Genotype-phenotype analysis across 130 422 genetic variants identifies RSPO3 as the first genome-wide significant modifier gene in primary sclerosing cholangitis

Alberts, R., de Vries, E. M., Alexander, G., Alvaro, D., Bergquist, A., Beuers, U., Bjornsson, E., Boberg, K. M., Bowlus, C. L., Chapman, R. W., Chazouilleres, O., Cheung, A., Dalekos, G., Eksteen, B., Ellinghaus, D., Farkkila, M., Festen, E. A., Floreani, A., Folseraas, T., Goode, E., Gotthardt, D. N., Hirschfield, G. M., van Hoek, B., Holm, K., Hohenester, S., Hov, J. R., Imhann, F., Invernizzi, P., Jiang, X., Eaton, J., Juran, B. D., Lazaridis, K. N., Leppa, V., Liu, J. Z., Lofberg, J., Manns, M. P., Marschall, H. U., Marzioni, M., Mason, A. L., Melum, E., Milkiewicz, P., Muller, T., Pares, A., Rupp, C., Rushbrook, S. M., Rust, C., Sampaziotis, F., Sandford, R. N., Schramm, C., Schreiber, Stefan, Schrumpf, E., Silverberg, M., Srivastava, B., Sterneck, M., Teufel, A., Tittmann, L., Vallier, L., Vila, A. V., de Vries, B., Weismuller, T. J., Wijmenga, C., Zachou, K., Franke, A., Anderson, C. A., Karlsen, T. H., Ponsioen, C. Y. and Weersma, R. K. (2016) Genotype-phenotype analysis across 130 422 genetic variants identifies RSPO3 as the first genome-wide significant modifier gene in primary sclerosing cholangitis Journal of Crohns & Colitis, 10 . S5-S7. DOI 10.1186/s12881-016-0289-z.

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Supplementary data:



Ulcerative colitis (UC), a complex polygenic disorder, is one of the main subphenotypes of inflammatory bowel disease. A comprehensive dissection of the genetic etiology of UC needs to assess the contribution of rare genetic variants including copy number variations (CNVs) to disease risk. In this study, we performed a multi-step genome-wide case-control analysis to interrogate the presence of disease-relevant rare copy number variants.

One thousand one hundred twenty-one German UC patients and 1770 healthy controls were initially screened for rare deletions and duplications employing SNP-array data. Quantitative PCR and high density custom array-CGH were used for validation of identified CNVs and fine mapping. Two main follow-up panels consisted of an independent cohort of 451 cases and 1274 controls, in which CNVs were assayed through quantitative PCR, and a British cohort of 2396 cases versus 4886 controls with CNV genotypes based on array data. Additional sample sets were assessed for targeted and in silico replication.

Twenty-four rare copy number variants (14 deletions and 10 duplications), overrepresented in UC patients were identified in the initial screening panel. Follow-up of these CNV regions in four independent case-control series as well as an additional public in silico control group (totaling 4439 UC patients and 15,961 healthy controls) revealed three copy number variants enriched in UC patients; a 15.8 kb deletion upstream of ABCC4 and CLDN10 at13q32.1 (0.43 % cases, 0.11 % controls), a 119 kb duplication at 7p22.1, overlapping RNF216, ZNF815, OCM and CCZ1 (0.13 % cases, 0.01 % controls) and a 134 kb large duplication upstream of the KCNK9 gene at 8q24.3 (0.22 % carriers among cases, 0.03 % carriers among controls). The trend of association with UC was present after the P-values were corrected for combining data from different subpopulations. Break-point mapping of the deleted region suggested non-allelic homologous recombination as the mechanism underlying its formation.

Our study presents a pragmatic approach for effective rare CNV screening of SNP-array data sets and implicates the potential contribution of rare structural variants in the pathogenesis of UC.

Document Type: Article
Additional Information: Times Cited: 0 Alberts, R. de Vries, E. M. Alexander, G. Alvaro, D. Bergquist, A. Beuers, U. Bjornsson, E. Boberg, K. M. Bowlus, C. L. Chapman, R. W. Chazouilleres, O. Cheung, A. Dalekos, G. Eksteen, B. Ellinghaus, D. Farkkila, M. Festen, E. A. Floreani, A. Folseraas, T. Goode, E. Gotthardt, D. N. Hirschfield, G. M. van Hoek, B. Holm, K. Hohenester, S. Hov, J. R. Imhann, F. Invernizzi, P. Jiang, X. Eaton, J. Juran, B. D. Lazaridis, K. N. Leppa, V. Liu, J. Z. Lofberg, J. Manns, M. P. Marschall, H-U Marzioni, M. Mason, A. L. Melum, E. Milkiewicz, P. Muller, T. Pares, A. Rupp, C. Rushbrook, S. M. Rust, C. Sampaziotis, F. Sandford, R. N. Schramm, C. Schreiber, S. Schrumpf, E. Silverberg, M. Srivastava, B. Sterneck, M. Teufel, A. Tittmann, L. Vallier, L. Vila, A. V. de Vries, B. Weismuller, T. J. Wijmenga, C. Zachou, K. Franke, A. Anderson, C. A. Karlsen, T. H. Ponsioen, C. Y. Weersma, R. K. 1
Research affiliation: OceanRep > The Future Ocean - Cluster of Excellence
Kiel University
Refereed: Yes
DOI etc.: 10.1186/s12881-016-0289-z
ISSN: 1873-9946
Projects: Future Ocean
Date Deposited: 01 Mar 2017 09:00
Last Modified: 19 Dec 2017 12:44

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