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

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

%B Nature %V 480 %P 201-8 %8 2011 Nov 30 %G eng %N 7376 %1 http://www.ncbi.nlm.nih.gov/pubmed/22139419?dopt=Abstract %R 10.1038/nature10659 %0 Journal Article %J Hum Mol Genet %D 2014 %T Trans-ethnic meta-analysis of white blood cell phenotypes. %A Keller, Margaux F %A Reiner, Alexander P %A Okada, Yukinori %A van Rooij, Frank J A %A Johnson, Andrew D %A Chen, Ming-Huei %A Smith, Albert V %A Morris, Andrew P %A Tanaka, Toshiko %A Ferrucci, Luigi %A Zonderman, Alan B %A Lettre, Guillaume %A Harris, Tamara %A Garcia, Melissa %A Bandinelli, Stefania %A Qayyum, Rehan %A Yanek, Lisa R %A Becker, Diane M %A Becker, Lewis C %A Kooperberg, Charles %A Keating, Brendan %A Reis, Jared %A Tang, Hua %A Boerwinkle, Eric %A Kamatani, Yoichiro %A Matsuda, Koichi %A Kamatani, Naoyuki %A Nakamura, Yusuke %A Kubo, Michiaki %A Liu, Simin %A Dehghan, Abbas %A Felix, Janine F %A Hofman, Albert %A Uitterlinden, André G %A van Duijn, Cornelia M %A Franco, Oscar H %A Longo, Dan L %A Singleton, Andrew B %A Psaty, Bruce M %A Evans, Michelle K %A Cupples, L Adrienne %A Rotter, Jerome I %A O'Donnell, Christopher J %A Takahashi, Atsushi %A Wilson, James G %A Ganesh, Santhi K %A Nalls, Mike A %K African Americans %K Asian Continental Ancestry Group %K Bayes Theorem %K European Continental Ancestry Group %K Genome, Human %K Genome-Wide Association Study %K Genotype %K Humans %K Leukocyte Count %K Leukocytes %K Linkage Disequilibrium %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

White blood cell (WBC) count is a common clinical measure used as a predictor of certain aspects of human health, including immunity and infection status. WBC count is also a complex trait that varies among individuals and ancestry groups. Differences in linkage disequilibrium structure and heterogeneity in allelic effects are expected to play a role in the associations observed between populations. Prior genome-wide association study (GWAS) meta-analyses have identified genomic loci associated with WBC and its subtypes, but much of the heritability of these phenotypes remains unexplained. Using GWAS summary statistics for over 50 000 individuals from three diverse populations (Japanese, African-American and European ancestry), a Bayesian model methodology was employed to account for heterogeneity between ancestry groups. This approach was used to perform a trans-ethnic meta-analysis of total WBC, neutrophil and monocyte counts. Ten previously known associations were replicated and six new loci were identified, including several regions harboring genes related to inflammation and immune cell function. Ninety-five percent credible interval regions were calculated to narrow the association signals and fine-map the putatively causal variants within loci. Finally, a conditional analysis was performed on the most significant SNPs identified by the trans-ethnic meta-analysis (MA), and nine secondary signals within loci previously associated with WBC or its subtypes were identified. This work illustrates the potential of trans-ethnic analysis and ascribes a critical role to multi-ethnic cohorts and consortia in exploring complex phenotypes with respect to variants that lie outside the European-biased GWAS pool.

%B Hum Mol Genet %V 23 %P 6944-60 %8 2014 Dec 20 %G eng %N 25 %1 http://www.ncbi.nlm.nih.gov/pubmed/25096241?dopt=Abstract %R 10.1093/hmg/ddu401 %0 Journal Article %J Am J Hum Genet %D 2017 %T Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis. %A van Rooij, Frank J A %A Qayyum, Rehan %A Smith, Albert V %A Zhou, Yi %A Trompet, Stella %A Tanaka, Toshiko %A Keller, Margaux F %A Chang, Li-Ching %A Schmidt, Helena %A Yang, Min-Lee %A Chen, Ming-Huei %A Hayes, James %A Johnson, Andrew D %A Yanek, Lisa R %A Mueller, Christian %A Lange, Leslie %A Floyd, James S %A Ghanbari, Mohsen %A Zonderman, Alan B %A Jukema, J Wouter %A Hofman, Albert %A van Duijn, Cornelia M %A Desch, Karl C %A Saba, Yasaman %A Ozel, Ayse B %A Snively, Beverly M %A Wu, Jer-Yuarn %A Schmidt, Reinhold %A Fornage, Myriam %A Klein, Robert J %A Fox, Caroline S %A Matsuda, Koichi %A Kamatani, Naoyuki %A Wild, Philipp S %A Stott, David J %A Ford, Ian %A Slagboom, P Eline %A Yang, Jaden %A Chu, Audrey Y %A Lambert, Amy J %A Uitterlinden, André G %A Franco, Oscar H %A Hofer, Edith %A Ginsburg, David %A Hu, Bella %A Keating, Brendan %A Schick, Ursula M %A Brody, Jennifer A %A Li, Jun Z %A Chen, Zhao %A Zeller, Tanja %A Guralnik, Jack M %A Chasman, Daniel I %A Peters, Luanne L %A Kubo, Michiaki %A Becker, Diane M %A Li, Jin %A Eiriksdottir, Gudny %A Rotter, Jerome I %A Levy, Daniel %A Grossmann, Vera %A Patel, Kushang V %A Chen, Chien-Hsiun %A Ridker, Paul M %A Tang, Hua %A Launer, Lenore J %A Rice, Kenneth M %A Li-Gao, Ruifang %A Ferrucci, Luigi %A Evans, Michelle K %A Choudhuri, Avik %A Trompouki, Eirini %A Abraham, Brian J %A Yang, Song %A Takahashi, Atsushi %A Kamatani, Yoichiro %A Kooperberg, Charles %A Harris, Tamara B %A Jee, Sun Ha %A Coresh, Josef %A Tsai, Fuu-Jen %A Longo, Dan L %A Chen, Yuan-Tsong %A Felix, Janine F %A Yang, Qiong %A Psaty, Bruce M %A Boerwinkle, Eric %A Becker, Lewis C %A Mook-Kanamori, Dennis O %A Wilson, James G %A Gudnason, Vilmundur %A O'Donnell, Christopher J %A Dehghan, Abbas %A Cupples, L Adrienne %A Nalls, Michael A %A Morris, Andrew P %A Okada, Yukinori %A Reiner, Alexander P %A Zon, Leonard I %A Ganesh, Santhi K %X

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.

%B Am J Hum Genet %V 100 %P 51-63 %8 2017 Jan 05 %G eng %N 1 %R 10.1016/j.ajhg.2016.11.016 %0 Journal Article %J Nat Genet %D 2018 %T Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks. %A Demenais, Florence %A Margaritte-Jeannin, Patricia %A Barnes, Kathleen C %A Cookson, William O C %A Altmüller, Janine %A Ang, Wei %A Barr, R Graham %A Beaty, Terri H %A Becker, Allan B %A Beilby, John %A Bisgaard, Hans %A Bjornsdottir, Unnur Steina %A Bleecker, Eugene %A Bønnelykke, Klaus %A Boomsma, Dorret I %A Bouzigon, Emmanuelle %A Brightling, Christopher E %A Brossard, Myriam %A Brusselle, Guy G %A Burchard, Esteban %A Burkart, Kristin M %A Bush, Andrew %A Chan-Yeung, Moira %A Chung, Kian Fan %A Couto Alves, Alexessander %A Curtin, John A %A Custovic, Adnan %A Daley, Denise %A de Jongste, Johan C %A Del-Rio-Navarro, Blanca E %A Donohue, Kathleen M %A Duijts, Liesbeth %A Eng, Celeste %A Eriksson, Johan G %A Farrall, Martin %A Fedorova, Yuliya %A Feenstra, Bjarke %A Ferreira, Manuel A %A Freidin, Maxim B %A Gajdos, Zofia %A Gauderman, Jim %A Gehring, Ulrike %A Geller, Frank %A Genuneit, Jon %A Gharib, Sina A %A Gilliland, Frank %A Granell, Raquel %A Graves, Penelope E %A Gudbjartsson, Daniel F %A Haahtela, Tari %A Heckbert, Susan R %A Heederik, Dick %A Heinrich, Joachim %A Heliövaara, Markku %A Henderson, John %A Himes, Blanca E %A Hirose, Hiroshi %A Hirschhorn, Joel N %A Hofman, Albert %A Holt, Patrick %A Hottenga, Jouke %A Hudson, Thomas J %A Hui, Jennie %A Imboden, Medea %A Ivanov, Vladimir %A Jaddoe, Vincent W V %A James, Alan %A Janson, Christer %A Jarvelin, Marjo-Riitta %A Jarvis, Deborah %A Jones, Graham %A Jonsdottir, Ingileif %A Jousilahti, Pekka %A Kabesch, Michael %A Kähönen, Mika %A Kantor, David B %A Karunas, Alexandra S %A Khusnutdinova, Elza %A Koppelman, Gerard H %A Kozyrskyj, Anita L %A Kreiner, Eskil %A Kubo, Michiaki %A Kumar, Rajesh %A Kumar, Ashish %A Kuokkanen, Mikko %A Lahousse, Lies %A Laitinen, Tarja %A Laprise, Catherine %A Lathrop, Mark %A Lau, Susanne %A Lee, Young-Ae %A Lehtimäki, Terho %A Letort, Sébastien %A Levin, Albert M %A Li, Guo %A Liang, Liming %A Loehr, Laura R %A London, Stephanie J %A Loth, Daan W %A Manichaikul, Ani %A Marenholz, Ingo %A Martinez, Fernando J %A Matheson, Melanie C %A Mathias, Rasika A %A Matsumoto, Kenji %A Mbarek, Hamdi %A McArdle, Wendy L %A Melbye, Mads %A Melén, Erik %A Meyers, Deborah %A Michel, Sven %A Mohamdi, Hamida %A Musk, Arthur W %A Myers, Rachel A %A Nieuwenhuis, Maartje A E %A Noguchi, Emiko %A O'Connor, George T %A Ogorodova, Ludmila M %A Palmer, Cameron D %A Palotie, Aarno %A Park, Julie E %A Pennell, Craig E %A Pershagen, Göran %A Polonikov, Alexey %A Postma, Dirkje S %A Probst-Hensch, Nicole %A Puzyrev, Valery P %A Raby, Benjamin A %A Raitakari, Olli T %A Ramasamy, Adaikalavan %A Rich, Stephen S %A Robertson, Colin F %A Romieu, Isabelle %A Salam, Muhammad T %A Salomaa, Veikko %A Schlünssen, Vivi %A Scott, Robert %A Selivanova, Polina A %A Sigsgaard, Torben %A Simpson, Angela %A Siroux, Valérie %A Smith, Lewis J %A Solodilova, Maria %A Standl, Marie %A Stefansson, Kari %A Strachan, David P %A Stricker, Bruno H %A Takahashi, Atsushi %A Thompson, Philip J %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tiesler, Carla M T %A Torgerson, Dara G %A Tsunoda, Tatsuhiko %A Uitterlinden, André G %A van der Valk, Ralf J P %A Vaysse, Amaury %A Vedantam, Sailaja %A von Berg, Andrea %A von Mutius, Erika %A Vonk, Judith M %A Waage, Johannes %A Wareham, Nick J %A Weiss, Scott T %A White, Wendy B %A Wickman, Magnus %A Widen, Elisabeth %A Willemsen, Gonneke %A Williams, L Keoki %A Wouters, Inge M %A Yang, James J %A Zhao, Jing Hua %A Moffatt, Miriam F %A Ober, Carole %A Nicolae, Dan L %X

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

%B Nat Genet %V 50 %P 42-53 %8 2018 Jan %G eng %N 1 %R 10.1038/s41588-017-0014-7 %0 Journal Article %J Diabetes %D 2019 %T Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control. %A Pollack, Samuela %A Igo, Robert P %A Jensen, Richard A %A Christiansen, Mark %A Li, Xiaohui %A Cheng, Ching-Yu %A Ng, Maggie C Y %A Smith, Albert V %A Rossin, Elizabeth J %A Segrè, Ayellet V %A Davoudi, Samaneh %A Tan, Gavin S %A Chen, Yii-Der Ida %A Kuo, Jane Z %A Dimitrov, Latchezar M %A Stanwyck, Lynn K %A Meng, Weihua %A Hosseini, S Mohsen %A Imamura, Minako %A Nousome, Darryl %A Kim, Jihye %A Hai, Yang %A Jia, Yucheng %A Ahn, Jeeyun %A Leong, Aaron %A Shah, Kaanan %A Park, Kyu Hyung %A Guo, Xiuqing %A Ipp, Eli %A Taylor, Kent D %A Adler, Sharon G %A Sedor, John R %A Freedman, Barry I %A Lee, I-Te %A Sheu, Wayne H-H %A Kubo, Michiaki %A Takahashi, Atsushi %A Hadjadj, Samy %A Marre, Michel %A Trégouët, David-Alexandre %A McKean-Cowdin, Roberta %A Varma, Rohit %A McCarthy, Mark I %A Groop, Leif %A Ahlqvist, Emma %A Lyssenko, Valeriya %A Agardh, Elisabet %A Morris, Andrew %A Doney, Alex S F %A Colhoun, Helen M %A Toppila, Iiro %A Sandholm, Niina %A Groop, Per-Henrik %A Maeda, Shiro %A Hanis, Craig L %A Penman, Alan %A Chen, Ching J %A Hancock, Heather %A Mitchell, Paul %A Craig, Jamie E %A Chew, Emily Y %A Paterson, Andrew D %A Grassi, Michael A %A Palmer, Colin %A Bowden, Donald W %A Yaspan, Brian L %A Siscovick, David %A Cotch, Mary Frances %A Wang, Jie Jin %A Burdon, Kathryn P %A Wong, Tien Y %A Klein, Barbara E K %A Klein, Ronald %A Rotter, Jerome I %A Iyengar, Sudha K %A Price, Alkes L %A Sobrin, Lucia %X

To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts ( = 3,246) and seven African American cohorts ( = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a value <1 × 10 were investigated in replication cohorts that included 18,545 European, 16,453 Asian, and 2,710 Hispanic subjects. After correction for multiple testing, the C allele of rs142293996 in an intron of nuclear VCP-like () was associated with DR in European discovery cohorts ( = 2.1 × 10), but did not reach genome-wide significance after meta-analysis with replication cohorts. We applied the Disease Association Protein-Protein Link Evaluator (DAPPLE) to our discovery results to test for evidence of risk being spread across underlying molecular pathways. One protein-protein interaction network built from genes in regions associated with proliferative DR was found to have significant connectivity ( = 0.0009) and corroborated with gene set enrichment analyses. These findings suggest that genetic variation in as well as variation within a protein-protein interaction network that includes genes implicated in inflammation, may influence risk for DR.

%B Diabetes %V 68 %P 441-456 %8 2019 Feb %G eng %N 2 %R 10.2337/db18-0567 %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