Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps



Mahajan, Anubha, Taliun, Daniel, Thurner, Matthias, Robertson, Neil R, Torres, Jason M, Rayner, N William, Payne, Anthony J, Steinthorsdottir, Valgerdur, Scott, Robert A, Grarup, Niels
et al (show 105 more authors) (2018) Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. NATURE GENETICS, 50 (11). 1505 - 1513.

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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 <5%, 14 with estimated allelic odds ratio >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).

Item Type: Article
Depositing User: Symplectic Admin
Date Deposited: 15 Oct 2018 14:27
Last Modified: 11 Jun 2021 11:37
DOI: 10.1038/s41588-018-0241-6
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3027479