TY - JOUR
T1 - Pooled Resequencing of 122 Ulcerative Colitis Genes in a Large Dutch Cohort Suggests Population-Specific Associations of Rare Variants in MUC2
AU - Visschedijk, Marijn C.
AU - Alberts, Rudi
AU - Mucha, Soren
AU - Deelen, Patrick
AU - de Jong, Dirk J.
AU - Pierik, Marieke
AU - Spekhorst, Lieke M.
AU - Imhann, Floris
AU - van der Meulen-de Jong, Andrea E.
AU - van der Woude, C. Janneke
AU - van Bodegraven, Adriaan A.
AU - Oldenburg, Bas
AU - Lowenberg, Mark
AU - Dijkstra, Gerard
AU - Ellinghaus, David
AU - Schreiber, Stefan
AU - Wijmenga, Cisca
AU - Rivas, Manuel A.
AU - Franke, Andre
AU - van Diemen, Cleo C.
AU - Weersma, Rinse K.
PY - 2016/8/4
Y1 - 2016/8/4
N2 - 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.
AB - 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.
U2 - 10.1371/journal.pone.0159609
DO - 10.1371/journal.pone.0159609
M3 - Article
C2 - 27490946
SN - 1932-6203
VL - 11
JO - PLOS ONE
JF - PLOS ONE
IS - 8
M1 - e0159609
ER -