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Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.
Citation | “Exome Sequencing Of 20,791 Cases Of Type 2 Diabetes And 24,440 Controls.”. Nature, pp. 71-76. . |
Center | Boston Area UCSD-UCLA University of Chicago |
Multicenter |
Multicenter
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Author | Jason Flannick, Josep M Mercader, Christian Fuchsberger, Miriam S Udler, Anubha Mahajan, Jennifer Wessel, Tanya M Teslovich, Lizz Caulkins, Ryan Koesterer, Francisco Barajas-Olmos, Thomas W Blackwell, Eric Boerwinkle, Jennifer A Brody, Federico Centeno-Cruz, 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, 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, William Rayner, Alexander P Reiner, Cristina Revilla-Monsalve, Neil R Robertson, Nicola Santoro, Claudia Schurmann, Wing Yee So, Xavier Soberón, Heather M Stringham, Tim M Strom, Claudia H T 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 Shin Cho, 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, Shyong Tai, Tiinamaija Tuomi, Jaakko Tuomilehto, James G Wilson, Carlos A Aguilar-Salinas, Erwin Bottinger, Brian Burke, David J Carey, Juliana C N Chan, Josée Dupuis, Philippe Frossard, Susan R Heckbert, Mi Yeong Hwang, Young Jin Kim, Lester Kirchner, Jong-Young Lee, Juyoung Lee, Ruth J F Loos, Ronald C W 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, Philip Zeitler, Dana Dabelea, Goncalo Abecasis, Graeme I Bell, Nancy J Cox, Mark Seielstad, Rob Sladek, James B Meigs, Steve S Rich, Jerome I Rotter, DiscovEHR Collaboration, CHARGE, LuCamp, ProDiGY, GoT2D, ESP, SIGMA -T2D, T2D -GENES, AMP -T2D-GENES, David Altshuler, Noël P Burtt, Laura J Scott, Andrew P Morris, Jose C Florez, Mark I McCarthy, Michael Boehnke |
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) 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. |
Year of Publication |
2019
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Journal |
Nature
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Volume |
570
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Issue |
7759
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Number of Pages |
71-76
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Date Published |
12/2019
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ISSN Number |
1476-4687
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DOI |
10.1038/s41586-019-1231-2
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Alternate Journal |
Nature
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PMID |
31118516
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PMCID |
PMC6699738
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