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


Journal Article

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.

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Cited 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; 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

Published Date

  • June 2019

Published In

Volume / Issue

  • 570 / 7759

Start / End Page

  • 71 - 76

PubMed ID

  • 31118516

Pubmed Central ID

  • 31118516

Electronic International Standard Serial Number (EISSN)

  • 1476-4687

International Standard Serial Number (ISSN)

  • 0028-0836

Digital Object Identifier (DOI)

  • 10.1038/s41586-019-1231-2


  • eng