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

## TL;DR

This study explores the genetic basis of major depressive disorder in a Dutch population, identifying a new genetic locus and showing how harmonized data can improve genetic risk prediction.

## Contribution

The study identifies a novel genome-wide significant locus in PALMD and demonstrates the value of harmonized phenotyping in uncovering MDD's genetic architecture.

## Key findings

- A novel genome-wide significant locus in PALMD was identified and confirmed.
- Polygenic scores from BIONIC and PGC-MD predicted MDD across populations with minimal confounding.
- Twin concordance for MDD increased with polygenic burden, supporting genetic influence.

## Abstract

Harmonized phenotyping and diverse population-specific studies are crucial for advancing gene discovery in psychiatric genetics. We conducted a genome-wide association study (GWAS) 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 = 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 UKBiobank, 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.