Friligkou Eleni, Pathak Gita A, Tylee Daniel S, De Lillo Antonella, Koller Dora, Cabrera-Mendoza Brenda, Polimanti Renato
Department of Psychiatry, Yale School of Medicine, West Haven, CT, USA.
Aristotle University of Thessaloniki, Thessaloniki, Greece.
Psychol Med. 2025 May 13;55:e145. doi: 10.1017/S0033291725001217.
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.
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.
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).
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.
为了解精神分裂症（SCZ）、双相情感障碍（BP）和重度抑郁症（MDD）之间共有的致病机制，我们使用大规模全基因组和脑转录组数据研究了多效性机制。
我们使用PLEIO框架分析了精神疾病基因组学联盟提供的SCZ、BP和MDD全基因组关联数据集，并通过通路和组织富集分析对鉴定出的多效性位点进行了表征。还评估了多效性和疾病特异性位点。
我们基于多效性的全基因组分析确定了553个变异，其中包括192个在输入数据集中未达到全基因组显著性的位点。这些变异在五个分子通路中富集：钙黏蛋白信号通路（=2.18×10）、阿尔茨海默病-淀粉样前体蛋白切割酶通路（=4×10）、催产素受体介导的信号通路（=1.47×10）、代谢型谷氨酸受体III组通路（=5.82×10）和Wnt信号通路（=1.61×10）。多效性位点在大脑皮层（=5.8×10）、额叶皮层（=3×10）和小脑半球（=9.8×10）中表现出最强的富集。SCZ-BP-MDD多效性变异在与孕中期（妊娠21周，=7.35×10；妊娠17周，=6.36×10）和出生后第一年（=3.25×10）相关的神经发育脑转录组图谱中也有富集。
SCZ、BP和MDD之间共有的遗传机制似乎与早期神经元发育有关。由于精神病理学的遗传结构跨越诊断界限，聚焦多效性的分析可以增加基因发现，并为相关致病机制提供新的见解。
