Limited evidence for parent-of-origin effects in inflammatory bowel disease associated loci

Karin Fransen; Mitja Mitrovic; Cleo C van Diemen; B K Thelma; Ajit Sood; Andre Franke; Stefan Schreiber; Vandana Midha; Garima Juyal; Uros Potocnik; Jingyuan Fu; Ilja Nolte; Rinse K Weersma

doi:10.1371/journal.pone.0045287

Limited evidence for parent-of-origin effects in inflammatory bowel disease associated loci

PLoS One. 2012;7(9):e45287. doi: 10.1371/journal.pone.0045287. Epub 2012 Sep 27.

Authors

Karin Fransen¹, Mitja Mitrovic, Cleo C van Diemen, B K Thelma, Ajit Sood, Andre Franke, Stefan Schreiber, Vandana Midha, Garima Juyal, Uros Potocnik, Jingyuan Fu, Ilja Nolte, Rinse K Weersma

Affiliation

¹ Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.

Abstract

Background: 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. 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.

Methods: We 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.

Results: We 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).

Conclusions: Little 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Butyrophilins
Child
Colitis, Ulcerative / genetics*
Crohn Disease / genetics*
Female
Gene Expression
Genetic Loci*
Genetic Predisposition to Disease
Genome-Wide Association Study
Genomic Imprinting*
Humans
Inheritance Patterns
Interleukin-10 / genetics
Interleukin-12 Subunit p40 / genetics
Male
Membrane Glycoproteins / genetics
Nod2 Signaling Adaptor Protein / genetics
Polymorphism, Single Nucleotide*
Positive Regulatory Domain I-Binding Factor 1
Repressor Proteins / genetics
Risk
White People / genetics*

Substances

BTNL2 protein, human
Butyrophilins
IL10 protein, human
IL12B protein, human
Interleukin-12 Subunit p40
Membrane Glycoproteins
NOD2 protein, human
Nod2 Signaling Adaptor Protein
Repressor Proteins
Interleukin-10
PRDM1 protein, human
Positive Regulatory Domain I-Binding Factor 1

Grants and funding

K. Fransen was supported by a MD/PhD grant from GUIDE at University Medical Center Groningen. M. Mitrovic was supported by a PhD grant from Slovenian Research Agency (Grant No. 630-39/2012-1). U. Potocnik was supported by a grant from Slovenian Research Agency (Grant No. J3-2175). R.K. Weersma is supported by a clinical fellowship grant (90.700.281) from the Netherlands Organization for Scientific Research (NWO) and the Broad Medical Research Program of The Broad Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.