Loos, Ruth J F %A Florez, Jose C %A Rader, Daniel J %A Ritchie, Marylyn D %A Zöllner, Sebastian %A Mägi, Reedik %A Marston, Nicholas A %A Ruff, Christian T %A van Heel, David A %A Finer, Sarah %A Denny, Joshua C %A Yamauchi, Toshimasa %A Kadowaki, Takashi %A Chambers, John C %A Ng, Maggie C Y %A Sim, Xueling %A Below, Jennifer E %A Tsao, Philip S %A Chang, Kyong-Mi %A McCarthy, Mark I %A Meigs, James B %A Mahajan, Anubha %A Spracklen, Cassandra N %A Mercader, Josep M %A Boehnke, Michael %A Rotter, Jerome I %A Vujkovic, Marijana %A Voight, Benjamin F %A Morris, Andrew P %A Zeggini, Eleftheria %X

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes and molecular mechanisms that are often specific to cell type. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

%B Nature %8 2024 Feb 19 %G eng %R 10.1038/s41586-024-07019-6