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

By A. Mahajan, D. Taliun, Matthias Thurner, N. Robertson, Jason M. Torres, N. W. Rayner, Anthony J. Payne, V. Steinthorsdottir, Robert A. Scott, N. Grarup and 105 more. Nature Genetics, 2018

1,485 citations recorded by the source corpus.

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). Combining 32 genome-wide association studies with high-density imputation provides a comprehensive view of the genetic contribution to type 2 diabetes in individuals of European ancestry with respect to locus discovery, causal-variant resolution, and mechanistic insight.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a4e0977a148e9f09838dd5cb52d93e435b9879ee

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Citations in the corpus

• Genome-wide association studies in ancestrally diverse populations: opportunities, methods, pitfalls, and recommendations. (2019, background): “Fine-mapping studies in samples of European ancestry have made important advances, with some loci resolved even to single-variant resolution ​(Huang et al., 2017; Mahajan et al., 2018)​.”