Zhao Qiyu, Wang Shuo, Xiong Di, Liu Mengge, Zhang Yujie, Zhao Guoshu, Zhao Jiaxuan, Shi Ziqing, Zhang Zhihui, Lei Minghuan, Zhai Ying, Xu Jinglei, Hao Xiaoke, Li Shen, Liu Feng
Department of Radiology, Tianjin Key Lab of Functional Imaging & Tianjin Institute of Radiology, Tianjin Medical University General Hospital, Tianjin, 300052, China.
Department of Medical Ultrasound, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Abdominal Medical Imaging, Jinan, 250013, Shandong, China.
Mol Psychiatry. 2025 Feb 19. doi: 10.1038/s41380-025-02932-2.
Depression, a complex and heritable psychiatric disorder, is associated with alterations in white matter microstructure, yet their shared genetic basis remains largely unclear. Utilizing the largest available genome-wide association study (GWAS) datasets for depression (N = 674,452) and white matter microstructure (N = 33,224), assessed through diffusion tensor imaging metrics such as fractional anisotropy (FA) and mean diffusivity (MD), we employed linkage disequilibrium score regression method to estimate global genetic correlations, local analysis of [co]variant association approach to pinpoint genomic regions with local genetic correlations, and conjunctional false discovery rate analysis to identify shared variants. Our findings revealed that depression showed significant local genetic correlations with FA in 37 genomic regions and with MD in 59 regions, while global genetic correlations were weak. Variant-level analysis identified 78 distinct loci jointly associated with depression (25 novel loci) and FA (35 novel loci), and 41 distinct loci associated with depression (17 novel loci) and MD (25 novel loci). Further analyses showed that these shared loci exhibited both concordant and discordant effect directions between depression and white matter traits, as well as distinct yet overlapping hemispheric patterns in their genetic architecture. Enrichment analysis of these shared loci implicated biological processes related to metabolism and regulation. This study provides evidence of a mixed-direction shared genetic architecture between depression and white matter microstructure. The identification of specific loci and pathways offers potential insights for developing targeted interventions to improve white matter integrity and alleviate depressive symptoms.
抑郁症是一种复杂的遗传性精神疾病，与白质微观结构改变有关，但其共同的遗传基础仍不清楚。利用现有的最大规模抑郁症全基因组关联研究（GWAS）数据集（N = 674,452）和通过扩散张量成像指标（如分数各向异性（FA）和平均扩散率（MD））评估的白质微观结构数据集（N = 33,224），我们采用连锁不平衡评分回归方法估计全局遗传相关性，采用[共]变量关联方法进行局部分析以确定具有局部遗传相关性的基因组区域，并采用联合错误发现率分析来识别共享变异。我们的研究结果表明，抑郁症在37个基因组区域与FA以及在59个区域与MD存在显著的局部遗传相关性，而全局遗传相关性较弱。变异水平分析确定了78个与抑郁症（25个新位点）和FA（35个新位点）共同相关的不同位点，以及41个与抑郁症（17个新位点）和MD（25个新位点）相关的不同位点。进一步分析表明，这些共享位点在抑郁症和白质特征之间表现出一致和不一致的效应方向，以及在其遗传结构中不同但重叠的半球模式。对这些共享位点的富集分析涉及与代谢和调节相关的生物学过程。本研究提供了抑郁症和白质微观结构之间混合方向共享遗传结构的证据。特定位点和途径的识别为开发有针对性的干预措施以改善白质完整性和减轻抑郁症状提供了潜在的见解。
