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Background and Aims:  Hirschsprung’s disease (HSCR) is a rare genetically heterogeneous congenital disorder. A recent study based on whole genome sequencing demonstrated that common variants at four novel loci, which contained two intronic variants on  CASQ2  and  PLD1 , and intergenic variants located between  SLC4A7  and  EOMES  at 3p24.1, and between  LINC01518  and  LOC283028  at 10q11.21, were associated with HSCR susceptibility. To validate these associations with HSCR susceptibility, we performed a case–control study in a Han Chinese sample set.   Methods:  We selected four previously identified single nucleotide polymorphisms (SNPs) for replication, along with tag SNPs to cover the four associated regions. In total, 61 SNPs were genotyped in 420 HSCR patients and 1,665 healthy controls from the Han Chinese population.   Results:  None of the 14 tag SNPs in the  CASQ2  gene region, including the previously associated rs9428225, showed an association with HSCR. Among the 24 tag SNPs from the  SLC4A7 - EOMES  region at 3p24.1, rs2642925 [odds ratio (OR) = 1.41, 95% confidence interval (95% CI) = 1.10–1.79;  P  Additive  = 0.007] and the previously associated SNP rs9851320 showed a suggestive association (OR = 1.22, 95% CI = 1.01–1.47;  P  Additive  = 0.042). A non-synonymous SNP, rs2287579, in  PLD1  showed a suggestive association with HSCR susceptibility (OR = 1.71, 95% CI = 1.18–2.46;  P  Additive  = 0.004). Additionally, the previously associated  PLD1  SNP rs12632766 showed a suggestive significance (OR = 1.20, 95% CI = 1.01–1.42,  P  Additive  = 0.038). In the  LINC01518 - LOC283028  region at 10q11.21, three SNPs meet the study-wide significance threshold. Rs17153309 was the most associated SNP (OR = 1.60, 95% CI = 1.34–1.90;  P  Additive  = 1.13 × 10 –7 ). The previously associated SNP rs1414027 also showed significant association (OR = 1.43, 95% CI = 1.20–1.70,  P  Additive  = 3.92 × 10 –5 ). Two associated SNPs at 10q11.21 (rs1414027 and rs624804) were expression quantitative trait loci in digestive tract tissues from GTEx databases.   Conclusions:  Our results confirmed that variants of the  LINC01518-LOC283028  region were associated with HSCR in the Han Chinese population. Additionally, the susceptibility of SNPs in the  LINC01518-LOC283028  region were associated with the expression levels of nearby genes. These results provide new insight into the pathogenesis of HSCR.

Association of Variants in PLD1, 3p24.1, and 10q11.21 Regions With Hirschsprung’s Disease in Han Chinese Population