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