研究人员用大规模平行报告试验筛选了5706个从全基因组关联研究中发现的，阿尔茨海默病（AD）和进行性核上性麻痹（PSP）变体，在27个基因座中发现了320个功能调节变体（frVars），包括复杂的17q21.31区域。研究人员用CRISPR干扰或切除来鉴定并验证了多个风险位点，包括AD中的补体4（C4A）和APOC1，PSP中的PLEKHM1和KANSL1。功能性变体破坏了PSP和AD中具有细胞类型特异性活跃增强子的转录因子结合位点，暗示神经元SP1驱动的调控网络在PSP的发病机制中。
这些分析表明，非编码遗传风险是由常见的遗传变异体通过其对特定转录程序的聚集活性驱动的。
据介绍，预测非编码变异的功能是现代遗传学的一个主要挑战。
附：英文原文
Title: Functional regulatory variants implicate distinct transcriptional networks in dementia
Author: Yonatan A. Cooper, Noam Teyssier, Nina M. Drger, Qiuyu Guo, Jessica E. Davis, Sydney M. Sattler, Zhongan Yang, Abdulsamie Patel, Sarah Wu, Sriram Kosuri, Giovanni Coppola, Martin Kampmann, Daniel H. Geschwind
Issue&Volume: 2022-08-19
Abstract: 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.
DOI: abi8654
Source: https://www.science.org/doi/10.1126/science.abi8654