Askarova Aydan, Yaa Reuben M, Marzi Sarah J, Nott Alexi
Department of Brain Sciences, Imperial College London, London, United Kingdom.
United Kingdom Dementia Research Institute, Imperial College London, London, United Kingdom.
PLoS Genet. 2025 Apr 9;21(4):e1011407. doi: 10.1371/journal.pgen.1011407. eCollection 2025 Apr.
Genome-wide association studies have identified thousands of common variants associated with an increased risk of neurodegenerative disorders. However, the noncoding localization of these variants has made the assignment of target genes for brain cell types challenging. Genomic approaches that infer chromosomal 3D architecture can link noncoding risk variants and distal gene regulatory elements such as enhancers to gene promoters. By using enhancer-to-promoter interactome maps for human microglia, neurons, and oligodendrocytes, we identified cell-type-specific enrichment of genetic heritability for brain disorders through stratified linkage disequilibrium score regression. Our analysis suggests that genetic heritability for multiple neurodegenerative disorders is enriched at microglial chromatin contact sites, while schizophrenia heritability is predominantly enriched at chromatin contact sites in neurons followed by oligodendrocytes. Through Hi-C coupled multimarker analysis of genomic annotation (H-MAGMA), we identified disease risk genes for Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis and schizophrenia. We found that disease-risk genes were overrepresented in microglia compared to other brain cell types across neurodegenerative conditions and within neurons for schizophrenia. Notably, the microglial risk genes and pathways identified were largely specific to each disease. Our findings reinforce microglia as an important, genetically informed cell type for therapeutic interventions in neurodegenerative conditions and highlight potentially targetable disease-relevant pathways.
全基因组关联研究已经确定了数千种与神经退行性疾病风险增加相关的常见变异。然而，这些变异的非编码定位使得确定脑细胞类型的靶基因具有挑战性。推断染色体三维结构的基因组方法可以将非编码风险变异和远端基因调控元件（如增强子）与基因启动子联系起来。通过使用人类小胶质细胞、神经元和少突胶质细胞的增强子到启动子相互作用组图谱，我们通过分层连锁不平衡评分回归确定了脑部疾病遗传力的细胞类型特异性富集。我们的分析表明，多种神经退行性疾病的遗传力在小胶质细胞染色质接触位点富集，而精神分裂症的遗传力主要在神经元的染色质接触位点富集，其次是少突胶质细胞。通过基因组注释的Hi-C耦合多标记分析（H-MAGMA），我们确定了阿尔茨海默病、帕金森病、多发性硬化症、肌萎缩侧索硬化症和精神分裂症的疾病风险基因。我们发现，在神经退行性疾病中，与其他脑细胞类型相比，小胶质细胞中的疾病风险基因占比过高，而在精神分裂症中，神经元中的疾病风险基因占比过高。值得注意的是，所确定的小胶质细胞风险基因和通路在很大程度上因疾病而异。我们的研究结果强化了小胶质细胞作为神经退行性疾病治疗干预中一种重要的、具有遗传信息的细胞类型，并突出了潜在的可靶向疾病相关通路。
