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

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 etiology remains unclear. Thus, we aimed to identify genetic variants and susceptibility genes for MDD with a genome-wide study (GWAS) approach. 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). We identified two novel MDD associated genes, <i>KCNQ5</i> (lead SNP rs867262, p = 3.82 × 10⁻⁹) and <i>CTNNA2</i> (rs6729523, p = 1.25 × 10⁻⁸). The gene-based analysis revealed another six genes (p &lt; 2.703 × 10⁻⁶): <i>GRM7</i>, <i>CTNT4</i>, <i>SNRK</i>, <i>SRGAP3</i>, <i>TRAPPC9</i> and <i>FHIT</i>. No replication of the genome-wide significant SNPs was found in the independent cohort, even if 14 SNPs around <i>CTNNA2</i> showed association with MDD and related phenotypes at the nominal level of p (&lt;0.05). Furthermore, the PRS model developed on discovery cohort discriminated cases and controls in the replication cohort. Our work suggests new possible genes associated with MDD, and the PRS analysis confirms the polygenic nature of this disorder. Future studies are required to better understand the role of these findings in MDD.