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

Anubha Mahajan (Lead / Corresponding author), Daniel Taliun, Matthias Thurner, Neil R. Robertson, Jason M. Torres, N. William Rayner, Anthony J. Payne, Valgerdur Steinthorsdottir, Robert A. Scott, Niels Grarup, James P. Cook, Ellen M. Schmidt, Matthias Wuttke, Chloé Sarnowski, Reedik Mägi, Jana Nano, Christian Gieger, Stella Trompet, Cécile Lecoeur, Michael H. PreussBram Peter Prins, Xiuqing Guo, Lawrence F. Bielak, Jennifer E. Below, Donald W. Bowden, John Campbell Chambers, Young Jin Kim, Maggie C. Y. Ng, Lauren E. Petty, Xueling Sim, Weihua Zhang, Amanda J. Bennett, Jette Bork-Jensen, Chad M. Brummett, Mickaël Canouil, Kai Uwe Ec kardt, Krista Fischer, Sharon L. R. Kardia, Florian Kronenberg, Kristi Läll, Ching Ti Liu, Adam E. Locke, Jian’an Luan, Ioanna Ntalla, Vibe Nylander, Sebastian Schönherr, Claudia Schurmann, Andrew D. Morris, Colin N. A. Palmer, Mark I. McCarthy

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196 Citations (Scopus)

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).

Original languageEnglish
Pages (from-to)1505-1513
Number of pages9
JournalNature Genetics
Volume50
Issue number11
DOIs
Publication statusPublished - 8 Oct 2018

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    Mahajan, A., Taliun, D., Thurner, M., Robertson, N. R., Torres, J. M., Rayner, N. W., Payne, A. J., Steinthorsdottir, V., Scott, R. A., Grarup, N., Cook, J. P., Schmidt, E. M., Wuttke, M., Sarnowski, C., Mägi, R., Nano, J., Gieger, C., Trompet, S., Lecoeur, C., ... McCarthy, M. I. (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. https://doi.org/10.1038/s41588-018-0241-6