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

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Mahajan, Anubha, Taliun, Daniel, Thurner, Matthias, Robertson, Neil R, Torres, Jason M, Rayner, N William, Payne, Anthony J, Steinthorsdottir, Valgerdur, Scott, Robert A, Grarup, Niels et al (show 105 more authors) , Cook, James P, Schmidt, Ellen M, Wuttke, Matthias, Sarnowski, Chloe, Magill, Reedik, Nano, Jana, Gieger, Christian, Trompet, Stella, Lecoeur, Cecile, Preuss, Michael H, Prins, Bram Peter, Guo, Xiuqing, Bielak, Lawrence F, Below, Jennifer E, Bowden, Donald W, Chambers, John Campbell, Kim, Young Jin, Ng, Maggie CY, Petty, Lauren E, Sim, Xueling, Zhang, Weihua, Bennett, Amanda J, Bork-Jensen, Jette, Brummett, Chad M, Canouil, Mickael, Kardt, Kai-Uwe Ec, Fischer, Krista, Kardia, Sharon LR, Kronenberg, Florian, Lall, Kristi, Liu, Ching-Ti, Locke, Adam E, Luan, Jian'an, Ntalla, Loanna, Nylander, Vibe, Schoenherr, Sebastian, Schurmann, Claudia, Yengo, Loic, Bottinger, Erwin P, Brandslund, Ivan, Christensen, Cramer, Dedoussis, George, Florez, Jose C, Ford, Ian, France, Oscar H, Frayling, Timothy M, Giedraitis, Vilmantas, Hackinger, Sophie, Hattersley, Andrew T, Herder, Christian, Ikram, M Arfan, Ingelsson, Martin, Jorgensen, Marit E, Jorgensen, Torben, Kriebel, Jennifer, Kuusisto, Johanna, Ligthart, Symen, Lindgren, Cecilia M, Linneberg, Allan, Lyssenko, Valeriya, Mamakou, Vasiliki, Meitinger, Thomas, Mohlke, Karen L, Morris, Andrew D, Nadkarni, Girish, Pankow, James S, Peters, Annette, Sattar, Naveed, Stancakova, Alena, Strauch, Konstantin, Taylor, Kent D, Thorand, Barbara, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tuomilehto, Jaakko, Witte, Daniel R, Dupuis, Josee, Peyser, Patricia A, Zeggini, Eleftheria, Loos, Ruth JF, Froguel, Philippe, Ingelsson, Erik, Lind, Lars, Groop, Leif, Laakso, Markku, Collins, Francis S, Jukema, J Wouter, Palmer, Colin NA, Grallert, Harald, Metspalu, Andres, Dehghan, Abbas, Koettgen, Anna, Abecasis, Goncalo R, Meigs, James B, Rotter, Jerome I, Marchini, Jonathan, Pedersen, Oluf, Hansen, Torben, Langenberg, Claudia, Wareham, Nicholas J, Stefansson, Kari, Gloyn, Anna L, Morris, Andrew P, Boehnke, Michael and McCarthy, Mark 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). pp. 1505-1513.

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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).

Item Type:	Article
Uncontrolled Keywords:	Islets of Langerhans, Humans, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, Body Mass Index, Case-Control Studies, Chromosome Mapping, Sex Factors, Epigenesis, Genetic, Gene Frequency, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Genome, Human, Female, Male, Meta-Analysis as Topic, Genome-Wide Association Study, Genetic Loci, High-Throughput Screening Assays, White People
Depositing User:	Symplectic Admin
Date Deposited:	15 Oct 2018 14:27
Last Modified:	19 Jan 2023 01:14
DOI:	10.1038/s41588-018-0241-6
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3027479