Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls
Creators: name: Teslovich, T.M.
name: Cox, N.J.
name: T2D-GENES
name: Laakso, M.
name: Pihoker, C.
name: Groop, L.
name: Tuomilehto, J.
name: Han, S.
name: Mahajan, A.
name: Mercader, J.M.
name: Vasan, R.S.
name: Gabriel, S.
name: Chan, J.C.N.
name: McCarthy, M.I.
name: de Vries, P.S.
name: Hanis, C.L.
name: Loos, R.J.F.
name: Tomlinson, B.
name: Pankow, J.
name: Kwak, S.H.
name: Barzilai, N.
name: Seielstad, M.
name: Revilla-Monsalve, C.
name: Teo, Y.Y.
name: Ma, R.C.W.
name: Tracy, R.P.
name: Glaser, B.
name: Atzmon, G.
name: Elliott, A.
name: Wong, T.-Y.
name: van Dam, R.M.
name: Chen, L.
name: Torres, J.M.
name: Lehman, D.M.
name: Meigs, J.B.s
name: Morris, A.D.
name: Psaty, B.M.
name: Zeitler, P.
name: Henderson, B.E.
name: Dolan, L.
name: Dupuis, J.
name: Kooner, J.S.
name: Rasheed, A.
name: Manning, A.K.
name: Post, W.S.
name: Grarup, N.
name: Tam, C.H.T.
name: Cheng, C.-Y.
name: Mendoza-Caamal, E.
name: ESP
name: Duggirala, R.
name: Floyd, J.S.
name: Kuusisto, J.
name: Morris, A.P.
name: Blackwell, T.W.
name: Gross, M.
name: García-Ortiz, H.
name: DeFronzo, R.A.
name: Small, K.S.
name: Martínez-Hernández, A.
name: Burtt, N.P.
name: Fuchsberger, C.
name: Liu, J.
name: Tuomi, T.
name: Koistinen, H.A.
name: Vujkovic, M.
name: Pedersen, O.
name: Altshuler, D.
name: Morrison, A.C.
name: Kim, Y.J.
name: Lee, J.
name: Florez, J.C.
name: O&apos;Dushlaine, C.
name: Blangero, J.
name: Chan, E.
name: Dewey, F.E.
name: Córdova, E.
name: Correa, A.
name: GoT2D
name: SIGMA-T2D
name: Thameem, F.
name: Tai, E.S.
name: Hwang, M.Y.
name: Soberón, X.
name: Lee, J.-Y.
name: Boerwinkle, E.
name: Welch, R.P.
name: Mohlke, K.L.
name: Udler, M.S.
name: Saleheen, D.
name: Spector, T.D.
name: Lyssenko, V.
name: Heckbert, S.R.
name: Sladek, R.
name: Barajas-Olmos, F.
name: Brody, J.A.
name: Drews, K.L.
name: Leader, J.B.
name: Matsuo, K.
name: Cortes, M.
name: O&apos;Donnell, C.J.
name: Gieger, C.
name: Chambers, J.C.
name: Mayer-Davis, E.
name: ProDiGY
name: Nilsson, P.
name: Centeno-Cruz, F.
name: Jackson, A.U.
name: Bonnycastle, L.L.
name: Preuss, M.
name: Meitinger, T.
name: AMP-T2D-GENES
name: Heard-Costa, N.L.
name: Carey, D.J.
name: Haiman, C.
name: CHARGE
name: Bell, G.I.
name: Liu, C.-T.
name: Kang, H.M.
name: Robertson, N.R.
name: Garay-Sevilla, M.E.
name: Strauch, K.
name: Abecasis, G.
name: Schurmann, C.
name: Tusié-Luna, T.
name: Reiner, A.P.
name: Santoro, N.
name: Ng, M.C.Y.
name: Cho, Y.S.
name: Chen, S.
name: LuCamp
name: Sim, X.
name: Collins, F.S.
name: Witte, D.R.
name: Burke, B.
name: Bowden, D.W.
name: Aguilar-Salinas, C.A.
name: Rich, S.S.
name: Scott, L.J.
name: Boehnke, M.
name: So, W.Y.
name: Contreras-Cubas, C.
name: Gonzalez, M.E.
name: Hansen, T.
name: Ndungu, A.
name: Malacara-Hernandez, J.M.
name: Orozco, L.
name: Marcketta, A.
name: Strom, T.M.
name: Payne, A.J.
name: Rotter, J.I.
name: DiscovEHR Collaboration
name: Baras, A.
name: Kim, B.-J.
name: Park, K.S.
name: Jørgensen, M.E.
name: Palmer, C.N.A.
name: Lange, L.
name: Bottinger, E.
name: Frossard, P.
name: Caulkins, L.
name: Stringham, H.M.
name: Kelsey, M.
name: Flannick, J.
name: Kirchner, H.L.
name: Gonzalez, C.
name: Wang, S.
name: Linneberg, A.
name: Dabelea, D.
name: Wilson, J.G.
name: Broad Genomics Platform
name: Koesterer, R.
name: Wessel, J.
name: Rayner, N.W.
Publisher: name: Nature Publishing Group
Year: 2019

description: 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.