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

TitleExome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.
Publication TypeJournal Article
Year of Publication2019
AuthorsFlannick J, Mercader JM, Fuchsberger C, et al.
Secondary AuthorsBoehnke M
Corporate AuthorsBroad Genomics Platform, DiscovEHR Collaboration, CHARGE, LuCamp, ProDiGY, GoT2D, ESP, SIGMA-T2D, T2D-GENES, AMP-T2D-GENES
JournalNature
Volume570
Issue7759
Pagination71-76
Date Published2019 06
ISSN1476-4687
KeywordsAnimals, Case-Control Studies, Decision Support Techniques, Diabetes Mellitus, Type 2, Exome, Female, Gene Frequency, Genome-Wide Association Study, Humans, Male, Mice, Mice, Knockout, Whole Exome Sequencing
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.

DOI10.1038/s41586-019-1231-2
Alternate JournalNature
PubMed ID31118516
PubMed Central IDPMC6699738
Grant ListU01 HG007417 / HG / NHGRI NIH HHS / United States
R01 AG042188 / AG / NIA NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
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/ WT_ / Wellcome Trust / United Kingdom
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MC_PC_13040 / MRC_ / Medical Research Council / United Kingdom
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G0601261 / MRC_ / Medical Research Council / United Kingdom
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