Genome-Wide Association Study Identifies a Locus at 17p13 to Be Associated With Intestinal Malrotation

Intestinal malrotation is a congenital malformation of the embryonic gut that may cause midgut volvulus either in children or adults. Our understanding of its genetic background stems from reports of syndromic or familial forms and no genome-wide association studies (GWAS) have been reported. We perform the first GWAS to identify common variants associated with this malformation.

Subjects were enrolled and genotyped as part of the Mass General Brigham Biobank and individuals with diagnosis of intestinal malrotation were identified. Single nucleotide polymorphisms (SNPs) with minor allele frequency ≥ 5% were examined for association with intestinal malrotation using mixed linear model association analysis. SNPs that surpassed the significance threshold (p < 5E-08) were further examined in a separate validation cohort.

The derivation cohort included 11,106 individuals (70 [0.6%] cases), and the validation cohort included 4134 individuals (21 [0.5%] cases). Five exonic SNPs in two loci at chromosomes 17p13 (lead SNP rs75147837, beta = 0.0044, and p = 7.97E-10) and 10q26 (lead SNP rs3121846, beta = 0.0057, p = 3.28E-08) had p < 5E-08. After validation, 2 SNPs at 17p13 were associated with the phenotype (rs72631499 adjusted-p = 0.010 and rs148094507 adjusted-p = 0.014). eQTL (expression Quantitative Trait Loci) analysis mapped 6 genes to the identified locus (PITPNA, TRARG1, INPP5K, YWHAE, PITPNA-AS1, and FAM57A).

We report results from the first GWAS on intestinal malrotation. A locus at 17p13 is associated with intestinal malrotation and may guide genetic guidance and improve our understanding of this malformation. Rs72631499 was found to be a binding site for HNF4A, a transcription factor that plays important roles in normal embryonic gut development.