The trans-ancestral genomic architecture of glycemic traits

Chen, J.; Spracklen, C.N.; Marenne, G.; Varshney, A.; Corbin, L.J.; Luan, J.A.; ... ; Ka (2021)

Article / Letter to editor

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 x 10(-8)), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.

• All authors: Chen, J.; Spracklen, C.N.; Marenne, G.; Varshney, A.; Corbin, L.J.; Luan, J.A.; Willems, S.M.; Wu, Y.; Zhang, X.S.; Horikoshi, M.; Boutin, T.S.; Magi, R.; Waage, J.; Li-Gao, R.F.; Chan, K.H.K.; Yao, J.; Anasanti, M.D.; Chu, A.Y.; Claringbould, A.; Heikkinen, J.; Hong, J.; Hottenga, J.J.; Huo, S.F.; Kaakinen, M.A.; Louie, T.; Marz, W.; Moreno-Macias, H.; Ndungu, A.; Nelson, S.C.; Nolte, I.M.; North, K.E.; Raulerson, C.K.; Ray, D.; Rohde, R.; Rybin, D.; Schurmann, C.; Sim, X.L.; Southam, L.; Stewart, I.D.; Wang, C.A.; Wang, Y.J.; Wu, P.T.; Zhang, W.H.; Ahluwalia, T.S.; Appel, E.V.R.; Bielak, L.F.; Brody, J.A.; Burtt, N.P.; Cabrera, C.P.; Cade, B.E.; Chai, J.F.; Chai, X.R.; Chang, L.C.; Chen, C.H.; Chen, B.H.; Chitrala, K.N.; Chiu, Y.F.; Haan, H.G. de; Delgado, G.E.; Demirkan, A.; Duan, Q.; Engmann, J.; Fatumo, S.A.; Gayan, J.; Giulianini, F.; Gong, J.H.; Gustafsson, S.; Hai, Y.; Hartwig, F.P.; He, J.; Heianza, Y.; Huang, T.; Huerta-Chagoya, A.; Hwang, M.Y.; Jensen, R.A.; Kawaguchi, T.; Kentistou, K.A.; Kim, Y.J.; Kleber, M.E.; Kooner, I.K.; Lai, S.Q.; Lange, L.A.; Langefeld, C.D.; Lauzon, M.; Li, M.; Ligthart, S.; Liu, J.; Loh, M.; Long, J.R.; Lyssenko, V.; Mangino, M.; Marzi, C.; Montasser, M.E.; Nag, A.; Nakatochi, M.; Noce, D.; Noordam, R.; Pistis, G.; Preuss, M.; Raffield, L.; Rasmussen-Torvik, L.J.; Rich, S.S.; Robertson, N.R.; Rueedi, R.; Ryan, K.; Sanna, S.; Saxena, R.; Schraut, K.E.; Sennblad, B.; Setoh, K.; Smith, A.V.; Sparso, T.; Strawbridge, R.J.; Takeuchi, F.; Tan, J.Y.; Trompet, S.; Akker, E. van den; Most, P.J. van der; Verweij, N.; Vogel, M.; Wang, H.M.; Wang, C.L.; Wang, N.; Warren, H.R.; Wen, W.Q.; Wilsgaard, T.; Wong, A.; Wood, A.R.; Xie, T.; Zafarmand, M.H.; Zhao, J.H.; Zhao, W.; Amin, N.; Arzumanyan, Z.; Astrup, A.; Bakker, S.J.L.; Baldassarre, D.; Beekman, M.; Bergman, R.N.; Bertoni, A.; Bluher, M.; Bonnycastle, L.L.; Bornstein, S.R.; Bowden, D.W.; Cai, Q.Y.; Campbell, A.; Campbell, H.; Chang, Y.C.; Geus, E.J.C. de; Dehghan, A.; S.F. du; Eiriksdottir, G.; Farmaki, A.E.; Franberg, M.; Fuchsberger, C.; Gao, Y.T.; Gjesing, A.P.; Goel, A.; Han, S.; Hartman, C.A.; Herder, C.; Hicks, A.A.; Hsieh, C.H.; Hsueh, W.A.; Ichihara, S.; Igase, M.; Ikram, M.A.; Johnson, W.C.; Jorgensen, M.E.; Joshi, P.K.; Kalyani, R.R.; Kandeel, F.R.; Katsuya, T.; Khor, C.C.; Kiess, W.; Kolcic, I.; Kuulasmaa, T.; Kuusisto, J.; Lall, K.; Lam, K.; Lawlor, D.A.; Lee, N.R.; Lemaitre, R.N.; Li, H.L.; Lin, S.Y.; Lindstrom, J.; Linneberg, A.; Liu, J.J.; Lorenzo, C.; Matsubara, T.; Matsuda, F.; Mingrone, G.; Mooijaart, S.; Moon, S.; Nabika, T.; Nadkarni, G.N.; Nadler, J.L.; Nelis, M.; Neville, M.J.; Norris, J.M.; Ohyagi, Y.; Peters, A.; Peyser, P.A.; Polasek, O.; Qi, Q.B.; Raven, D.; Reilly, D.F.; Reiner, A.; Rivideneira, F.; Roll, K.; Rudan, I.; Sabanayagam, C.; Sandow, K.; Sattar, N.; Schurmann, A.; Shi, J.X.; Stringham, H.M.; Taylor, K.D.; Teslovich, T.M.; Thuesen, B.; Timmers, P.R.H.J.; Tremoli, E.; Tsai, M.Y.; Uitterlinden, A.; Dam, R.M. van; Heemst, D. van; Vlieg, A.V.; Vliet-Ostaptchouk, J.V. van; Vangipurapu, J.; Vestergaard, H.; Wang, T.; Dijk, K.W. van; Zemunik, T.; Abecasis, G.R.; Adair, L.S.; Aguilar-Salinas, C.A.; Alarcon-Riquelme, M.E.; An, P.; Aviles-Santa, L.; Becker, D.M.; Beilin, L.J.; Bergmann, S.; Bisgaard, H.; Black, C.; Boehnke, M.; Boerwinkle, E.; Bohm, B.O.; Bonnelykke, K.; Boomsma, D.I.; Bottinger, E.P.; Buchanan, T.A.; Canouil, M.; Caulfield, M.J.; Chambers, J.C.; Chasman, D.I.; Chen, Y.D.I.; Cheng, C.Y.; Collins, F.S.; Correa, A.; Cucca, F.; Silva, H.J. de; Dedoussis, G.; Elmstahl, S.; Evans, M.K.; Ferrannini, E.; Ferrucci, L.; Florez, J.C.; Franks, P.W.; Frayling, T.M.; Froguel, P.; Gigante, B.; Goodarzi, M.O.; Gordon-Larsen, P.; Grallert, H.; Grarup, N.; Grimsgaard, S.; Groop, L.; Gudnason, V.; Guo, X.Q.; Hamsten, A.; Hansen, T.; Hayward, C.; Heckbert, S.R.; Horta, B.L.; Huang, W.; Ingelsson, E.; James, P.S.; Jarvelin, M.R.; Jonas, J.B.; Jukema, J.W.; Kaleebu, P.; Ka
• Date: 2021-05-31
• Journal: Nature Genetics
• Volume: 53
• Issue: 6
• Pages: 840 - 860
• DOI: doi:10.1038/s41588-021-00852-9
• Link: https://discovery.dundee.ac.uk/ws/files/59072891/Trans_ancestry_MAGIC_10...