title: Limited evidence for parent-of-origin effects in inflammatory bowel disease associated loci.
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.
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
authors.forename: Karin
authors.initials: K
authors.lastname: Fransen
authors.forename: Mitja
authors.initials: M
authors.lastname: Mitrovic
authors.forename: Cleo C
authors.initials: CC
authors.lastname: van Diemen
authors.forename: B K
authors.initials: BK
authors.lastname: Thelma
authors.forename: Ajit
authors.initials: A
authors.lastname: Sood
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Vandana
authors.initials: V
authors.lastname: Midha
authors.forename: Garima
authors.initials: G
authors.lastname: Juyal
authors.forename: Uros
authors.initials: U
authors.lastname: Potocnik
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Fu
authors.forename: Ilja
authors.initials: I
authors.lastname: Nolte
authors.forename: Rinse K
authors.initials: RK
authors.lastname: Weersma
mesh_terms: D000071797:Butyrophilins; D002648:Child; D003093:Colitis, Ulcerative / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018392:Genomic Imprinting; D006801:Humans; D040582:Inheritance Patterns; D016753:Interleukin-10 / Q000235:genetics; D053762:Interleukin-12 Subunit p40 / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012097:Repressor Proteins / Q000235:genetics; D012306:Risk; D044465:White People / Q000235:genetics*
chemical_list: C408263:BTNL2 protein, human; D000071797:Butyrophilins; C508609:IL10 protein, human; C500879:IL12B protein, human; D053762:Interleukin-12 Subunit p40; D008562:Membrane Glycoproteins; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D012097:Repressor Proteins; D016753:Interleukin-10; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1