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 ( = 2.18 × 10), Alzheimer's disease-amyloid secretase ( = 4 × 10), oxytocin receptor-mediated signaling ( = 1.47 × 10), metabotropic glutamate receptor group III ( = 5.82 × 10) and Wnt signaling ( = 1.61 × 10). Pleiotropic loci demonstrated the strongest enrichment in the brain cortex ( = 5.8 × 10), frontal cortex ( = 3 × 10), and cerebellar hemisphere ( = 9.8 × 10). SCZ-BP-MDD pleiotropic variants were also enriched for neurodevelopmental brain transcriptomic profiles related to the second-trimester post-conception (week 21,  = 7.35 × 10; week 17,  = 6.36 × 10) and first year of life ( = 3.25 × 10).

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.