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

Broad Genomics Platform, DiscovEHR Collaboration, CHARGE, LuCamp, ProDiGY, GoT2D, ESP, SIGMA-T2D, T2D-GENES, AMP-T2D-GENES

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)71-76
Number of pages6
JournalNature
Volume570
Issue number7759
DOIs
StatePublished - Jun 6 2019

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Exome
Type 2 Diabetes Mellitus
Genes
Gene Knockout Techniques
Gene Frequency
Knockout Mice
Pharmaceutical Preparations
Alleles
Proteins

ASJC Scopus subject areas

  • General

Cite this

Broad Genomics Platform, DiscovEHR Collaboration, CHARGE, LuCamp, ProDiGY, GoT2D, ... AMP-T2D-GENES (2019). Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls. Nature, 570(7759), 71-76. https://doi.org/10.1038/s41586-019-1231-2

Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls. / Broad Genomics Platform; DiscovEHR Collaboration; CHARGE; LuCamp; ProDiGY; GoT2D; ESP; SIGMA-T2D; T2D-GENES; AMP-T2D-GENES.

In: Nature, Vol. 570, No. 7759, 06.06.2019, p. 71-76.

Research output: Contribution to journalArticle

Broad Genomics Platform, DiscovEHR Collaboration, CHARGE, LuCamp, ProDiGY, GoT2D, ESP, SIGMA-T2D, T2D-GENES & AMP-T2D-GENES 2019, 'Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls', Nature, vol. 570, no. 7759, pp. 71-76. https://doi.org/10.1038/s41586-019-1231-2
Broad Genomics Platform, DiscovEHR Collaboration, CHARGE, LuCamp, ProDiGY, GoT2D et al. Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls. Nature. 2019 Jun 6;570(7759):71-76. https://doi.org/10.1038/s41586-019-1231-2
Broad Genomics Platform ; DiscovEHR Collaboration ; CHARGE ; LuCamp ; ProDiGY ; GoT2D ; ESP ; SIGMA-T2D ; T2D-GENES ; AMP-T2D-GENES. / Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls. In: Nature. 2019 ; Vol. 570, No. 7759. pp. 71-76.
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