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Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls
- Source :
- Nature, vol 570, iss 7759
- Publication Year :
- 2019
- Publisher :
- eScholarship, University of California, 2019.
-
Abstract
- Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791individuals with type 2 diabetes (T2D) and 24,440non-diabetic control participants from 5ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4genes at exome-wide significance, including a series of more than 30SLC30A8 alleles that conveys protection against T2D, and in 12gene 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 75,000-185,000sequenced 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.
- Subjects :
- Male
General Science & Technology
Knockout
LuCamp
Whole Exome Sequencing
Decision Support Techniques
Mice
T2D-GENES
Gene Frequency
Exome Sequencing
Diabetes Mellitus
Genetics
Animals
Humans
2.1 Biological and endogenous factors
AMP-T2D-GENES
Exome
Aetiology
ESP
Metabolic and endocrine
Broad Genomics Platform
Prevention
Diabetes
Human Genome
ProDiGY
Case-Control Studies
DiscovEHR Collaboration
SIGMA-T2D
Female
CHARGE
Type 2
GoT2D
Genome-Wide Association Study
Biotechnology
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Nature, vol 570, iss 7759
- Accession number :
- edsair.dedup.wf.001..422a00f92ff1ca8af073bfd4a26ef831