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

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 C Y; O'Dushlaine, Colm; Payne, Anthony J; Pihoker, Catherine; 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 H T; 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 C N; Dupuis, Josée; Frossard, Philippe; Heckbert, Susan R; Hwang, Mi Yeong; Kim, Young Jin; Kirchner, H Lester; Lee, Jong-Young; Lee, Juyoung; Loos, Ruth J F; Ma, Ronald C W; Morris, Andrew D; O'Donnell, Christopher J; Palmer, Colin N A; 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; Altshuler, David; Burtt, Noël P; Scott, Laura J; Morris, Andrew P; Florez, Jose C; McCarthy, Mark I; Boehnke, Michael     «

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 E...     »

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.      «

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,...     »