| Title | {Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls |
| Publication Type | Journal Article |
| Year of Publication | 2019 |
| Authors | 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, C?rdova, E, Correa, A, Cortes, M, DeFronzo, RA, Dolan, L, Drews, KL, Elliott, A, Floyd, JS, Gabriel, S, Garay-Sevilla, ME, Garc?a-Ortiz, H, Gross, M, Han, S, Heard-Costa, NL, Jackson, AU, J?rgensen, ME, Kang, HM, Kelsey, M, Kim, BJ, Koistinen, HA, Kuusisto, J, Leader, JB, Linneberg, A, Liu, CT, Liu, J, Lyssenko, V, Manning, AK, Marcketta, A, Malacara-Hernandez, JM, Mart?nez-Hern?ndez, A, Matsuo, K, Mayer-Davis, E, Mendoza-Caamal, E, Mohlke, KL, Morrison, AC, Ndungu, A, Ng, MCY, O'Dushlaine, C, Payne, AJ, Pihoker, C, Post, WS, Preuss, M, Psaty, BM, Vasan, RS, Rayner, NW, Reiner, AP, Revilla-Monsalve, C, Robertson, NR, Santoro, N, Schurmann, C, So, WY, Sober?n, 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, TY, Atzmon, G, Barzilai, N, Blangero, J, Bonnycastle, LL, Bowden, DW, Chambers, JC, Chan, E, Cheng, CY, 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, JY, 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, Tusi?-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 |
| Journal | Nature |
| Volume | 570 |
| Pagination | 71–76 |
| Date Published | 06 |
| 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. |
