Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls
Open Access
- 22 May 2019
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 570 (7759), 71-76
- https://doi.org/10.1038/s41586-019-1231-2
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.This publication has 80 references indexed in Scilit:
- Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetesNature Genetics, 2018
- Prioritising Causal Genes at Type 2 Diabetes Risk LociCurrent Diabetes Reports, 2017
- An Expanded View of Complex Traits: From Polygenic to OmnigenicCell, 2017
- The genetic architecture of type 2 diabetesNature, 2016
- Loss-of-function mutations in SLC30A8 protect against type 2 diabetesNature Genetics, 2014
- Searching for missing heritability: Designing rare variant association studiesProceedings of the National Academy of Sciences of the United States of America, 2014
- The NHGRI GWAS Catalog, a curated resource of SNP-trait associationsNucleic Acids Research, 2013
- Validating therapeutic targets through human geneticsNature Reviews Drug Discovery, 2013
- Uncovering the roles of rare variants in common disease through whole-genome sequencingNature Reviews Genetics, 2010
- Genetic Mapping in Human DiseaseScience, 2008