biostudies-literatureFriligkou EOne MindNIMH NIH HHSe145https://www.ebi.ac.uk/biostudies/studies/S-EPMC12094657biostudies-literatureUnknown55<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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 (<i>p</i> = 2.18 × 10^-8), Alzheimer's disease-amyloid secretase (<i>p</i> = 4 × 10^-4), oxytocin receptor-mediated signaling (<i>p</i> = 1.47 × 10^-3), metabotropic glutamate receptor group III (<i>p</i> = 5.82 × 10^-4) and Wnt signaling (<i>p</i> = 1.61 × 10^-11). Pleiotropic loci demonstrated the strongest enrichment in the brain cortex (<i>p</i> = 5.8 × 10^-28), frontal cortex (<i>p</i> = 3 × 10^-31), and cerebellar hemisphere (<i>p</i> = 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, <i>p</i> = 7.35 × 10^-5; week 17, <i>p</i> = 6.36 × 10^-4) and first year of life (<i>p</i> = 3.25 × 10^-5).<h4>Conclusions</h4>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.Psychological medicineCharacterizing pleiotropy among bipolar disorder, schizophrenia, and major depression: a genome-wide cross-disorder meta-analysis.PMC12094657RF1 MH132337Tylee DSDe Lillo APathak GAKoller DFriligkou ECabrera-Mendoza BPolimanti RfalseCharacterizing pleiotropy among bipolar disorder, schizophrenia, and major depression: a genome-wide cross-disorder meta-analysis.<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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 (<i>p</i> = 2.18 × 10^-8), Alzheimer's disease-amyloid secretase (<i>p</i> = 4 × 10^-4), oxytocin receptor-mediated signaling (<i>p</i> = 1.47 × 10^-3), metabotropic glutamate receptor group III (<i>p</i> = 5.82 × 10^-4) and Wnt signaling (<i>p</i> = 1.61 × 10^-11). Pleiotropic loci demonstrated the strongest enrichment in the brain cortex (<i>p</i> = 5.8 × 10^-28), frontal cortex (<i>p</i> = 3 × 10^-31), and cerebellar hemisphere (<i>p</i> = 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, <i>p</i> = 7.35 × 10^-5; week 17, <i>p</i> = 6.36 × 10^-4) and first year of life (<i>p</i> = 3.25 × 10^-5).<h4>Conclusions</h4>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.2025-01-01T00:00:00Z2025 May2026-04-08T19:01:01.214Z2026-04-08T11:27:04.424ZS-EPMC120946574035792310.1017/S0033291725001217