Functional regulatory variants implicate distinct transcriptional networks in dementia
Functional regulatory variants implicate distinct transcriptional networks in dementia
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DOI：
10.1126/science.abi8654
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发表时间：
2022-08-19
期刊：
影响因子：
56.9
通讯作者：
Geschwind, Daniel H.
中科院分区：
文献类型：
--
作者：
Cooper, Yonatan A.;Teyssier, Noam;Geschwind, Daniel H.
预测非编码变异的功能是现代遗传学的一大挑战。在这项研究中，我们使用大规模平行报告分析来筛选从阿尔茨海默病(AD)和进行性核上性麻痹(PSP)的全基因组关联研究中识别的5706个变异，鉴定了27个基因座的320个功能调节变异(FrVars)，包括复杂的17q21.31区域。我们通过CRISPR干扰或切除来识别和验证多个风险基因，包括AD中的补体4(C4a)和APOC1，以及PSP中的PLEKHM1和KANSL1。在PSP和AD中，功能变异体破坏转录因子结合位点，使其聚集在具有细胞类型特异性活性的增强子上，暗示在PSP发病机制中存在神经SP1驱动的调控网络。这些分析表明，非编码遗传风险是由常见的遗传变异通过它们在特定转录程序上的聚合活动来驱动的。
Predicting the function of noncoding variation is a major challenge in modern genetics. In this study, we used massively parallel reporter assays to screen 5706 variants identified from genome-wide association studies for both Alzheimer's disease (AD) and progressive supranuclear palsy (PSP), identifying 320 functional regulatory variants (frVars) across 27 loci, including the complex 17q21.31 region. We identified and validated multiple risk loci using CRISPR interference or excision, including complement 4 (C4A) and APOC1 in AD and PLEKHM1 and KANSL1 in PSP. Functional variants disrupt transcription factor binding sites converging on enhancers with cell type-specific activity in PSP and AD, implicating a neuronal SP1-driven regulatory network in PSP pathogenesis. These analyses suggest that noncoding genetic risk is driven by common genetic variants through their aggregate activity on specific transcriptional programs.