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Research Article Details

Article ID: A00180
PMID: 31118516
Source: Nature
Title: Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.
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&#xa0;individuals with type 2 diabetes (T2D) and 24,440&#xa0;non-diabetic control participants from 5&#xa0;ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4&#xa0;genes at exome-wide significance, including a series of more than 30&#xa0;SLC30A8 alleles that conveys protection against T2D, and in 12&#xa0;gene sets, including those corresponding to T2D drug targets (P&#xa0;=&#xa0;6.1&#xa0;&#xd7;&#xa0;10<sup>-3</sup>) and candidate genes from knockout mice (P&#xa0;=&#xa0;5.2&#xa0;&#xd7;&#xa0;10<sup>-3</sup>). 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&#xa0;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.
DOI: 10.1038/s41586-019-1231-2