Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls
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- Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls
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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.
Original language | English |
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Journal | Nature |
Volume | 570 |
Issue number | 7759 |
Pages (from-to) | 71-76 |
Number of pages | 6 |
ISSN | 0028-0836 |
DOIs | |
Publication status | Published - Jun 2019 |
- Animals, Case-Control Studies, Decision Support Techniques, Diabetes Mellitus, Type 2/genetics, Exome/genetics, Female, Gene Frequency, Genome-Wide Association Study, Humans, Male, Mice, Mice, Knockout, Whole Exome Sequencing
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