Divergent genetic architecture of depression and suicidal behavior: insights from polygenic risk scores

Introduction :

Major Depressive Disorder (MDD) is a known clinical contributor of suicide attempt, yet suicidal behavior cannot be fully explained by depression alone. Genetic studies demonstrate both shared and distinct heritable components of these two phenomena. The relationship between genetic risk and various psychiatric phenotypes can be investigated using polygenic risk scores (PRS) from large genome-wide association studies (GWAS).

We aimed to investigate how genetic liability, captured by PRS-s calculated from large-sample genetic studies for depression and suicide attempt is reflected in related clinical outcomes, and investigate how genetic liability for both phenomena shapes the risk, hypothesizing that these associations would differ in their explanatory relevance across depressive and suicidal phenotypes.

Methods :

We calculated PRS-s for depression and suicide attempt (SA) (PRS-MDD and PRS-SA, respectively) using genome-wide association (GWAS) study statistical summaries from Psychiatric Genomics Consortium studies, including large recent GWAS-s on major depression (688,808 cases and 4,364,225 controls) [1] as well as on suicide attempt (43,871 cases and 915,025 controls) [2].

In an independent target sample (NewMood) we analysed the effects of PRS-MDD and PRS-SA on lifetime suicide attempt, lifetime depression, and current suicidal ideation severity . Logistic and linear regression models were applied, adjusting for age and sex. Model performance was evaluated using ROC analysis, OR, p-value and Nagelkerke R².

Results:

MDD-PRS was significantly associated with lifetime depression (OR ≈ 1.19, p < 0.001, AUC ≈ 0.62) and lifetime suicide attempt (OR ≈ 1.25, p ≈ 0.002, AUC ≈ 0.56). MDD-PRS was also associated with current suicidal ideation (β ≈ 0.065, p ≈ 0.006, R² ≈ 1%). Suicide attempt PRS showed its strongest association with lifetime suicide attempt (p ≈ 0.004, AUC ≈ 0.57, R² ≈ 1%), but it showed a non-significant association with lifetime depression (AUC ≈ 0.50–0.52, p > 0.05). Only weak effects with marginal significance were detected for current suicidal ideation (β ≈ 0.045, p ≈ 0.056, R² ≈ 1%).

Conclusion:

We observed that genetic liability, measured by polygenic risk scores, is not consistently manifested across related psychiatric phenotypes. MDD-PRS showed consistent associations with both depressive and suicidal behavior outcomes, demonstrating stronger predictive efficacy for depression. The results also pointed to a gradient-like pattern of declining strength of associations between depression and suicidal behaviour phenotypes, with strongest effects for depression and weaker associations with suicide attempt and suicidal ideations. Suicide attempt PRS, on the other hand, showed more restricted and phenotype-specific effects, lacking an association with depression and modest association with suicidal ideation. This indicates that genetic liability for suicide attempt, captured by PRS may not be uniformly exhibited across related psychiatric phenotypes and does not mirror the strong clinical overlap typically observed between depression and suicidal behavior. Observed disparity suggests that genetic risk associated with depression represents a wider range of variation in clinical outcomes, whereas genetic liability specific to suicide attempt contributes in a more limited way. These findings contribute to clearer comprehension of the relationship between genetic risk and clinically significant phenotypes.

References

1. Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium. Electronic address: andrew.mcintosh@ed.ac.uk, & Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (2025). Trans-ancestry genome-wide study of depression identifies 697 associations implicating cell types and pharmacotherapies. Cell, 188(3), 640–652.e9. https://doi.org/10.1016/j.cell.2024.12.002
2. Docherty, A. R., Mullins, N., Ashley-Koch, A. E., Qin, X., Coleman, J. R. I., Shabalin, A., Kang, J., Murnyak, B., Wendt, F., Adams, M., Campos, A. I., DiBlasi, E., Fullerton, J. M., Kranzler, H. R., Bakian, A. V., Monson, E. T., Rentería, M. E., Walss-Bass, C., Andreassen, O. A., Behera, C., … Ruderfer, D. M. (2023). GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors. The American journal of psychiatry, 180(10), 723–738. https://doi.org/10.1176/appi.ajp.21121266