%0 Journal Article %J Nature %D 2019 %T Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls. %A Flannick, Jason %A Mercader, Josep M %A Fuchsberger, Christian %A Udler, Miriam S %A Mahajan, Anubha %A Wessel, Jennifer %A Teslovich, Tanya M %A Caulkins, Lizz %A Koesterer, Ryan %A Barajas-Olmos, Francisco %A Blackwell, Thomas W %A Eric Boerwinkle %A Brody, Jennifer A %A Centeno-Cruz, Federico %A Chen, Ling %A Chen, Siying %A Contreras-Cubas, Cecilia %A Córdova, Emilio %A Correa, Adolfo %A Cortes, Maria %A DeFronzo, Ralph A %A Dolan, Lawrence %A Drews, Kimberly L %A Elliott, Amanda %A Floyd, James S %A Gabriel, Stacey %A Garay-Sevilla, Maria Eugenia %A García-Ortiz, Humberto %A Gross, Myron %A Han, Sohee %A Heard-Costa, Nancy L %A Jackson, Anne U %A Jørgensen, Marit E %A Kang, Hyun Min %A Kelsey, Megan %A Kim, Bong-Jo %A Koistinen, Heikki A %A Kuusisto, Johanna %A Leader, Joseph B %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Jianjun %A Lyssenko, Valeriya %A Manning, Alisa K %A Marcketta, Anthony %A Malacara-Hernandez, Juan Manuel %A Martínez-Hernández, Angélica %A Matsuo, Karen %A Mayer-Davis, Elizabeth %A Mendoza-Caamal, Elvia %A Mohlke, Karen L %A Morrison, Alanna C %A Ndungu, Anne %A Ng, Maggie C Y %A O'Dushlaine, Colm %A Payne, Anthony J %A Pihoker, Catherine %A Post, Wendy S %A Preuss, Michael %A Psaty, Bruce M %A Vasan, Ramachandran S %A Rayner, N William %A Reiner, Alexander P %A Revilla-Monsalve, Cristina %A Robertson, Neil R %A Santoro, Nicola %A Schurmann, Claudia %A So, Wing Yee %A Soberón, Xavier %A Stringham, Heather M %A Strom, Tim M %A Tam, Claudia H T %A Thameem, Farook %A Tomlinson, Brian %A Torres, Jason M %A Tracy, Russell P %A van Dam, Rob M %A Vujkovic, Marijana %A Wang, Shuai %A Welch, Ryan P %A Witte, Daniel R %A Wong, Tien-Yin %A Atzmon, Gil %A Barzilai, Nir %A Blangero, John %A Bonnycastle, Lori L %A Bowden, Donald W %A Chambers, John C %A Chan, Edmund %A Cheng, Ching-Yu %A Cho, Yoon Shin %A Collins, Francis S %A de Vries, Paul S %A Duggirala, Ravindranath %A Glaser, Benjamin %A Gonzalez, Clicerio %A Gonzalez, Ma Elena %A Groop, Leif %A Kooner, Jaspal Singh %A Kwak, Soo Heon %A Laakso, Markku %A Lehman, Donna M %A Nilsson, Peter %A Spector, Timothy D %A Tai, E Shyong %A Tuomi, Tiinamaija %A Tuomilehto, Jaakko %A Wilson, James G %A Aguilar-Salinas, Carlos A %A Bottinger, Erwin %A Burke, Brian %A Carey, David J %A Chan, Juliana C N %A Dupuis, Josée %A Frossard, Philippe %A Heckbert, Susan R %A Hwang, Mi Yeong %A Kim, Young Jin %A Kirchner, H Lester %A Lee, Jong-Young %A Lee, Juyoung %A Loos, Ruth J F %A Ma, Ronald C W %A Morris, Andrew D %A O'Donnell, Christopher J %A Palmer, Colin N A %A Pankow, James %A Park, Kyong Soo %A Rasheed, Asif %A Saleheen, Danish %A Sim, Xueling %A Small, Kerrin S %A Teo, Yik Ying %A Haiman, Christopher %A Hanis, Craig L %A Henderson, Brian E %A Orozco, Lorena %A Tusie-Luna, Teresa %A Dewey, Frederick E %A Baras, Aris %A Gieger, Christian %A Meitinger, Thomas %A Strauch, Konstantin %A Lange, Leslie %A Grarup, Niels %A Hansen, Torben %A Pedersen, Oluf %A Zeitler, Philip %A Dabelea, Dana %A Abecasis, Goncalo %A Bell, Graeme I %A Cox, Nancy J %A Seielstad, Mark %A Sladek, Rob %A Meigs, James B %A Rich, Steve S %A Rotter, Jerome I %A Altshuler, David %A Burtt, Noël P %A Scott, Laura J %A Morris, Andrew P %A Florez, Jose C %A McCarthy, Mark I %A Boehnke, Michael %K Animals %K Case-Control Studies %K Decision Support Techniques %K Diabetes Mellitus, Type 2 %K Exome %K Exome Sequencing %K Female %K Gene Frequency %K Genome-Wide Association Study %K Humans %K Male %K Mice %K Mice, Knockout %X

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) and candidate genes from knockout mice (P = 5.2 × 10). 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.

%B Nature %V 570 %P 71-76 %8 2019 Jun %G eng %N 7759 %1 https://www.ncbi.nlm.nih.gov/pubmed/31118516?dopt=Abstract %R 10.1038/s41586-019-1231-2