Genetic discovery and translational decision support from exome sequencing of 20,791 type 2 diabetes cases and 24,440 controls from five ancestries
Authors: Flannick Jason , Mercader Josep M , Fuchsberger Christian , Udler Miriam S , Mahajan Anubha , Wessel Jennifer , Teslovich Tanya M , Caulkins Lizz , Koesterer Ryan , Blackwell Thomas W , Boerwinkle Eric , Brody Jennifer A , 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 , Hanks Sarah , 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 CY , O’Dushlaine Colm , Payne Anthony J , Pihoker Catherine ,   Broad Genomics Platform, 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 , Stringham Heather M , Strom Tim M , Tam Claudia HT , 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 , Shin Yoon Cho , 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 , Dupuis Josée , Frossard Philippe , Heckbert Susan R , Hwang Mi Yeong , Kim Young Jin , Kirchner H Lester , Lee Jong-Young , Lee Juyoung , Loos Ruth , Ma Ronald CW , Morris Andrew D , O’Donnell Christopher J , Palmer Colin NA , 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 Phil , Dabelea Dana , Abecasis Goncalo , Bell Graeme I , Cox Nancy J , Seielstad Mark , Sladek Rob , Meigs James B , Rich Steve , Rotter Jerome I ,   DiscovEHR Collaboration,   CHARGE, LuCamp, ProDiGY, GoT2D, ESP, SIGMA-T2D, T2D-GENES, AMP-T2D-GENES, Altshuler David , Burtt Noёl P , Scott Laura J , Morris Andrew P , Florez Jose C , McCarthy Mark I , Boehnke Michael 
Published: August 2018

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.