{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Friligkou E"],"funding":["One Mind","NIMH NIH HHS"],"pagination":["e145"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12094657"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["55"],"pubmed_abstract":["<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<sup>-8</sup>), Alzheimer's disease-amyloid secretase (<i>p</i> = 4 × 10<sup>-4</sup>), oxytocin receptor-mediated signaling (<i>p</i> = 1.47 × 10<sup>-3</sup>), metabotropic glutamate receptor group III (<i>p</i> = 5.82 × 10<sup>-4</sup>) and Wnt signaling (<i>p</i> = 1.61 × 10<sup>-11</sup>). Pleiotropic loci demonstrated the strongest enrichment in the brain cortex (<i>p</i> = 5.8 × 10<sup>-28</sup>), frontal cortex (<i>p</i> = 3 × 10<sup>-31</sup>), and cerebellar hemisphere (<i>p</i> = 9.8 × 10<sup>-28</sup>). 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<sup>-5</sup>; week 17, <i>p</i> = 6.36 × 10<sup>-4</sup>) and first year of life (<i>p</i> = 3.25 × 10<sup>-5</sup>).<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."],"journal":["Psychological medicine"],"pubmed_title":["Characterizing pleiotropy among bipolar disorder, schizophrenia, and major depression: a genome-wide cross-disorder meta-analysis."],"pmcid":["PMC12094657"],"funding_grant_id":["RF1 MH132337"],"pubmed_authors":["Tylee DS","De Lillo A","Pathak GA","Koller D","Friligkou E","Cabrera-Mendoza B","Polimanti R"],"additional_accession":[]},"is_claimable":false,"name":"Characterizing pleiotropy among bipolar disorder, schizophrenia, and major depression: a genome-wide cross-disorder meta-analysis.","description":"<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<sup>-8</sup>), Alzheimer's disease-amyloid secretase (<i>p</i> = 4 × 10<sup>-4</sup>), oxytocin receptor-mediated signaling (<i>p</i> = 1.47 × 10<sup>-3</sup>), metabotropic glutamate receptor group III (<i>p</i> = 5.82 × 10<sup>-4</sup>) and Wnt signaling (<i>p</i> = 1.61 × 10<sup>-11</sup>). Pleiotropic loci demonstrated the strongest enrichment in the brain cortex (<i>p</i> = 5.8 × 10<sup>-28</sup>), frontal cortex (<i>p</i> = 3 × 10<sup>-31</sup>), and cerebellar hemisphere (<i>p</i> = 9.8 × 10<sup>-28</sup>). 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<sup>-5</sup>; week 17, <i>p</i> = 6.36 × 10<sup>-4</sup>) and first year of life (<i>p</i> = 3.25 × 10<sup>-5</sup>).<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.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 May","modification":"2026-04-08T19:01:01.214Z","creation":"2026-04-08T11:27:04.424Z"},"accession":"S-EPMC12094657","cross_references":{"pubmed":["40357923"],"doi":["10.1017/S0033291725001217"]}}