Dataset Information

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

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).

SUBMITTER: Mahajan A

PROVIDER: S-EPMC6287706 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Mahajan Anubha A Taliun Daniel D Thurner Matthias M Robertson Neil R NR Torres Jason M JM Rayner N William NW Payne Anthony J AJ Steinthorsdottir Valgerdur V Scott Robert A RA Grarup Niels N Cook James P JP Schmidt Ellen M EM Wuttke Matthias M Sarnowski Chloé C Mägi Reedik R Nano Jana J Gieger Christian C Trompet Stella S Lecoeur Cécile C Preuss Michael H MH Prins Bram Peter BP Guo Xiuqing X Bielak Lawrence F LF Below Jennifer E JE Bowden Donald W DW Chambers John Campbell JC Kim Young Jin YJ Ng Maggie C Y MCY Petty Lauren E LE Sim Xueling X Zhang Weihua W Bennett Amanda J AJ Bork-Jensen Jette J Brummett Chad M CM Canouil Mickaël M Ec Kardt Kai-Uwe KU Fischer Krista K Kardia Sharon L R SLR Kronenberg Florian F Läll Kristi K Liu Ching-Ti CT Locke Adam E AE Luan Jian'an J Ntalla Ioanna I Nylander Vibe V Schönherr Sebastian S Schurmann Claudia C Yengo Loïc L Bottinger Erwin P EP Brandslund Ivan I Christensen Cramer C Dedoussis George G Florez Jose C JC Ford Ian I Franco Oscar H OH Frayling Timothy M TM Giedraitis Vilmantas V Hackinger Sophie S Hattersley Andrew T AT Herder Christian C Ikram M Arfan MA Ingelsson Martin M Jørgensen Marit E ME Jørgensen Torben T Kriebel Jennifer J Kuusisto Johanna J Ligthart Symen S Lindgren Cecilia M CM Linneberg Allan A Lyssenko Valeriya V Mamakou Vasiliki V Meitinger Thomas T Mohlke Karen L KL Morris Andrew D AD Nadkarni Girish G Pankow James S JS Peters Annette A Sattar Naveed N Stančáková Alena A Strauch Konstantin K Taylor Kent D KD Thorand Barbara B Thorleifsson Gudmar G Thorsteinsdottir Unnur U Tuomilehto Jaakko J Witte Daniel R DR Dupuis Josée J Peyser Patricia A PA Zeggini Eleftheria E Loos Ruth J F RJF Froguel Philippe P Ingelsson Erik E Lind Lars L Groop Leif L Laakso Markku M Collins Francis S FS Jukema J Wouter JW Palmer Colin N A CNA Grallert Harald H Metspalu Andres A Dehghan Abbas A Köttgen Anna A Abecasis Goncalo R GR Meigs James B JB Rotter Jerome I JI Marchini Jonathan J Pedersen Oluf O Hansen Torben T Langenberg Claudia C Wareham Nicholas J NJ Stefansson Kari K Gloyn Anna L AL Morris Andrew P AP Boehnke Michael M McCarthy Mark I MI

Nature genetics 20181008 11

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) sub ...[more]

PMID: 30297969

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Dataset Information

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

Publications

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

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