Parent of origin effects for IL12B and NOD2 in Inflammatory Bowel Disease
K. Fransen1,2 ,MD, M. Mitrovic1,3 , C.C. van Diemen1, PhD, B.K. Thelma 4, PhD, S. Senapati4, U.
Potocnik3, PhD, H. W. Verspagert5, MD, PhD, C.IJ. Ponsioen6, MD, D. de Jong7, MD, PhD, I.
Nolte8, PhD, R. K. Weersma2 *, MD, PhD.
1Department
of Genetics, University Medical Centre Groningen and University of Groningen,
Groningen, the Netherlands
2Department
of Gastroenterology and Hepatology, University Medical Centre Groningen,
University of Groningen, Groningen, the Netherlands
3Center
for Human Molecular Genetics and Pharmacogenomics, Medical Faculty, University of
Maribor, Maribor, Slovenia
4 Department
of Genetics, University of Delhi, South Campus, New Delhi, India,
5Department
of Gastroenterology and Hepatology, University Medical Centre Leiden, University
of Leiden, Leiden, the Netherlands
6Department
of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The
Netherlands
7Department
of Gastroenterology and Hepatology, Radboud University Nijmegen Medical
Centre, Nijmegen, The Netherlands
8Department
of epidemiology, University Medical Centre Groningen and University of
Groningen, Groningen, the Netherlands

equal contribution
* Corresponding author
Phone: +31 503610426
Fax:+31 503619306
E-mail: r.k.weersma@umcg.nl
Abstract
Genome-wide association studies (GWAS) for the two main forms of inflammatory bowel
diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC) have identified 99 independent
susceptibility loci explaining ~23% of the total genetic risk for IBD. In the post-GWAS era the
challenge is to uncover the remaining so-called hidden heritability. One of the sources might be
a parent of origin (POO) dependent risk per allele, named genomic imprinting. This is
characterized by a consecutive activation or inactivation of one of the copies of an allele
depending on the parent from which it is inherited. An epidemiological study has shown that
children from mothers with CD more often get CD than children from fathers with CD, indicating
the existence of such a POO effect. We are the first to test for POO effects in IBD.
For DNA genotyping we used a custom-made chip, the immunochip, which contains a dense
map of ~180 immune disease related loci and ~200.000 variants. In a case-control study of 1367
cases and 2098 controls of Dutch ancestry we confirmed the association of 19 of the 99 known
IBD loci (p value<0.001). To test for POO effects we used a recently developed POO-likelihoodratio model that proved successful in determining a PPO effect in type I diabetes. For this study,
we tested the 28 loci that are associated with both CD and UC in 187 Dutch child parent trios in
which the child suffers from either UC or CD. Additionally, we tested the three known NOD2
variants in CD trios and the UC gene BTNL2 in UC trios, since this gene is already known to be
imprinted.
In the analysis of the Dutch trios a significant POO effect in the IL12B locus was found (P= 0.019
OR=3.2). In the NOD2 locus the reported frame-shift mutation (rs2066847) showed a POO effect
(p=0.013 OR=21.0). No significant POO effects were detected in the BTNL2 locus. Conclusions:
Very little is known on the effect of genomic imprinting in complex diseases like IBD. Here we
show for the first time that there is a POO effect for IL12B and NOD2 in the Dutch population. In
the post GWAS era it is of utmost importance to study new sources to identify the hidden
heritability. Follow-up studies with bigger cohort sizes and preferably including different
ethnicities are necessary to confirm our findings and unravel the observed maternal imprinting
in IBD. Currently we are analyzing a cohort of trios of Indian descent. We will test POO effects of
11 shared risk loci between Indian UC and Caucasian UC cases.