Genetics of Major Depressive Disorder in a Homogeneous Population with Uniform Phenotyping

Harmonized phenotyping and diverse population-specific studies are crucial for advancing gene discovery in psychiatric genetics. We conducted a genome-wide association (GWAS) mega-analysis of DSM-defined lifetime major depressive disorder (MDD) in 64 941 participants (25.7% cases) from the Dutch BIObanks Netherlands Internet Collaboration (BIONIC) consortium. SNP-based heritability was estimated at 13.4%, exceeding recent global meta-analyses, with a high genetic correlation ( r _G = 0.89) to the latest major depression GWAS by the Psychiatric Genetics Consortium (PGC-MD). We identified a novel genome-wide significant locus in PALMD ( p = 3.26 × 10⁻⁸), that was confirmed by GWAS-by-subtraction. Polygenic scores (PGSs) based on BIONIC predicted MDD in UK Biobank, and PGSs from PGC-MD predicted into BIONIC, with within-family analyses indicating minimal confounding. Genetic causal inference revealed associations with over 30 phenotypes. Twin concordance for MDD increased with polygenic burden, reinforcing its genetic architecture. This study emphasizes the power of harmonized phenotyping and regional biobanks in uncovering the genetic architecture of MDD, highlighting the value of population-specific studies for improving risk prediction and advancing psychiatric genetics.