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

  • Author(s): Flannick, Jason
  • Mercader, Josep M
  • Fuchsberger, Christian
  • Udler, Miriam S
  • Mahajan, Anubha
  • Wessel, Jennifer
  • Teslovich, Tanya M
  • Caulkins, Lizz
  • Koesterer, Ryan
  • Barajas-Olmos, Francisco
  • Blackwell, Thomas W
  • Boerwinkle, Eric
  • Brody, Jennifer A
  • Centeno-Cruz, Federico
  • 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
  • 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
  • Soberón, Xavier
  • 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
  • Cho, Yoon Shin
  • 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 CN
  • Dupuis, Josée
  • Frossard, Philippe
  • Heckbert, Susan R
  • Hwang, Mi Yeong
  • Kim, Young Jin
  • Kirchner, H Lester
  • Lee, Jong-Young
  • Lee, Juyoung
  • Loos, Ruth JF
  • 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, Philip
  • Dabelea, Dana
  • Abecasis, Goncalo
  • Bell, Graeme I
  • Cox, Nancy J
  • Seielstad, Mark
  • Sladek, Rob
  • Meigs, James B
  • Rich, Steve S
  • Rotter, Jerome I
  • DiscovEHR Collaboration
  • CHARGE
  • LuCamp
  • ProDiGY
  • GoT2D
  • ESP
  • SIGMA-T2D
  • T2D-GENES
  • AMP-T2D-GENES
  • Altshuler, David
  • Burtt, Noël P
  • Scott, Laura J
  • Morris, Andrew P
  • Florez, Jose C
  • McCarthy, Mark I
  • Boehnke, Michael
  • et al.
Abstract

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.

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