Nature genetics · 2018

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

СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен

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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, Cook James P, Schmidt Ellen M, Wuttke Matthias, Sarnowski Chloé, Mägi Reedik, Nano Jana, Gieger Christian, Trompet Stella, Lecoeur Cécile, 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 C Y, Petty Lauren E, Sim Xueling, Zhang Weihua, Bennett Amanda J, Bork-Jensen Jette, Brummett Chad M, Canouil Mickaël, Ec Kardt Kai-Uwe, Fischer Krista, Kardia Sharon L R, Kronenberg Florian, Läll Kristi, Liu Ching-Ti, Locke Adam E, Luan Jian'an, Ntalla Ioanna, Nylander Vibe, Schönherr Sebastian, Schurmann Claudia, Yengo Loïc, Bottinger Erwin P, Brandslund Ivan, Christensen Cramer, Dedoussis George, Florez Jose C, Ford Ian, Franco Oscar H, Frayling Timothy M, Giedraitis Vilmantas, Hackinger Sophie, Hattersley Andrew T, Herder Christian, Ikram M Arfan, Ingelsson Martin, Jørgensen Marit E, Jørgensen 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, Stančáková Alena, Strauch Konstantin, Taylor Kent D, Thorand Barbara, Thorleifsson Gudmar, Thorsteinsdottir Unnur, Tuomilehto Jaakko, Witte Daniel R, Dupuis Josée, Peyser Patricia A, Zeggini Eleftheria, Loos Ruth J F, Froguel Philippe, Ingelsson Erik, Lind Lars, Groop Leif, Laakso Markku, Collins Francis S, Jukema J Wouter, Palmer Colin N A, Grallert Harald, Metspalu Andres, Dehghan Abbas, Köttgen 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, McCarthy Mark I

Аннотация

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).

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

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