The trans-ancestral genomic architecture of glycemic traits

Chen, J. et al. (2021) The trans-ancestral genomic architecture of glycemic traits. Nature Genetics, 53(6), pp. 840-860. (doi: 10.1038/s41588-021-00852-9) (PMID:34059833) (PMCID:PMC7610958)

Abstract

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 × 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sattar, Professor Naveed and Strawbridge, Dr Rona and Padmanabhan, Professor Sandosh
• Authors: Chen, J., Spracklen, C. N., Marenne, G., Varshney, A., Corbin, L. J., Luan, J.’a., Willems, S. M., Wu, Y., Zhang, X., Horikoshi, M., Boutin, T. S., Mägi, R., Waage, J., Li-Gao, R., Chan, K. H. K., Yao, J., Anasanti, M. D., Chu, A. Y., Claringbould, A., Heikkinen, J., Hong, J., Hottenga, J.-J., Huo, S., Kaakinen, M. A., Louie, T., März, 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., Southam, L., Stewart, I. D., Wang, C. A., Wang, Y., Wu, P., Zhang, W., 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., Chang, L.-C., Chen, C.-H., Chen, B. H., Chitrala, K. N., Chiu, Y.-F., de Haan, H. G., Delgado, G. E., Demirkan, A., Duan, Q., Engmann, J., Fatumo, S. A., Gayán, 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., Lange, L. A., Langefeld, C. D., Lauzon, M., Li, M., Ligthart, S., Liu, J., Loh, M., Long, J., 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., Sparsø, T., Strawbridge, R. J., Takeuchi, F., Tan, J., Trompet, S., van den Akker, E., van der Most, P. J., Verweij, N., Vogel, M., Wang, H., Wang, C., Wang, N., Warren, H. R., Wen, W., 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., Blüher, M., Bonnycastle, L. L., Bornstein, S. R., Bowden, D. W., Cai, Q., Campbell, A., Campbell, H., Chang, Y. C., de Geus, E. J. C., Dehghan, A., Du, S., Eiriksdottir, G., Farmaki, A. E., Frånberg, M., Fuchsberger, C., Gao, Y., 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., Jørgensen, M. E., Joshi, P. K., Kalyani, R. R., Kandeel, F. R., Katsuya, T., Khor, C. C., Kiess, W., Kolcic, I., Kuulasmaa, T., Kuusisto, J., Läll, K., Lam, K., Lawlor, D. A., Lee, N. R., Lemaitre, R. N., Li, H., Lin, S.-Y., Lindström, J., Linneberg, A., Liu, 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., Raven, D., Reilly, D. F., Reiner, A., Rivideneira, F., Roll, K., Rudan, I., Sabanayagam, C., Sandow, K., Sattar, N., Schürmann, A., Shi, J., Stringham, H. M., Taylor, K. D., Teslovich, T. M., Thuesen, B., Timmers, P. R. H. J., Tremoli, E., Tsai, M. Y., Uitterlinden, A., van Dam, R. M., van Heemst, D., van Hylckama Vlieg, A., van Vliet-Ostaptchouk, J. V., Vangipurapu, J., Vestergaard, H., Wang, T., Willems van Dijk, K., Zemunik, T., Abecasis, G. R., Adair, L. S., Aguilar-Salinas, C. A., Alarcón-Riquelme, M. E., An, P., Aviles-Santa, L., Becker, D. M., Beilin, L. J., Bergmann, S., Bisgaard, H., Black, C., Boehnke, M., Boerwinkle, E., Böhm, B. O., Bønnelykke, 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., de Silva, H. J., Dedoussis, G., Elmståhl, 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., 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., Kaplan, R., Kardia, S. L. R., Kato, N., Keinanen-Kiukaanniemi, S. M., Kim, B.-J., Kivimaki, M., Koistinen, H. A., Kooner, J. S., Körner, A., Kovacs, P., Kuh, D., Kumari, M., Kutalik, Z., Laakso, M., Lakka, T. A., Launer, L. J., Leander, K., Li, H., Lin, X., Lind, L., Lindgren, C., Liu, S., Loos, R. J. F., Magnusson, P. K. E., Mahajan, A., Metspalu, A., Mook-Kanamori, D. O., Mori, T. A., Munroe, P. B., Njølstad, I., O’Connell, J. R., Oldehinkel, A. J., Ong, K. K., Padmanabhan, S., Palmer, C. N. A., Palmer, N. D., Pedersen, O., Pennell, C. E., Porteous, D. J., Pramstaller, P. P., Province, M. A., Psaty, B. M., Qi, L., Raffel, L. J., Rauramaa, R., Redline, S., Ridker, P. M., Rosendaal, F. R., Saaristo, T. E., Sandhu, M., Saramies, J., Schneiderman, N., Schwarz, P., Scott, L. J., Selvin, E., Sever, P., Shu, X.-o., Slagboom, P. E., Small, K. S., Smith, B. H., Snieder, H., Sofer, T., Sørensen, T. I. A., Spector, T. D., Stanton, A., Steves, C. J., Stumvoll, M., Sun, L., Tabara, Y., Tai, E. S., Timpson, N. J., Tönjes, A., Tuomilehto, J., Tusie, T., Uusitupa, M., van der Harst, P., van Duijn, C., Vitart, V., Vollenweider, P., Vrijkotte, T. G. M., Wagenknecht, L. E., Walker, M., Wang, Y. X., Wareham, N. J., Watanabe, R. M., Watkins, H., Wei, W. B., Wickremasinghe, A. R., Willemsen, G., Wilson, J. F., Wong, T.-Y., Wu, J.-Y., Xiang, A. H., Yanek, L. R., Yengo, L., Yokota, M., Zeggini, E., Zheng, W., Zonderman, A. B., Rotter, J. I., Gloyn, A. L., McCarthy, M. I., Dupuis, J., Meigs, J. B., Scott, R. A., Prokopenko, I., Leong, A., Liu, C.-T., Parker, S. C. J., Mohlke, K. L., Langenberg, C., Wheeler, E., Morris, A. P., and Barroso, I.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Mental Health and Wellbeing
• Journal Name: Nature Genetics
• Publisher: Nature Research
• ISSN: 1061-4036
• ISSN (Online): 1546-1718
• Published Online: 31 May 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Nature Genetics 53(6): 840-860
• Publisher Policy: Reproduced in accordance with the publisher copyright policy