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

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Mahajan , A , Taliun , D , Thurner , M , Robertson , N R , Torres , J M , Rayner , N W , Payne , A J , Steinthorsdottir , V , Scott , R A , Grarup , N , Cook , J P , Schmidt , E M , Wuttke , M , Sarnowski , C , Magill , R , Nano , J , Gieger , C , Trompet , S , Lecoeur , C , Preuss , M H , Prins , B P , Guo , X , Bielak , L F , Below , J E , Bowden , D W , Chambers , J C , Kim , Y J , Ng , M C Y , Petty , L E , Sim , X , Zhang , W , Bennett , A J , Bork-Jensen , J , Brummett , C M , Canouil , M , Kardt , K-U E , Fischer , K , Kardia , S L R , Kronenberg , F , Lall , K , Liu , C-T , Locke , A E , Luan , J , Ntalla , L , Nylander , V , Schoenherr , S , Schurmann , C , Yengo , L , Bottinger , E P , Brandslund , I , Christensen , C , Dedoussis , G , Florez , J C , Ford , I , France , O H , Frayling , T M , Giedraitis , V , Hackinger , S , Hattersley , A T , Herder , C , Ikram , M A , Ingelsson , M , Jorgensen , M E , Jorgensen , T , Kriebel , J , Kuusisto , J , Ligthart , S , Lindgren , C M , Linneberg , A , Lyssenko , V , Mamakou , V , Meitinger , T , Mohlke , K L , Morris , A D , Nadkarni , G , Pankow , J S , Peters , A , Sattar , N , Stancakova , A , Strauch , K , Taylor , K D , Thorand , B , Thorleifsson , G , Thorsteinsdottir , U , Tuomilehto , J , Witte , D R , Dupuis , J , Peyser , P A , Zeggini , E , Loos , R J F , Froguel , P , Ingelsson , E , Lind , L , Groop , L , Laakso , M , Collins , F S , Jukema , J W , Palmer , C N A , Grallert , H , Metspalu , A , Dehghan , A , Koettgen , A , Abecasis , G R , Meigs , J B , Rotter , J , Marchini , J , Pedersen , O , Hansen , T , Langenberg , C , Wareham , N J , Stefansson , K , Gloyn , A L , Morris , A P , Boehnke , M & McCarthy , M 2018 , ' Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps ' , Nature Genetics , vol. 50 , no. 11 , pp. 1505-+ . https://doi.org/10.1038/s41588-018-0241-6

Title: Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps
Author: 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, 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 C. Y.; 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 L. R.; 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 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; Koettgen, Anna; Abecasis, Goncalo R.; Meigs, James B.; Rotter, Jerome; Marchini, Jonathan; Pedersen, Oluf; Hansen, Torben; Langenberg, Claudia; Wareham, Nicholas J.; Stefansson, Kari; Gloyn, Anna L.; Morris, Andrew P.; Boehnke, Michael; McCarthy, Mark
Contributor: University of Helsinki, Centre of Excellence in Complex Disease Genetics
Date: 2018-11
Language: eng
Number of pages: 11
Belongs to series: Nature Genetics
ISSN: 1061-4036
URI: http://hdl.handle.net/10138/306613
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 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).
Subject: GENOME-WIDE ASSOCIATION
SUSCEPTIBILITY LOCI
GENETIC ARCHITECTURE
DISEASE
IDENTIFICATION
EXPRESSION
METAANALYSIS
PHENOTYPES
TRAITS
SCORE
3111 Biomedicine
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