Ma Yunlong, Jiang Dingping, Li Jingjing, Zheng Gongwei, Deng Yao, Gou Xuanxuan, Gao Shuaishuai, Chen Cheng, Zhou Yijun, Zhang Yaru, Deng Chunyu, Yao Yinghao, Han Haijun, Su Jianzhong
Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Transl Psychiatry. 2025 Jan 25;15(1):24. doi: 10.1038/s41398-025-03243-4.
Advancements in single-cell multimodal techniques have greatly enhanced our understanding of disease-relevant loci identified through genome-wide association studies (GWASs). To investigate the biological connections between the eye and brain, we integrated bulk and single-cell multiomic profiles with GWAS summary statistics for eight neuropsychiatric and five ocular diseases. Our analysis uncovered five latent factors explaining 61.7% of the genetic variance across these 13 diseases, revealing diverse correlational patterns among them. We identified 45 pleiotropic loci with 91 candidate genes that contribute to disease risk. By integrating GWAS and single-cell profiles, we implicated excitatory neurons and microglia as key contributors in the eye-brain connections. Polygenic enrichment analysis further identified 15 pleiotropic regulons in excitatory neurons and 16 in microglia that were linked to comorbid conditions. Functionally, excitatory neuron-specific regulons were involved in axon guidance and synaptic activity, while microglia-specific regulons were associated with immune response and cell activation. In sum, these findings underscore the genetic link between psychiatric disorders and ocular diseases.
单细胞多模态技术的进步极大地增进了我们对通过全基因组关联研究（GWAS）确定的疾病相关基因座的理解。为了研究眼睛和大脑之间的生物学联系，我们将大量和单细胞多组学图谱与8种神经精神疾病和5种眼部疾病的GWAS汇总统计数据进行了整合。我们的分析发现了5个潜在因素，解释了这13种疾病中61.7%的遗传变异，揭示了它们之间不同的相关模式。我们确定了45个多效性基因座，其中有91个候选基因与疾病风险有关。通过整合GWAS和单细胞图谱，我们发现兴奋性神经元和小胶质细胞是眼脑连接中的关键因素。多基因富集分析进一步确定了兴奋性神经元中有15个多效性调控子，小胶质细胞中有16个多效性调控子与共病状况有关。在功能上，兴奋性神经元特异性调控子参与轴突导向和突触活动，而小胶质细胞特异性调控子与免疫反应和细胞激活有关。总之，这些发现强调了精神疾病和眼部疾病之间的遗传联系。
