Genome-wide association analyses identify distinct genetic architectures for early-onset and late-onset depression

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<sub>g</sub> = 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.

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Publication Details

Journal
Nature Genetics
Published
2025-11-13
DOI
https://doi.org/10.1038/s41588-025-02396-8
Citations
4
Primary Topic
Genetic Associations and Epidemiology
Type
article
Field-Weighted Citation Impact
7.27

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article

Genome-wide association analyses identify distinct genetic architectures for early-onset and late-onset depression

Arvid Harder, Ted Reichborn‐Kjennerud, Yi Lu, Alkistis Skalkidou et al.
4 citations
Nature Genetics
Genetic Associations and Epidemiology
7.27
article

Genome-wide association analyses identify distinct genetic architectures for early-onset and late-onset depression

Arvid Harder, Ted Reichborn‐Kjennerud, Yi Lu, Alkistis Skalkidou, Ole A. Andreassen, Mikael Landén, Jacob Bergstedt, Kelli Lehto, Espen Hagen, Joeri Meijsen, Alfonso Buil, John Shorter, Thomas Werge, Jesper R. Gådin, John Wallert, Iiris Hovatta, Martin Tesli, Andreas Jangmo, Siim Kurvits, Patrick F. Sullivan, Elise Koch, Joëlle A. Pasman, Sara Hägg, Christian Rück, Kaarina Kowalec, Joonas Naamanka, Oleksandr Frei, Bayram Cevdet Akdeniz, Ying Xiong, Richard Zetterberg, Nelli Frilander
article en
4 citations

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<sub>g</sub> = 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.

Nature GeneticsVol. 57(12)
Roskilde University (DK), University of North Carolina at Chapel Hill (US), Uppsala University (SE), University of Copenhagen (DK), Oslo University Hospital (NO), Norwegian Institute of Public Health (NO), University of Helsinki (FI), University of Oslo (NO), Sankt Hans Hospital (DK), Mental Health Services (DK), Karolinska Institutet (SE), Central Institute of Mental Health (DE), Diakonhjemmet Hospital (NO), Stockholm Health Care Services (SE), Amsterdam University Medical Centers (NL), Østfold Hospital Trust (NO), University of Manitoba (CA), University of Tartu (EE), University of Gothenburg (SE), University of Amsterdam (NL)
Bristol-Myers Squibb, Pfizer, AstraZeneca, GlaxoSmithKline, Sanofi, Biogen, Celgene, Maze Therapeutics, European Commission, Stiftelsen för Strategisk Forskning, Eesti Teadusagentuur, Helse- og Omsorgsdepartementet, Karolinska Institutet, Vetenskapsrådet, NordForsk, Universitetet i Oslo, Norges Forskningsråd, Forskningsrådet om Hälsa, Arbetsliv och Välfärd, Tartu Ülikool, Business Finland, Genentech, European Regional Development Fund, Uppsala Multidisciplinary Center for Advanced Computational Science
Openalex Percentile: Top 3%
Genetic Associations and Epidemiology
7.27
DOIOpen Access PDFOpenAlex
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