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Genetic discovery and translational decision support from exome sequencing of 20,791 type 2 diabetes cases and 24,440 controls from five ancestries

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

Posted 31 Jul 2018
bioRxiv DOI: 10.1101/371450

Protein-coding genetic variants that strongly affect disease risk can provide important clues into disease pathogenesis. Here we report an exome sequence analysis of 20,791 type 2 diabetes (T2D) cases and 24,440 controls from five ancestries. We identify rare (minor allele frequency<0.5%) variant gene-level associations in (a) three genes at exome-wide significance, including a T2D protective series of >30 SLC30A8 alleles, and (b) within 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 rare variant gene-level signals explain at most 25% of the heritability of the strongest common single variant signals, and the rare variant gene-level effect sizes we observe in established T2D drug targets will require 110K-180K sequenced cases to exceed exome-wide significance. To help prioritize genes using associations from current smaller sample sizes, we present a Bayesian framework to recalibrate association p-values as posterior probabilities of association, estimating that reaching p<0.05 (p<0.005) in our study increases the odds of causal T2D association for a nonsynonymous variant by a factor of 1.8 (5.3). To help guide target or gene prioritization efforts, our data are freely available for analysis at www.type2diabetesgenetics.org.

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