Transmission distortion in Crohn's disease risk gene ATG16L1 leads to sex difference in disease association.

backgroundCrohn's disease (CD), an inflammatory disease of the bowel, affects millions of people around the world. Evidence suggests that disease onset and pathogenesis differ between males and females. Yet no comprehensive efforts exist to assess the sex-specific genetic architecture of CD.

methodsWe used genotyping data from a cohort of 1748 CD cases and 2938 controls to investigate 71 meta-analysis-confirmed CD risk loci for sex differences in disease risk. We further validated the significant results in separate cohorts of 968 CD cases and 2809 controls, and performed a meta-analysis across datasets.

resultsThe single nucleotide polymorphism (SNP) rs3792106 (C/T) in ATG16L1 showed a significant sex effect with P-value 6.9 × 10(-13) and allelic odds ratio 1.48 in females, and P-value 0.013 and odds ratio 1.22 in males (odds ratio heterogeneity P-value 0.037). Surprisingly, the difference was found to arise from a discrepancy in allele frequencies between male and female controls (P-value 0.0045) rather than cases. We found similar results for this SNP in the separate validation datasets. Using 155 HapMap 3 trios, we detected significant maternal overtransmission of the T allele at rs3792106 (P-value 0.027).

conclusionsOur results indicate that different transmission patterns between sexes may sustain the disparate allele frequencies at rs3792106 in healthy populations, and furthermore that a virus-risk variant mechanism implicated in CD alters the distribution in diseased patients. To our knowledge, this is the first report of sex-specific CD association in ATG16L1. The possible implications in CD and basic human biology present interesting areas for future investigation.