Fine mapping of Hirschsprung’s disease loci in 9q31

Abstract

Hirschsprung’s disease (HSCR) is a congenital disorder in which there is an absence of ganglion cells in variable portions of the lower digestive tract, according to which patients are classified. The RET gene is the largest risk factor in HSCR, although reduced penetrance of RET mutations, absence of RET mutations in some patients, and variable expression of the HSCR phenotype indicate that more than one gene is involved. A RET-dependent modifier which segregates in families harboring no or hypomorphic RET mutations was mapped to 9q31. Fine mapping of the region performed on 142 Dutch trios by genotyping 370 tag-SNPs spanning approximately 7 Mb (from 108.5-115.5 Mb) of 9q31 on an Illumina GoldenGate platform identified two different 9q31 HSCR-associated regions in which genes with biological plausibility lie. Since evaluation of an association in a population of different origin from that of the initial finding increases the association confidence and, since linkage disequilibrium (LD) differences across populations can be used to narrow the regions of interest, we genotyped 181 Chinese HSCR patients and 179 controls for 38 tag-SNPs chosen from the CHB population spanning the 9q31 regions of interest. In addition, we made use of genotype data for the 9q31 region obtained from a genome-wide association study recently conducted in Chinese HSCR patients. Only one of the two 9q31 HSCR-associated regions identified in the Dutch population was associated in Chinese (p = 0.021), although the most associated SNPs within the region differed, probably due to differences in LD and/or different genotyping densities. Importantly, the associated region encompasses IKBKAP and CTNNAL1, which have been linked to neurodevelopmental disorders.