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Pathway Analysis of GWAS Provides New Insights into Genetic Susceptibility to 3 Inflammatory Diseases

Eleftherohorinou, H; Wright, V; Hoggart, C; Hartikainen, AL; Jarvelin, MR; Balding, D; Coin, L; (2009) Pathway Analysis of GWAS Provides New Insights into Genetic Susceptibility to 3 Inflammatory Diseases. PLOS ONE , 4 (11) , Article e8068. 10.1371/journal.pone.0008068. Green open access

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Abstract

Although the introduction of genome-wide association studies (GWAS) have greatly increased the number of genes associated with common diseases, only a small proportion of the predicted genetic contribution has so far been elucidated. Studying the cumulative variation of polymorphisms in multiple genes acting in functional pathways may provide a complementary approach to the more common single SNP association approach in understanding genetic determinants of common disease. We developed a novel pathway-based method to assess the combined contribution of multiple genetic variants acting within canonical biological pathways and applied it to data from 14,000 UK individuals with 7 common diseases. We tested inflammatory pathways for association with Crohn's disease (CD), rheumatoid arthritis (RA) and type 1 diabetes (T1D) with 4 non-inflammatory diseases as controls. Using a variable selection algorithm, we identified variants responsible for the pathway association and evaluated their use for disease prediction using a 10 fold cross-validation framework in order to calculate out-of-sample area under the Receiver Operating Curve (AUC). The generalisability of these predictive models was tested on an independent birth cohort from Northern Finland. Multiple canonical inflammatory pathways showed highly significant associations (p 10(-3) -10(-20)) with CD, T1D and RA. Variable selection identified on average a set of 205 SNPs (149 genes) for T1D, 350 SNPs (189 genes) for RA and 493 SNPs (277 genes) for CD. The pattern of polymorphisms at these SNPS were found to be highly predictive of T1D (91% AUC) and RA (85% AUC), and weakly predictive of CD (60% AUC). The predictive ability of the T1D model (without any parameter refitting) had good predictive ability (79% AUC) in the Finnish cohort. Our analysis suggests that genetic contribution to common inflammatory diseases operates through multiple genes interacting in functional pathways.

Type: Article
Title: Pathway Analysis of GWAS Provides New Insights into Genetic Susceptibility to 3 Inflammatory Diseases
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0008068
Publisher version: http://dx.doi.org/10.1371/journal.pone.0008068
Language: English
Additional information: © 2009 Eleftherohorinou et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding for the WTCCC project was provided by the Wellcome Trust under award 076113. For the NFBC1966, the financial support was received from the Academy of Finland (project grants 104781, 120315), Biocenter, University of Oulu, Finland, NHLBI grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01), ENGAGE project and grant agreement HEALTH-F4-2007-201413. Lachlan Coin is supported by a research council UK fellowship; Victoria Wright is supported by a grant from ESPID, Clive Hoggart is supported by the European Network for Genetic-Epidemiological Studies, Hariklia Eleftherohorinou is supported by the Imperial College Faculty of Medicine studentship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords: GENOME-WIDE ASSOCIATION, NF-KAPPA-B, TYPE-1 DIABETES RISK, 7 COMMON DISEASES, RHEUMATOID-ARTHRITIS, CROHNS-DISEASE, FOUNDER POPULATION, AUTOIMMUNE-DISEASE, PROMOTER REGION, COMPLEX DISEASE
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
URI: https://discovery.ucl.ac.uk/id/eprint/146201
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