Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps
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Open Access
- 8 October 2018
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Genetics
- Vol. 50 (11), 1505-1513
- https://doi.org/10.1038/s41588-018-0241-6
Abstract
We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency 2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).Keywords
This publication has 73 references indexed in Scilit:
- Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetesNature Genetics, 2012
- Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traitsNature Genetics, 2012
- Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east AsiansNature Genetics, 2011
- Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypesNature Genetics, 2011
- Meta‐analysis of sex‐specific genome‐wide association studiesGenetic Epidemiology, 2010
- Biological, clinical and population relevance of 95 loci for blood lipidsNature, 2010
- Twelve type 2 diabetes susceptibility loci identified through large-scale association analysisNature Genetics, 2010
- Variance component model to account for sample structure in genome-wide association studiesNature Genetics, 2010
- A map of open chromatin in human pancreatic isletsNature Genetics, 2010
- A second generation human haplotype map of over 3.1 million SNPsNature, 2007