Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.

TitleExome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.
Publication TypeJournal Article
Year of Publication2019
AuthorsFlannick, J, Mercader, JM, Fuchsberger, C, Udler, MS, Mahajan, A, Wessel, J, Teslovich, TM, Caulkins, L, Koesterer, R, Barajas-Olmos, F, Blackwell, TW, Boerwinkle, E, Brody, JA, Centeno-Cruz, F, Chen, L, Chen, S, Contreras-Cubas, C, Córdova, E, Correa, A, Cortes, M, DeFronzo, RA, Dolan, L, Drews, KL, Elliott, A, Floyd, JS, Gabriel, S, Garay-Sevilla, MEugenia, García-Ortiz, H, Gross, M, Han, S, Heard-Costa, NL, Jackson, AU, Jørgensen, ME, Kang, HMin, Kelsey, M, Kim, B-J, Koistinen, HA, Kuusisto, J, Leader, JB, Linneberg, A, Liu, C-T, Liu, J, Lyssenko, V, Manning, AK, Marcketta, A, Malacara-Hernandez, JManuel, Martínez-Hernández, A, Matsuo, K, Mayer-Davis, E, Mendoza-Caamal, E, Mohlke, KL, Morrison, AC, Ndungu, A, C Y Ng, M, O'Dushlaine, C, Payne, AJ, Pihoker, C, Post, WS, Preuss, M, Psaty, BM, Vasan, RS, N Rayner, W, Reiner, AP, Revilla-Monsalve, C, Robertson, NR, Santoro, N, Schurmann, C, So, WYee, Soberón, X, Stringham, HM, Strom, TM, Tam, CHT, Thameem, F, Tomlinson, B, Torres, JM, Tracy, RP, van Dam, RM, Vujkovic, M, Wang, S, Welch, RP, Witte, DR, Wong, T-Y, Atzmon, G, Barzilai, N, Blangero, J, Bonnycastle, LL, Bowden, DW, Chambers, JC, Chan, E, Cheng, C-Y, Cho, YShin, Collins, FS, de Vries, PS, Duggirala, R, Glaser, B, Gonzalez, C, Gonzalez, MElena, Groop, L, Kooner, JSingh, Kwak, SHeon, Laakso, M, Lehman, DM, Nilsson, P, Spector, TD, E Tai, S, Tuomi, T, Tuomilehto, J, Wilson, JG, Aguilar-Salinas, CA, Bottinger, E, Burke, B, Carey, DJ, Chan, JCN, Dupuis, J, Frossard, P, Heckbert, SR, Hwang, MYeong, Kim, YJin, H Kirchner, L, Lee, J-Y, Lee, J, Loos, RJF, Ma, RCW, Morris, AD, O'Donnell, CJ, Palmer, CNA, Pankow, J, Park, KSoo, Rasheed, A, Saleheen, D, Sim, X, Small, KS, Teo, YYing, Haiman, C, Hanis, CL, Henderson, BE, Orozco, L, Tusie-Luna, T, Dewey, FE, Baras, A, Gieger, C, Meitinger, T, Strauch, K, Lange, L, Grarup, N, Hansen, T, Pedersen, O, Zeitler, P, Dabelea, D, Abecasis, G, Bell, GI, Cox, NJ, Seielstad, M, Sladek, R, Meigs, JB, Rich, SS, Rotter, JI, Altshuler, D, Burtt, NP, Scott, LJ, Morris, AP, Florez, JC, McCarthy, MI, Boehnke, M
Corporate AuthorsBroad Genomics Platform, DiscovEHR Collaboration, CHARGE, LuCamp, ProDiGY, GoT2D, ESP, SIGMA-T2D, T2D-GENES, AMP-T2D-GENES
JournalNature
Volume570
Issue7759
Pagination71-76
Date Published2019 06
ISSN1476-4687
KeywordsAnimals, Case-Control Studies, Decision Support Techniques, Diabetes Mellitus, Type 2, Exome, Female, Gene Frequency, Genome-Wide Association Study, Humans, Male, Mice, Mice, Knockout, Whole Exome Sequencing
Abstract

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10) and candidate genes from knockout mice (P = 5.2 × 10). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.

DOI10.1038/s41586-019-1231-2
Alternate JournalNature
PubMed ID31118516
PubMed Central IDPMC6699738
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