Abstract
BackgroundGenome-wide association studies of two main forms of inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), have identified 99 susceptibility loci, but these explain only ∼23% of the genetic risk. Part of the ‘hidden heritability’ could be in transmissible genetic effects in which mRNA expression in the offspring depends on the parental origin of the allele (genomic imprinting), since children whose mothers have CD are more often affected than children with affected fathers. We analyzed parent-of-origin (POO) effects in Dutch and Indian cohorts of IBD patients.MethodsWe selected 28 genetic loci associated with both CD and UC, and tested them for POO effects in 181 Dutch IBD case-parent trios. Three susceptibility variants in NOD2 were tested in 111 CD trios and a significant finding was re-evaluated in 598 German trios. The UC-associated gene, BTNL2, reportedly imprinted, was tested in 70 Dutch UC trios. Finally, we used 62 independent Indian UC trios to test POO effects of five established Indian UC risk loci.ResultsWe identified POO effects for NOD2 (L1007fs; OR = 21.0, P-value = 0.013) for CD; these results could not be replicated in an independent cohort (OR = 0.97, P-value = 0.95). A POO effect in IBD was observed for IL12B (OR = 3.2, P-value = 0.019) and PRDM1 (OR = 5.6, P-value = 0.04). In the Indian trios the IL10 locus showed a POO effect (OR = 0.2, P-value = 0.03).ConclusionsLittle is known about the effect of genomic imprinting in complex diseases such as IBD. We present limited evidence for POO effects for the tested IBD loci. POO effects explain part of the hidden heritability for complex genetic diseases but need to be investigated further.
Highlights
Crohn’s disease (CD) and ulcerative colitis (UC) are the two main forms of chronic relapsing inflammatory bowel diseases (IBD)
All 115 CD trios were of western European descent from the Netherlands and were collected at the IBD Center in the Department of Gastroenterology and Hepatology, University Medical Center Groningen (UMCG), the Netherlands
DNA of 249 complete IBD trios was available for our study, of which four CD (4/115) and two Dutch UC trios (2/72) did not pass the quality control
Summary
Crohn’s disease (CD) and ulcerative colitis (UC) are the two main forms of chronic relapsing inflammatory bowel diseases (IBD). With a cumulative prevalence of up to 800 per 100,000 in Europe and 570 in North America [1], it is considered one of the most common immune-related diseases worldwide From their second or third decade on, patients suffer from a chronic relapsing inflammation of the gut, which is often accompanied by extra-intestinal manifestations and complications that can be extremely debilitating and severe. Genome-wide association studies of two main forms of inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), have identified 99 susceptibility loci, but these explain only ,23% of the genetic risk. We analyzed parent-of-origin (POO) effects in Dutch and Indian cohorts of IBD patients
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