Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. (November 2018)

• Record Type: Journal Article
• Authors: Mahajan, Anubha; Taliun, Daniel; Thurner, Matthias; Robertson, Neil; Torres, Jason; Rayner, N.; Payne, Anthony; Steinthorsdottir, Valgerdur; Scott, Robert; Grarup, Niels; Cook, James; Schmidt, Ellen; Wuttke, Matthias; Sarnowski, Chloé; Mägi, Reedik; Nano, Jana; Gieger, Christian; Trompet, Stella; Lecoeur, Cécile; Preuss, Michael; Prins, Bram; Guo, Xiuqing; Bielak, Lawrence; Below, Jennifer; Bowden, Donald; Chambers, John; Kim, Young; Ng, Maggie; Petty, Lauren; Sim, Xueling; Zhang, Weihua; Bennett, Amanda; Bork-Jensen, Jette; Brummett, Chad; Canouil, Mickaël; Ec kardt, Kai-Uwe; Fischer, Krista; Kardia, Sharon; Kronenberg, Florian; Läll, Kristi; Liu, Ching-Ti; Locke, Adam; Luan, Jian'an; Ntalla, Ioanna; Nylander, Vibe; Schönherr, Sebastian; Schurmann, Claudia; Yengo, Loïc; Bottinger, Erwin; Brandslund, Ivan; Christensen, Cramer; Dedoussis, George; Florez, Jose; Ford, Ian; Franco, Oscar; Frayling, Timothy; Giedraitis, Vilmantas; Hackinger, Sophie; Hattersley, Andrew; Herder, Christian; Ikram, M.; Ingelsson, Martin; Jørgensen, Marit; Jørgensen, Torben; Kriebel, Jennifer; Kuusisto, Johanna; Ligthart, Symen; Lindgren, Cecilia; Linneberg, Allan; Lyssenko, Valeriya; Mamakou, Vasiliki; Meitinger, Thomas; Mohlke, Karen; Morris, Andrew; Nadkarni, Girish; Pankow, James; Peters, Annette; Sattar, Naveed; Stančáková, Alena; Strauch, Konstantin; Taylor, Kent; Thorand, Barbara; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Tuomilehto, Jaakko; Witte, Daniel; Dupuis, Josée; Peyser, Patricia; Zeggini, Eleftheria; Loos, Ruth; Froguel, Philippe; Ingelsson, Erik; Lind, Lars; Groop, Leif; Laakso, Markku; Collins, Francis; Jukema, J.; Palmer, Colin; Grallert, Harald; Metspalu, Andres; Dehghan, Abbas; Köttgen, Anna; Abecasis, Goncalo; Meigs, James; Rotter, Jerome; Marchini, Jonathan; Pedersen, Oluf; Hansen, Torben; Langenberg, Claudia; Wareham, Nicholas; Stefansson, Kari; Gloyn, Anna; Morris, Andrew; Boehnke, Michael; McCarthy, Mark;
• Is Part Of: Nature genetics. Volume 50:Number 11(2018)
• Page Start: 1505
• Page End: 1513
• Publication Date: 2018-11
• Subjects: Human genetics -- Periodicals; 576.505
• DOI: 10.1038/s41588-018-0241-6
• Languages: English
• ISSNs: 1061-4036

Abstract

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). 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.