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Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls
  • 작성일2020-02-07
  • 최종수정일2020-02-07
  • 담당부서연구기획과
  • 연락처043-719-8033
  • 871

Nature, 2019. 570(7759), 71-76, DOI: https://doi.org/10.1038/s41586-019-1231-2


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

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. Torres10; 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; E. 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; H. 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 × 10−3) 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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  • This research was supported by a fund by Research of Korea Centers for Disease Control and Prevention.


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