Genomi-wide association study on anorectal malformations in the Chinese population

Abstract

Anorectal malformations (ARM) represent a complex group of congenital diseases characterized by the obstruction of anal opening. Occurring in 1 out of every 4,000 to 5,000 individuals, ARMs are one of the most common pediatric surgical problems. The spectrum of ARMs ranges from anal stenosis to anal atresia/imperforated anus with/without fistula to persistent cloaca. The etiology of ARMs remains unknown, although there is strong evidence for a genetic component. This is indicated by the very early developmental disruption, its recurrence in families and the high concordance of its existence with some abnormalities. Though several candidate genes e.g. endothelin-β receptor (EDNRB) and sonic hedgehog (Shh) were proposed for their potential roles in the development of ARMs, the causes of ARMs still remain unknown. To explore the genetic contribution to the pathogenesis of ARM, we performed systematic analyses of genetic markers, in 176 Chinese patients and 2986 ethnically matched individuals as controls. The genome-wide association study (GWAS) was performed using the Illumina Human 610-Quad BeadChips with 488, 394 SNPs successfully genotyped. An association peak encompassing two gene members of the solute carrier (SLC) family was observed, with p-value= (odds ratio 1.94, 95% CI: 1.54-2.45 for allele C) for the most associated SNP (rs11045422). To confirm the observed association, those statistically significant SNPs will be genotyped in an independent set of cases and controls. Bioinformatics and experimental analysis will be used to study the biological relevance of SLC genes in ARMs.