2025/11/13 by John Shorter, Joëlle A. Pasman, Siim Kurvits +29 · 1 voice
Biochemistry, Genetics and Molecular Biology · Psychology · Neuroscience · #Genetic Associations and Epidemiology #Cognitive Abilities and Testing #Neurotransmitter Receptor Influence on Behavior
paper · pdf · doi:10.1038/s41588-025-02396-8
openalex publication_date 2025/11/13 · openalex created_date 2025/11/13 · openalex updated_date 2026/07/31
Abstract Major depressive disorder (MDD) is a common and heterogeneous disorder of complex etiology. Studying more homogeneous groups stratified according to clinical characteristics, such as age of onset, can improve the identification of the underlying genetic causes and lead to more targeted treatment strategies. We leveraged Nordic biobanks with longitudinal health registries to investigate differences in the genetic architectures of early-onset (eoMDD; n = 46,708 cases) and late-onset (loMDD; n = 37,168 cases) MDD. We identified 12 genomic loci for eoMDD and two for loMDD. Overall, the two MDD subtypes correlated moderately (genetic correlation, r g = 0.58) and differed in their genetic correlations with related traits. These findings suggest that eoMDD and loMDD have partially distinct genetic signatures, with a specific developmental brain signature for eoMDD. Importantly, we demonstrate that polygenic risk scores (PRS) for eoMDD predict suicide attempts within the first 10 years after the initial diagnosis: the absolute risk for suicide attempt was 26% in the top PRS decile, compared to 12% and 20% in the bottom decile and the intermediate group, respectively. Taken together, our findings can inform precision psychiatry approaches for MDD.