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Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps
Univ Oxford, Wellcome Ctr Human Genet, Nuffield Dept Med, Oxford, England;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Radcliffe Dept Med, Oxford, England.ORCID iD: 0000-0001-5585-3420
Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA.
Univ Oxford, Wellcome Ctr Human Genet, Nuffield Dept Med, Oxford, England;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Radcliffe Dept Med, Oxford, England.
Univ Oxford, Wellcome Ctr Human Genet, Nuffield Dept Med, Oxford, England;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Radcliffe Dept Med, Oxford, England.
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2018 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 50, no 11, p. 1505-+Article in journal (Refereed) Published
Abstract [en]

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).

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2018. Vol. 50, no 11, p. 1505-+
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Medical Genetics
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URN: urn:nbn:se:uu:diva-370007DOI: 10.1038/s41588-018-0241-6ISI: 000448398000006PubMedID: 30297969OAI: oai:DiVA.org:uu-370007DiVA, id: diva2:1275970
Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-01-07Bibliographically approved

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Mahajan, AnubhaSteinthorsdottir, ValgerdurSchmidt, Ellen M.Preuss, Michael H.Kronenberg, FlorianGiedraitis, VilmantasHattersley, Andrew T.Ingelsson, MartinLinneberg, AllanLoos, Ruth J. F.Ingelsson, ErikLind, Lars
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