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OP017. Cross-disease study determines extent of sharing of associated loci between five seronegative auto-inflammatory diseases

D. Ellinghaus1, L. Jostins2, A. Cortes3, O. Andreassen4, Y. Wang5, S. Spain6, Inflammatory Bowel Disease Genetics Consortium7, International Genetics of Ankylosing Spondylitis Consortium8, The International PSC Study Group9, Collaborative Association Study of Psoriasis10, Psoriasis Association Genetics Extension11, Genetic Analysis of Psoriasis Consortium12, Wellcome Trust Case Control Consortium 213, J. Elder14, R. Trembath6, J. Barker6, T. Karlsen15, A. Dale16, D. McGovern17, S. Schreiber18, M. Brown19, J. Barrett2, M. Parkes20, A. Franke1, 1Christian-Albrechts-University Kiel, Institute of Clinical Molecular Biology, Kiel, Germany, 2Wellcome Trust Genome Campus, Wellcome Trust Sanger Institute, Cambridge, United Kingdom, 3University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia, 4University of Oslo, Institute of Clinical Medicine, Oslo, Norway, 5Oslo University Hospital, Division of Mental Health and Addiction, Oslo, Norway, 6King's College London, Division of Genetics and Molecular Medicine, London, United Kingdom, 7on behalf of IIBDGC, Germany, 8on behalf of IGAS, Australia, 9on behalf of IPSCSG, Norway, 10on behalf of CASP, United Kingdom, 11on behalf of PAGE, United States, 12on behalf of GAPC, United Kingdom, 13on behalf of WTCCC2, United Kingdom, 14University of Michigan, Department of Dermatology, Ann Arbor, United States, 15Oslo University Hospital, Research Institute of Internal Medicine, Oslo, Norway, 16University of California, Department of Neurosciences, San Diego La Jolla, United States, 17Los Angeles, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Los Angeles, United States, 18University Hospital Schleswig-Holstein, Clinic of Internal Medicine I, Kiel, Germany, 19Translational Research Institute, University of Queensland Diamantina Institute, Brisbane, Australia, 20University of Cambridge, Inflammatory Bowel Disease Research Group, Cambridge, United Kingdom

Background

Diseases have historically been defined along organ structures. However, recent genetic discoveries indicate that such a definition may not be appropriate in elucidating the genetic pathology, since one gene can be causative for several diseases. Analysing diseases along etiological pathways may improve our future ability to develop more effective therapeutic strategies. Cross-disease studies may provide a more comprehensive picture of the shared and distinct genetic architecture of immune-mediated conditions.

Methods

We analysed Immunochip genotype data of five seronegative diseases simultaneously, including 8,547 ankylosing spondylitis (AS), 18,437 Crohn's disease (CD), 3,388 primary sclerosing cholangitis (PSC), 6,463 psoriasis (PS) and 14,156 ulcerative colitis (UC) patients as well as 33,895 healthy controls. We used subset-based association tests and multinomial regression modelling and explored all possible subsets of diseases to identify the strongest association signal, accounting for disease heterogeneity and signals with effects in opposite directions. The test-statistic is obtained by maximising the subset-specific test-statistics over all possible disease subsets while adjusting for multiple-testing and shared controls.

Results

In total we identified 267 non-HLA loci that meet genome-wide significance (adjusted P < 5×10−8). Out of these, 146, 195, 126, 137 and 132 loci include AS, CD, PS, PSC, and UC, respectively, in the best subset of diseases that was identified to be most strongly associated with an allele at the locus. The same allele often confers risk for multiple diseases, but some alleles increase risk for one disease and are protective for another.

Conclusion

Although affecting different organs the five seronegative diseases under study share a large proportion of susceptibility loci, which highlights their close relationship on the genetic level. However many nuances exist with respect to the extent of sharing and the degree of heterogeneity between the diseases.