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P732 Pooled resequencing of 122 ulcerative colitis genes in a large Dutch population suggests population-specific association of rare variants in MUC2

M.C. Visschedijk*1, 2, R. Alberts1, S. Mucha3, P. Deelen2, D. J. de Jong4, M. Pierik5, A. E. van der Meulen-de Jong6, C. J. van der Woude7, A. A. van Bodegraven8, B. Oldenburg9, M. Lowenberg10, G. Dijkstra1, D. Ellinghaus3, S. Schreiber11, C. Wijmenga2, M. A. Rivas12, A. Franke3, C. C. van Diemen2, R.K. Weersma1

1University of Groningen and University Medical Centre Groningen, Department of Gastroenterology and Hepatology, Groningen, Netherlands, 2University of Groningen and University Medical Centre Groningen, Department of Genetics, Groningen, Netherlands, 3Kiel University, Institute of Clinical Molecular Biology, Kiel, Germany, 4University Medical Centre St. Radboud, Department of Gastroenterology and Hepatology, Nijmegen, Netherlands, 5University Medical Centre Maastricht, Division of Gastroenterology and Hepatology, Maastricht, Netherlands, 6Leiden University Medical Centre, Department of Gastroenterology and Hepatology, Leiden, Netherlands, 7Erasmus Medical Centre, Department of Gastroenterology and Hepatology, Rotterdam, Netherlands, 8VU University Medical Centre, Department of Gastroenterology and Hepatology, Amsterdam, Netherlands, 9University Medical Centre Utrecht, Department of Gastroenterology and Hepatology, Utrecht, Netherlands, 10Amsterdam Medical Centre, Department of Gastroenterology and Hepatology, Amsterdam, Netherlands, 11University Medical Centre Schleswig-Holstein, Department of Internal Medicine, Kiel, Germany, 12The Broad Institute, Centre for the Study of IBD (SCIBD) Genetics, Cambridge, United States

Background

Large sequencing studies have revealed that a large number of low-frequency genetic variants (1%≤ minor allele frequencies [MAF] < 5%) and rare variants (MAF < 1%) are more likely to have a deleterious effect on health compared with variants with high frequency (MAF > 5%). Although the role of rare variants in Mendelian diseases is well known, the contribution of rare variants to complex disease susceptibility is still being elucidated. Common loci identified by genome-wide association studies in ulcerative colitis (UC) only explain approximately 8.2% of the disease variance, and much of the debate about the missing heritability in UC has been focused on the contribution of low-frequency and rare variants with strong effect to the disease.

Methods

In this study we performed deep targeted resequencing of 122 genes in Dutch UC patients to investigate in the contribution of rare variants to genetic susceptibility for UC. The selection of genes consists of 111 established UC genes and 11 genes that lead to spontaneous colitis in knockout mice. Additionally, we included the promoter regions of genes with a known cis-eQTL effect. Targeted resequencing was performed in a pooled fashion on 790 Dutch cases, and on 500 healthy controls of the Genome of the Netherlands cohort. After quality control and prioritisation based on allele frequency and likely pathogenicity, follow-up genotyping of 171 rare variants was performed on 1 021 Dutch UC cases and 1 166 controls.

Results

Single-variant association and gene-based analyses identified an association of the MUC2 gene with UC. None of the associated variants in the Dutch population could be replicated in a German replication cohort (1 026 UC cases, and 3 532 controls).

Conclusion

This study has identified a putative role of the MUC2 gene in the Dutch population and suggests a population-specific contribution of rare variants to UC susceptibility. Whole genome or exome sequencing studies in multiple populations are thus crucial to achieving the statistical power needed to identify the role of rare coding and non-coding variants in complex disease susceptibility.