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Meta-Analysis
. 2025 May 13:55:e145.
doi: 10.1017/S0033291725001217.

Characterizing pleiotropy among bipolar disorder, schizophrenia, and major depression: a genome-wide cross-disorder meta-analysis

Eleni Friligkou  1   2 , Gita A Pathak  1   3 , Daniel S Tylee  1   3 , Antonella De Lillo  1   4 , Dora Koller  1   3   5 , Brenda Cabrera-Mendoza  1   3 , Renato Polimanti  1   3
Affiliations
Meta-Analysis

Characterizing pleiotropy among bipolar disorder, schizophrenia, and major depression: a genome-wide cross-disorder meta-analysis

Eleni Friligkou et al. Psychol Med. .

Abstract

Background: To understand the pathogenetic mechanisms shared among schizophrenia (SCZ), bipolar disorder (BP), and major depression (MDD), we investigated the pleiotropic mechanisms using large-scale genome-wide and brain transcriptomic data.

Methods: We analyzed SCZ, BP, and MDD genome-wide association datasets available from the Psychiatric Genomics Consortium using the PLEIO framework and characterized the pleiotropic loci identified using pathway and tissue enrichment analyses. Pleiotropic and disorder-specific loci were also assessed.

Results: Our pleiotropy-informed genome-wide analysis identified 553 variants that included 192 loci not reaching genome-wide significance in input datasets. These were enriched for five molecular pathways: cadherin signaling (p = 2.18 × 10-8), Alzheimer's disease-amyloid secretase (p = 4 × 10-4), oxytocin receptor-mediated signaling (p = 1.47 × 10-3), metabotropic glutamate receptor group III (p = 5.82 × 10-4) and Wnt signaling (p = 1.61 × 10-11). Pleiotropic loci demonstrated the strongest enrichment in the brain cortex (p = 5.8 × 10-28), frontal cortex (p = 3 × 10-31), and cerebellar hemisphere (p = 9.8 × 10-28). SCZ-BP-MDD pleiotropic variants were also enriched for neurodevelopmental brain transcriptomic profiles related to the second-trimester post-conception (week 21, p = 7.35 × 10-5; week 17, p = 6.36 × 10-4) and first year of life (p = 3.25 × 10-5).

Conclusions: Genetic mechanisms shared among SCZ, BP, and MDD appear to be related to early neuronal development. Because the genetic architecture of psychopathology transcends diagnostic boundaries, pleiotropy-focused analyses can lead to increased gene discovery and novel insights into relevant pathogenic mechanisms.

Keywords: bipolar disorder; depression; genetic correlation; genome-wide association study; pleiotropy; schizophrenia.

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Conflict of interest statement

R.P. received an honorarium from Karger Publishers for his work on Complex Psychiatry and a research grant from Alkermes outside the scope of this manuscript. D.K. is the founder and CEO of EndoCare Therapeutics. The remaining authors declare no competing interests exist.

Figures

Figure 1.
Figure 1.
(a) Statistically overrepresented pathways based on the genome-wide pleiotropy among schizophrenia (SCZ), bipolar disorder (BP), and major depressive disorder (MDD). (b) Pathway enrichment analysis by subgroups.
Figure 2.
Figure 2.
(a) Tissue-specific enrichments for the genome-wide pleiotropy statistics. (b) Temporal enrichments of the genome-wide pleiotropy statistics for 29 brain development stages.
Figure 3.
Figure 3.
Distribution of statistically significant pleiotropic variants by disease-specific effect.
See this image and copyright information in PMC

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