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

  • Author(s): Flannick, Jason;
  • Mercader, Josep M;
  • Fuchsberger, Christian;
  • Udler, Miriam S;
  • Mahajan, Anubha;
  • Wessel, Jennifer;
  • Teslovich, Tanya M;
  • Caulkins, Lizz;
  • Koesterer, Ryan;
  • Barajas-Olmos, Francisco;
  • Blackwell, Thomas W;
  • Boerwinkle, Eric;
  • Brody, Jennifer A;
  • Centeno-Cruz, Federico;
  • Chen, Ling;
  • Chen, Siying;
  • Contreras-Cubas, Cecilia;
  • Córdova, Emilio;
  • Correa, Adolfo;
  • Cortes, Maria;
  • DeFronzo, Ralph A;
  • Dolan, Lawrence;
  • Drews, Kimberly L;
  • Elliott, Amanda;
  • Floyd, James S;
  • Gabriel, Stacey;
  • Garay-Sevilla, Maria Eugenia;
  • García-Ortiz, Humberto;
  • Gross, Myron;
  • Han, Sohee;
  • Heard-Costa, Nancy L;
  • Jackson, Anne U;
  • Jørgensen, Marit E;
  • Kang, Hyun Min;
  • Kelsey, Megan;
  • Kim, Bong-Jo;
  • Koistinen, Heikki A;
  • Kuusisto, Johanna;
  • Leader, Joseph B;
  • Linneberg, Allan;
  • Liu, Ching-Ti;
  • Liu, Jianjun;
  • Lyssenko, Valeriya;
  • Manning, Alisa K;
  • Marcketta, Anthony;
  • Malacara-Hernandez, Juan Manuel;
  • Martínez-Hernández, Angélica;
  • Matsuo, Karen;
  • Mayer-Davis, Elizabeth;
  • Mendoza-Caamal, Elvia;
  • Mohlke, Karen L;
  • Morrison, Alanna C;
  • Ndungu, Anne;
  • Ng, Maggie CY;
  • O'Dushlaine, Colm;
  • Payne, Anthony J;
  • Pihoker, Catherine;
  • Broad Genomics Platform;
  • Post, Wendy S;
  • Preuss, Michael;
  • Psaty, Bruce M;
  • Vasan, Ramachandran S;
  • Rayner, N William;
  • Reiner, Alexander P;
  • Revilla-Monsalve, Cristina;
  • Robertson, Neil R;
  • Santoro, Nicola;
  • Schurmann, Claudia;
  • So, Wing Yee;
  • Soberón, Xavier;
  • Stringham, Heather M;
  • Strom, Tim M;
  • Tam, Claudia HT;
  • Thameem, Farook;
  • Tomlinson, Brian;
  • Torres, Jason M;
  • Tracy, Russell P;
  • van Dam, Rob M;
  • Vujkovic, Marijana;
  • Wang, Shuai;
  • Welch, Ryan P;
  • Witte, Daniel R;
  • Wong, Tien-Yin;
  • Atzmon, Gil;
  • Barzilai, Nir;
  • Blangero, John;
  • Bonnycastle, Lori L;
  • Bowden, Donald W;
  • Chambers, John C;
  • Chan, Edmund;
  • Cheng, Ching-Yu;
  • Cho, Yoon Shin;
  • Collins, Francis S;
  • de Vries, Paul S;
  • Duggirala, Ravindranath;
  • Glaser, Benjamin;
  • Gonzalez, Clicerio;
  • Gonzalez, Ma Elena;
  • Groop, Leif;
  • Kooner, Jaspal Singh;
  • Kwak, Soo Heon;
  • Laakso, Markku;
  • Lehman, Donna M;
  • Nilsson, Peter;
  • Spector, Timothy D;
  • Tai, E Shyong;
  • Tuomi, Tiinamaija;
  • Tuomilehto, Jaakko;
  • Wilson, James G;
  • Aguilar-Salinas, Carlos A;
  • Bottinger, Erwin;
  • Burke, Brian;
  • Carey, David J;
  • Chan, Juliana CN;
  • Dupuis, Josée;
  • Frossard, Philippe;
  • Heckbert, Susan R;
  • Hwang, Mi Yeong;
  • Kim, Young Jin;
  • Kirchner, H Lester;
  • Lee, Jong-Young;
  • Lee, Juyoung;
  • Loos, Ruth JF;
  • Ma, Ronald CW;
  • Morris, Andrew D;
  • O'Donnell, Christopher J;
  • Palmer, Colin NA;
  • Pankow, James;
  • Park, Kyong Soo;
  • Rasheed, Asif;
  • Saleheen, Danish;
  • Sim, Xueling;
  • Small, Kerrin S;
  • Teo, Yik Ying;
  • Haiman, Christopher;
  • Hanis, Craig L;
  • Henderson, Brian E;
  • Orozco, Lorena;
  • Tusié-Luna, Teresa;
  • Dewey, Frederick E;
  • Baras, Aris;
  • Gieger, Christian;
  • Meitinger, Thomas;
  • Strauch, Konstantin;
  • Lange, Leslie;
  • Grarup, Niels;
  • Hansen, Torben;
  • Pedersen, Oluf;
  • Zeitler, Philip;
  • Dabelea, Dana;
  • Abecasis, Goncalo;
  • Bell, Graeme I;
  • Cox, Nancy J;
  • Seielstad, Mark;
  • Sladek, Rob;
  • Meigs, James B;
  • Rich, Steve S;
  • Rotter, Jerome I;
  • DiscovEHR Collaboration;
  • CHARGE;
  • LuCamp;
  • ProDiGY;
  • GoT2D;
  • ESP;
  • SIGMA-T2D;
  • T2D-GENES;
  • AMP-T2D-GENES;
  • Altshuler, David;
  • Burtt, Noël P;
  • Scott, Laura J;
  • Morris, Andrew P;
  • Florez, Jose C;
  • McCarthy, Mark I;
  • Boehnke, Michael
  • et al.
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.

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