A Genome-wide Association Study Reveals a Novel Susceptibility Locus for Pancreas Divisum at 3q29

Introduction

Pancreas divisum (PD) is a common congenital anomaly of the pancreas, but its genetic basis remains unknown. The purpose of this genome-wide association study was to identify genetic loci associated with PD.

Methods

Using the Mass General Brigham Biobank, patients diagnosed with PD were identified. Quality control and imputation were performed using standard approaches. Single nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) ≥ 5% were tested for association with PD using mixed linear model-based association analysis. The significance threshold was set at 5 × 10⁻⁸.

Results

A total of 13,940 subjects were included, of which 251 (1.8%) were diagnosed with PD. A genetic locus in chromosome 3q29 was found to be associated with PD (lead SNP rs3850646, MAF_PD = 34.6% vs. MAF_controls = 26.4%, beta = 0.0106, P = 1.47 × 10⁻⁸). The identified locus is located in the phosphatidylinositol glycan anchor biosynthesis class Xand p21 activated kinase 2genes. The heritability of PD was estimated at 27.5%. (Expression quantitative trait loci) and chromatin interaction analysis found 12 genes whose expression may be regulated by SNPs in this genomic locus.

Conclusions

The results of this study suggest that a genetic locus at 3q29 is associated with PD. This locus is in the phosphatidylinositol glycan anchor biosynthesis class X and p21 activated kinase 2 genes. Twelve candidate genes were identified whose expression may be regulated by this locus. These findings may help us understand both normal and aberrant pancreatic development and may aid in clinical evaluation and genetic counseling of patients with PD and associated diseases, such as acute pancreatitis.