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

2019; Nature Portfolio; Volume: 570; Issue: 7759 Linguagem: Inglês

10.1038/s41586-019-1231-2

1476-4687

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

Bioinformatics and Genomic Networks

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. Exome-sequencing analyses of a large cohort of patients with type 2 diabetes and control individuals without diabetes from five ancestries are used to identify gene-level associations of rare variants that are associated with type 2 diabetes.