title: Pooled Resequencing of 122 Ulcerative Colitis Genes in a Large Dutch Cohort Suggests Population-Specific Associations of Rare Variants in MUC2.
abstract: Genome-wide association studies have revealed several common genetic risk variants for ulcerative colitis (UC). However, little is known about the contribution of rare, large effect genetic variants to UC susceptibility. In this study, we performed a deep targeted re-sequencing of 122 genes in Dutch UC patients in order to investigate the contribution of rare variants to the genetic susceptibility to UC. The selection of genes consists of 111 established human UC susceptibility genes and 11 genes that lead to spontaneous colitis when knocked-out in mice. In addition, we sequenced the promoter regions of 45 genes where known variants exert cis-eQTL-effects. Targeted pooled re-sequencing was performed on DNA of 790 Dutch UC cases. The Genome of the Netherlands project provided sequence data of 500 healthy controls. After quality control and prioritization based on allele frequency and pathogenicity probability, follow-up genotyping of 171 rare variants was performed on 1021 Dutch UC cases and 1166 Dutch controls. Single-variant association and gene-based analyses identified an association of rare variants in the MUC2 gene with UC. The associated variants in the Dutch population could not be replicated in a German replication cohort (1026 UC cases, 3532 controls). In conclusion, this study has identified a putative role for MUC2 on UC susceptibility in the Dutch population and suggests a population-specific contribution of rare variants to UC.
authors.affiliation: Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, 9700 RB, Groningen, The Netherlands.|Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, 9700 RB, Groningen, The Netherlands.
authors.forename: Marijn C
authors.initials: MC
authors.lastname: Visschedijk
authors.affiliation: Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, 9700 RB, Groningen, The Netherlands.
authors.forename: Rudi
authors.initials: R
authors.lastname: Alberts
authors.affiliation: Institute of Clinical Molecular Biology, Kiel University, D-24105, Kiel, Germany.
authors.forename: Soren
authors.initials: S
authors.lastname: Mucha
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, 9700 RB, Groningen, The Netherlands.
authors.forename: Patrick
authors.initials: P
authors.lastname: Deelen
authors.affiliation: Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Centre, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: de Jong
authors.affiliation: Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, 6229 HX, Maastricht, The Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: Pierik
authors.affiliation: Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, 9700 RB, Groningen, The Netherlands.
authors.forename: Lieke M
authors.initials: LM
authors.lastname: Spekhorst
authors.affiliation: Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, 9700 RB, Groningen, The Netherlands.
authors.forename: Floris
authors.initials: F
authors.lastname: Imhann
authors.affiliation: Department of Gastroenterology and Hepatology, Leiden University Medical Centre, 2333 ZA, Leiden, The Netherlands.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: van der Meulen-de Jong
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, 3015 CE, Rotterdam, The Netherlands.
authors.forename: C Janneke
authors.initials: CJ
authors.lastname: van der Woude
authors.affiliation: Department of Gastroenterology and Hepatology, VU University Medical Centre, 1081 HZ, Amsterdam, The Netherlands.
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: van Bodegraven
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, 3584 CX, Utrecht, The Netherlands.
authors.forename: Bas
authors.initials: B
authors.lastname: Oldenburg
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Centre, 1105 AZ, Amsterdam, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Löwenberg
authors.affiliation: Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, 9700 RB, Groningen, The Netherlands.
authors.forename: Gerard
authors.initials: G
authors.lastname: Dijkstra
authors.affiliation: Institute of Clinical Molecular Biology, Kiel University, D-24105, Kiel, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Ellinghaus
authors.affiliation: Department of Internal Medicine I, University Medical Centre Schleswig-Holstein, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, 9700 RB, Groningen, The Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Centre for the Study of IBD (SCIBD) Genetics, The Broad Institute, Cambridge, Massachusetts, United States of America.
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Rivas
authors.affiliation: Institute of Clinical Molecular Biology, Kiel University, D-24105, Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, 9700 RB, Groningen, The Netherlands.
authors.forename: Cleo C
authors.initials: CC
authors.lastname: van Diemen
authors.affiliation: Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, 9700 RB, Groningen, The Netherlands.
authors.forename: Rinse K
authors.initials: RK
authors.lastname: Weersma
mesh_terms: D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000473:pathology; D004247:DNA / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D055262:Mucin-2 / Q000235:genetics*; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D040641:Quantitative Trait Loci; D017422:Sequence Analysis, DNA
chemical_list: C524625:MUC2 protein, human; D055262:Mucin-2; D004247:DNA