Genome-wide association studies on Northern Italy isolated populations provide further support concerning genetic susceptibility for major depressive disorder

Objectives Major depressive disorder (MDD) is a psychiatric disorder with pathogenesis influenced by both genetic and environmental factors. To date, the molecular-level understanding of its aetiology remains unclear. Thus, we aimed to identify genetic variants and susceptibility genes for MDD with a genome-wide association study (GWAS) approach. Methods We performed a meta-analysis of GWASs and a gene-based analysis on two Northern Italy isolated populations (cases/controls n = 166/472 and 33/320), followed by replication and polygenic risk score (PRS) analyses in Italian independent samples (cases n = 464, controls n = 339). Results We identified two novel MDD-associated genes, KCNQ5 (lead SNP rs867262, p = 3.82 x 10(-9)) and CTNNA2 (rs6729523, p = 1.25 x 10(-8)). The gene-based analysis revealed another six genes (p < 2.703 x 10(-6)): GRM7, CTNT4, SNRK, SRGAP3, TRAPPC9, and FHIT. No replication of the genome-wide significant SNPs was found in the independent cohort, even if 14 SNPs around CTNNA2 showed association with MDD and related phenotypes at the nominal level of p (