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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 S 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, Ramachandran S Vasan, 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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