1. Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.
- Author
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Flannick, 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, ME, García-Ortiz, H, Gross, M, Han, S, Heard-Costa, NL, Jackson, AU, Jørgensen, ME, Kang, HM, 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, JM, Martínez-Hernández, A, Matsuo, K, Mayer-Davis, E, Mendoza-Caamal, E, Mohlke, KL, Morrison, AC, Ndungu, A, Ng, MCY, O'Dushlaine, C, Payne, AJ, Pihoker, C, Broad Genomics Platform, Post, WS, Preuss, M, Psaty, BM, Vasan, RS, Rayner, NW, Reiner, AP, Revilla-Monsalve, C, Robertson, NR, Santoro, N, Schurmann, C, So, WY, 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, YS, Collins, FS, de Vries, PS, Duggirala, R, Glaser, B, Gonzalez, C, Gonzalez, ME, Groop, L, Kooner, JS, Kwak, SH, Laakso, M, Lehman, DM, Nilsson, P, Spector, TD, Tai, ES, Tuomi, T, Tuomilehto, J, Wilson, JG, Aguilar-Salinas, CA, Bottinger, E, Burke, B, Carey, DJ, Chan, JCN, Dupuis, J, Frossard, P, Heckbert, SR, Hwang, MY, Kim, YJ, Kirchner, HL, Lee, J-Y, Lee, J, Loos, RJF, Ma, RCW, Morris, AD, O'Donnell, CJ, Palmer, CNA, Pankow, J, Park, KS, Rasheed, A, Saleheen, D, Sim, X, Small, KS, Teo, YY, Haiman, C, Hanis, CL, Henderson, BE, Orozco, L, Tusié-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, DiscovEHR Collaboration, CHARGE, LuCamp, ProDiGY, GoT2D, ESP, SIGMA-T2D, T2D-GENES, AMP-T2D-GENES, Altshuler, D, Burtt, NP, Scott, LJ, Morris, AP, Florez, JC, McCarthy, MI, Boehnke, M, Flannick, 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, ME, García-Ortiz, H, Gross, M, Han, S, Heard-Costa, NL, Jackson, AU, Jørgensen, ME, Kang, HM, 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, JM, Martínez-Hernández, A, Matsuo, K, Mayer-Davis, E, Mendoza-Caamal, E, Mohlke, KL, Morrison, AC, Ndungu, A, Ng, MCY, O'Dushlaine, C, Payne, AJ, Pihoker, C, Broad Genomics Platform, Post, WS, Preuss, M, Psaty, BM, Vasan, RS, Rayner, NW, Reiner, AP, Revilla-Monsalve, C, Robertson, NR, Santoro, N, Schurmann, C, So, WY, 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, YS, Collins, FS, de Vries, PS, Duggirala, R, Glaser, B, Gonzalez, C, Gonzalez, ME, Groop, L, Kooner, JS, Kwak, SH, Laakso, M, Lehman, DM, Nilsson, P, Spector, TD, Tai, ES, Tuomi, T, Tuomilehto, J, Wilson, JG, Aguilar-Salinas, CA, Bottinger, E, Burke, B, Carey, DJ, Chan, JCN, Dupuis, J, Frossard, P, Heckbert, SR, Hwang, MY, Kim, YJ, Kirchner, HL, Lee, J-Y, Lee, J, Loos, RJF, Ma, RCW, Morris, AD, O'Donnell, CJ, Palmer, CNA, Pankow, J, Park, KS, Rasheed, A, Saleheen, D, Sim, X, Small, KS, Teo, YY, Haiman, C, Hanis, CL, Henderson, BE, Orozco, L, Tusié-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, DiscovEHR Collaboration, CHARGE, LuCamp, ProDiGY, GoT2D, ESP, SIGMA-T2D, T2D-GENES, AMP-T2D-GENES, Altshuler, D, Burtt, NP, Scott, LJ, Morris, AP, Florez, JC, McCarthy, MI, and Boehnke, M
- 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 × 10-3) and candidate genes from knockout mice (P = 5.2 × 10-3). 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.
- Published
- 2019