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

Nat Genet
Authors
Keywords
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).

Year of Publication
2018
Journal
Nat Genet
Volume
50
Issue
11
Pages
1505-1513
Date Published
2018 11
ISSN
1546-1718
DOI
10.1038/s41588-018-0241-6
PubMed ID
30297969
PubMed Central ID
PMC6287706
Links
Grant list
U01 DK105556 / DK / NIDDK NIH HHS / United States
MC_UU_12015/1 / MRC_ / Medical Research Council / United Kingdom
R01 DK072193 / DK / NIDDK NIH HHS / United States
R01 DK066358 / DK / NIDDK NIH HHS / United States
K24 DK080140 / DK / NIDDK NIH HHS / United States
U01 DK078616 / DK / NIDDK NIH HHS / United States
U01 DK062370 / DK / NIDDK NIH HHS / United States
G0601261 / MRC_ / Medical Research Council / United Kingdom
P30 DK020572 / DK / NIDDK NIH HHS / United States
P30 DK116074 / DK / NIDDK NIH HHS / United States
098381 / WT_ / Wellcome Trust / United Kingdom
R01 DK093757 / DK / NIDDK NIH HHS / United States
R01 DK078616 / DK / NIDDK NIH HHS / United States
R01 HL119443 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
R01 DK087914 / DK / NIDDK NIH HHS / United States
U01 DK105535 / DK / NIDDK NIH HHS / United States