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

Article

关键词: GENOME-WIDE ASSOCIATION;    COMMON GENETIC-VARIATION;    LOW-FREQUENCY;    RARE VARIANTS;    MUTATIONS;    RISK;    IDENTIFICATION;    HERITABILITY;    ARCHITECTURE;    METAANALYSIS;   

DOI  :  10.1038/s41586-019-1231-2

来源: SCIE

【 摘 要 】

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 x 10(-3)) and candidate genes from knockout mice (P = 5.2 x 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.

【 授权许可】

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