Evidence of transmission ratio distortion of DLG5 R30Q variant in general and implication of an association with Crohn disease in men

Abstract

Recently, we described the association of genetic variation in the discs large homolog 5 (DLG5) gene with inflammatory bowel disease (IBD) in a large European study sample (Stoll et al. in Nat Genet 36:476-480, 2004). Here, we report that the R30Q variant constitutes a susceptibility factor for Crohn disease (CD) in men [odds ratio (OR)=2.49, 95% confidence interval (CI) 1.53-4.06, P<0.001] but not women (OR=1.01, 95% CI=0.70-1.45, P=0.979) using multivariate logistic regression analyses in a unified study sample from Germany, Italy and Quebec. R30Q is a significant predictor for CD in men even when accounting for CARD15 and IBD5 risk variants (adjusted OR=2.41, 95% CI=1.41-4.12, P=0.001). The observed association is driven by a gender-dependent transmission ratio distortion (TRD) among healthy controls (frequency of Q allele: men 5.2%, women 11.3%), an effect that is offset in CD patients (frequency of Q allele: men 10.1%, women 10.9%). This finding is further substantiated by two non-IBD study samples, one of which consists of a newborn screening sample (newborn males 7.1%; newborn females 11%, P=0.036). Further investigation of the observed TRD may contribute towards enlightening the role of DLG5 in physiological processes influencing transmission of chromosomes to the surviving offspring, which, in turn, may help in understanding its implication in the development of CD among men.

A Flexible Bayesian Model for Testing for Transmission Ratio Distortion

“…We found several coincidences that are worth mentioning: for instance, DLG5, which is necessary for the polarization of citron kinase in mitotic neural precursors (Chang et al 2010). This locus is associated with Crohn's disease and the susceptibility allele is transmission distorted among male progeny (Friedrichs et al 2006). Another relevant gene is MEGF9 that might have Table 3 Gene ontology enrichment analysis of the regions with highly significant transmission ratio distortion signals (Bayes factor > 100), obtained with the Cytoscape plugin BiNGO (Maere et al 2005) and DAVID tools (Huang et al 2009 a tumor suppressor function and showed a TRD pattern in human pedigrees from the Framingham Heart Study (Paterson et al 2009).…”

Genetic Association of DLG5 R30Q with Familial and Sporadic Inflammatory Bowel Disease in Men

“…Stoll et al, [12] identified an IBD risk-associated DLG5 haplotype D that is uniquely distinguished by the 113A variant of R30Q. The association of R30Q with IBD has been replicated in other studies from several different patient populations [24][25][26]. Friedrichs et al, found a male-specific association of the R30Q variant with CD, with no association of the R30Q variant with women, nor with the entire sample of men and women [27].…”

Inflammatory bowel disease: Genetic and epidemiologic considerations

“…Present approaches have not been able to discern whether these other genes or the class Ⅱ genes are the true risk genes in the HLA locus. [79][80][81][82] , multiple polymorphisms in the MDR1/ABCB1 gene on chromosome 7q [83][84][85][86][87][88][89][90][91][92] , and polymorphisms in the DLG5 gene on chromosome 10q [70,[93][94][95][96][97][98][99][100][101][102] . (See section C.4.1.)…”