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

  • 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
  • And 80 more
Publication Date
Jun 01, 2019
eScholarship - University of California
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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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