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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).

Original publication

DOI

10.1038/s41588-018-0241-6

Type

Journal article

Journal

Nature genetics

Publication Date

11/2018

Volume

50

Pages

1505 - 1513

Addresses

Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK. anubha@well.ox.ac.uk.

Keywords

Islets of Langerhans, Humans, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, Body Mass Index, Case-Control Studies, Chromosome Mapping, Sex Factors, Epigenesis, Genetic, Gene Frequency, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Genome, Human, European Continental Ancestry Group, Female, Male, Meta-Analysis as Topic, Genome-Wide Association Study, Genetic Loci, High-Throughput Screening Assays