학술논문
Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls
Document Type
Article
Author
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 C. Y.; O’Dushlaine, Colm; Payne, Anthony J.; Pihoker, Catherine; 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 H. T.; 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 C. N.; Dupuis, Josée; Frossard, Philippe; Heckbert, Susan R.; Hwang, Mi Yeong; Kim, Young Jin; Kirchner, H. Lester; Lee, Jong-Young; Lee, Juyoung; Loos, Ruth J. F.; Ma, Ronald C. W.; Morris, Andrew D.; O’Donnell, Christopher J.; Palmer, Colin N. A.; 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.; Altshuler, David; Burtt, Noël P.; Scott, Laura J.; Morris, Andrew P.; Florez, Jose C.; McCarthy, Mark I.; Boehnke, Michael
Source
Nature; June 2019, Vol. 570 Issue: 7759 p71-76, 6p
Subject
Language
ISSN
00280836; 14764687
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 SLC30A8alleles 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.