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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

ABSTRACT: We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.

SUBMITTER: Gaulton KJ

PROVIDER: S-EPMC4666734 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

Gaulton Kyle J KJ Ferreira Teresa T Lee Yeji Y Raimondo Anne A Mägi Reedik R Reschen Michael E ME Mahajan Anubha A Locke Adam A Rayner N William NW Robertson Neil N Scott Robert A RA Prokopenko Inga I Scott Laura J LJ Green Todd T Sparso Thomas T Thuillier Dorothee D Yengo Loic L Grallert Harald H Wahl Simone S Frånberg Mattias M Strawbridge Rona J RJ Kestler Hans H Chheda Himanshu H Eisele Lewin L Gustafsson Stefan S Steinthorsdottir Valgerdur V Thorleifsson Gudmar G Qi Lu L Karssen Lennart C LC van Leeuwen Elisabeth M EM Willems Sara M SM Li Man M Chen Han H Fuchsberger Christian C Kwan Phoenix P Ma Clement C Linderman Michael M Lu Yingchang Y Thomsen Soren K SK Rundle Jana K JK Beer Nicola L NL van de Bunt Martijn M Chalisey Anil A Kang Hyun Min HM Voight Benjamin F BF Abecasis Gonçalo R GR Almgren Peter P Baldassarre Damiano D Balkau Beverley B Benediktsson Rafn R Blüher Matthias M Boeing Heiner H Bonnycastle Lori L LL Bottinger Erwin P EP Burtt Noël P NP Carey Jason J Charpentier Guillaume G Chines Peter S PS Cornelis Marilyn C MC Couper David J DJ Crenshaw Andrew T AT van Dam Rob M RM Doney Alex S F AS Dorkhan Mozhgan M Edkins Sarah S Eriksson Johan G JG Esko Tonu T Eury Elodie E Fadista João J Flannick Jason J Fontanillas Pierre P Fox Caroline C Franks Paul W PW Gertow Karl K Gieger Christian C Gigante Bruna B Gottesman Omri O Grant George B GB Grarup Niels N Groves Christopher J CJ Hassinen Maija M Have Christian T CT Herder Christian C Holmen Oddgeir L OL Hreidarsson Astradur B AB Humphries Steve E SE Hunter David J DJ Jackson Anne U AU Jonsson Anna A Jørgensen Marit E ME Jørgensen Torben T Kao Wen-Hong L WH Kerrison Nicola D ND Kinnunen Leena L Klopp Norman N Kong Augustine A Kovacs Peter P Kraft Peter P Kravic Jasmina J Langford Cordelia C Leander Karin K Liang Liming L Lichtner Peter P Lindgren Cecilia M CM Lindholm Eero E Linneberg Allan A Liu Ching-Ti CT Lobbens Stéphane S Luan Jian'an J Lyssenko Valeriya V Männistö Satu S McLeod Olga O Meyer Julia J Mihailov Evelin E Mirza Ghazala G Mühleisen Thomas W TW Müller-Nurasyid Martina M Navarro Carmen C Nöthen Markus M MM Oskolkov Nikolay N NN Owen Katharine R KR Palli Domenico D Pechlivanis Sonali S Peltonen Leena L Perry John R B JR Platou Carl G P CG Roden Michael M Ruderfer Douglas D Rybin Denis D van der Schouw Yvonne T YT Sennblad Bengt B Sigurðsson Gunnar G Stančáková Alena A Steinbach Gerald G Storm Petter P Strauch Konstantin K Stringham Heather M HM Sun Qi Q Thorand Barbara B Tikkanen Emmi E Tonjes Anke A Trakalo Joseph J Tremoli Elena E Tuomi Tiinamaija T Wennauer Roman R Wiltshire Steven S Wood Andrew R AR Zeggini Eleftheria E Dunham Ian I Birney Ewan E Pasquali Lorenzo L Ferrer Jorge J Loos Ruth J F RJ Dupuis Josée J Florez Jose C JC Boerwinkle Eric E Pankow James S JS van Duijn Cornelia C Sijbrands Eric E Meigs James B JB Hu Frank B FB Thorsteinsdottir Unnur U Stefansson Kari K Lakka Timo A TA Rauramaa Rainer R Stumvoll Michael M Pedersen Nancy L NL Lind Lars L Keinanen-Kiukaanniemi Sirkka M SM Korpi-Hyövälti Eeva E Saaristo Timo E TE Saltevo Juha J Kuusisto Johanna J Laakso Markku M Metspalu Andres A Erbel Raimund R Jöcke Karl-Heinz KH Moebus Susanne S Ripatti Samuli S Salomaa Veikko V Ingelsson Erik E Boehm Bernhard O BO Bergman Richard N RN Collins Francis S FS Mohlke Karen L KL Koistinen Heikki H Tuomilehto Jaakko J Hveem Kristian K Njølstad Inger I Deloukas Panagiotis P Donnelly Peter J PJ Frayling Timothy M TM Hattersley Andrew T AT de Faire Ulf U Hamsten Anders A Illig Thomas T Peters Annette A Cauchi Stephane S Sladek Rob R Froguel Philippe P Hansen Torben T Pedersen Oluf O Morris Andrew D AD Palmer Collin N A CN Kathiresan Sekar S Melander Olle O Nilsson Peter M PM Groop Leif C LC Barroso Inês I Langenberg Claudia C Wareham Nicholas J NJ O'Callaghan Christopher A CA Gloyn Anna L AL Altshuler David D Boehnke Michael M Teslovich Tanya M TM McCarthy Mark I MI Morris Andrew P AP

Nature genetics 20151109 12

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprec ...[more]

PMID: 26551672

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Project description:Heritable diseases often manifest in a highly tissue-specific manner, with different disease loci mediated by genes in distinct tissues or cell types. We propose Tissue-Gene Fine-Mapping (TGFM), a fine-mapping method that infers the posterior probability (PIP) for each gene-tissue pair to mediate a disease locus by analyzing GWAS summary statistics (and in-sample LD) and leveraging eQTL data from diverse tissues to build cis-predicted expression models; TGFM also assigns PIPs to causal variants that are not mediated by gene expression in assayed genes and tissues. TGFM accounts for both co-regulation across genes and tissues and LD between SNPs (generalizing existing fine-mapping methods), and incorporates genome-wide estimates of each tissue's contribution to disease as tissue-level priors. TGFM was well-calibrated and moderately well-powered in simulations; unlike previous methods, TGFM was able to attain correct calibration by modeling uncertainty in cis-predicted expression models. We applied TGFM to 45 UK Biobank diseases/traits (average N=316K) using eQTL data from 38 GTEx tissues. TGFM identified an average of 147 PIP > 0.5 causal genetic elements per disease/trait, of which 11% were gene-tissue pairs. Implicated gene-tissue pairs were concentrated in known disease-critical tissues, and causal genes were strongly enriched in disease-relevant gene sets. Causal gene-tissue pairs identified by TGFM recapitulated known biology (e.g., TPO-thyroid for Hypothyroidism), but also included biologically plausible novel findings (e.g., SLC20A2-artery aorta for Diastolic blood pressure). Further application of TGFM to single-cell eQTL data from 9 cell types in peripheral blood mononuclear cells (PBMC), analyzed jointly with GTEx tissues, identified 30 additional causal gene-PBMC cell type pairs at PIP > 0.5-primarily for autoimmune disease and blood cell traits, including the well-established role of CTLA4 in CD8+ T cells for All autoimmune disease. In conclusion, TGFM is a robust and powerful method for fine-mapping causal tissues and genes at disease-associated loci.

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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

Publications

Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

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