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Mercader, Josep M; Udler, Miriam S; Wessel, Jennifer; Teslovich, Tanya M; Caulkins, Lizz; Barajas-Olmos, Francisco; Boerwinkle, Eric; Chen, Ling; Contreras-Cubas, Cecilia; Córdova, Emilio; Correa, Adolfo; DeFronzo, Ralph A; Dolan, Lawrence; Elliott, Amanda; Floyd, James S; Garay-Sevilla, Maria Eugenia; García-Ortiz, Humberto; Heard-Costa, Nancy L; Jørgensen, Marit E; Kang, Hyun Min; Kelsey, Megan; Linneberg, Allan; Liu, Ching-Ti; Liu, Jianjun; Lyssenko, Valeriya; Marcketta, Anthony; Martínez-Hernández, Angélica; Mayer-Davis, Elizabeth; Morrison, Alanna C; Ndungu, Anne; Ng, Maggie C Y; O'Dushlaine, Colm; Post, Wendy S; Vasan, Ramachandran S; Rayner, N William; Revilla-Monsalve, Cristina; Santoro, Nicola; Schurmann, Claudia; Soberón, Xavier; Strom, Tim M; Thameem, Farook; Torres, Jason M; Vujkovic, Marijana; Witte, Daniel R; Atzmon, Gil; Blangero, John; Bonnycastle, Lori L; Chan, Edmund; Cheng, Ching-Yu; Collins, Francis S; de Vries, Paul S; Glaser, Benjamin; Gonzalez, Ma Elena; Groop, Leif; Kooner, Jaspal Singh; Kwak, Soo Heon; Laakso, Markku; Nilsson, Peter; Spector, Timothy D; Tai, E Shyong; Tuomilehto, Jaakko; Wilson, James G; Burke, Brian; Carey, David J; Frossard, Philippe; 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; Palmer, Colin N A; Pankow, James; Rasheed, Asif; Saleheen, Danish; Sim, Xueling; Small, Kerrin S; Teo, Yik Ying; Haiman, Christopher; Hanis, Craig L; Dewey, Frederick E; Baras, Aris; Gieger, Christian; Meitinger, Thomas; Lange, Leslie; Pedersen, Oluf; Zeitler, Philip; Dabelea, Dana; Abecasis, Goncalo; Cox, Nancy J; Sladek, Rob; Meigs, James B; Rotter, Jerome I; Altshuler, David; Burtt, Noël P; Morris, Andrew P; Florez, Jose C; Boehnke, Michael
Nature, 06/2019, Letnik: 570, Številka: 7759Journal Article
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 ) and candidate genes from knockout mice (P = 5.2 × 10 ). 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.
