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).
Bibliographical noteFunding Information:
This work was supported primarily by the NIDDK as part of the Accelerating Medicines Partnership-T2D, funded by U01DK105535 (M.I.M.), U01DK062370 (M.B.), and U01DK078616 (J.M.) grants. Part of this work was conducted using the UK Biobank resource under application number 9161. A full list of acknowledgements appears in the Supplementary Note.
J.C.F. has received consulting honoraria from Merck and from Boehringer-Ingelheim. O.H.F. works at ErasmusAGE, a center for aging research across the course of life, funded by Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA. E.I. is a scientific advisor for Precision Wellness and Olink Proteomics for work unrelated to the present project. A.D. has received consultancy fees and research support from Metagenics Inc. (outside the scope of the present work). T.M.F. has consulted for Boeringer Ingelheim and Sanofi-Aventis on the genetics of diabetes and has an MRC CASE studentship with GSK. G.R.A. is a consultant for 23andMe, Regeneron, Merck, and Helix. R.A.S. is an employee of and shareholder in GlaxoSmithKline. N.S. is working with Boehringer-Ingelheim on a genetics project but has received no remuneration. M.I.M. has served on advisory panels for NovoNordisk and Pfizer, and has received honoraria from NovoNordisk, Pfizer, Sanofi-Aventis, and Eli Lilly. The companies named above had no role in the design or conduct of this study; collection, management, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript. Authors affiliated with deCODE (V.S., G.T., U.T. and K.S.) are employed by deCODE Genetics/Amgen, Inc.