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

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.