Coexistence of Multiple Functional Variants and Genes Underlies Genetic Risk Locus 11p11.2 of Alzheimer’s Disease

生物 遗传学 染色质 基因座(遗传学) 基因 全基因组关联研究 表观遗传学 等位基因 表观遗传学 功能基因组学 DNA甲基化 基因组学 基因组 单核苷酸多态性 基因表达 基因型
作者
Min Xu,Qianjin Liu,Rui Bi,Yu Li,Hongli Li,Wei-Bo Kang,Zhongjiang Yan,Quanzhen Zheng,Chunli Sun,Maosen Ye,Bo-Lin Xiang,Xiong‐Jian Luo,Ming Li,Dengfeng Zhang,Yong‐Gang Yao
出处
期刊:Biological Psychiatry [Elsevier]
卷期号:94 (9): 743-759 被引量:9
标识
DOI:10.1016/j.biopsych.2023.05.020
摘要

Genome-wide association studies have identified dozens of genetic risk loci for Alzheimer's disease (AD), yet the underlying causal variants and biological mechanisms remain elusive, especially for loci with complex linkage disequilibrium and regulation.To fully untangle the causal signal at a single locus, we performed a functional genomic study of 11p11.2 (the CELF1/SPI1 locus). Genome-wide association study signals at 11p11.2 were integrated with datasets of histone modification, open chromatin, and transcription factor binding to distill potentially functional variants (fVars). Their allelic regulatory activities were confirmed by allele imbalance, reporter assays, and base editing. Expressional quantitative trait loci and chromatin interaction data were incorporated to assign target genes to fVars. The relevance of these genes to AD was assessed by convergent functional genomics using bulk brain and single-cell transcriptomic, epigenomic, and proteomic datasets of patients with AD and control individuals, followed by cellular assays.We found that 24 potential fVars, rather than a single variant, were responsible for the risk of 11p11.2. These fVars modulated transcription factor binding and regulated multiple genes by long-range chromatin interactions. Besides SPI1, convergent evidence indicated that 6 target genes (MTCH2, ACP2, NDUFS3, PSMC3, C1QTNF4, and MADD) of fVars were likely to be involved in AD development. Disruption of each gene led to cellular amyloid-β and phosphorylated tau changes, supporting the existence of multiple likely causal genes at 11p11.2.Multiple variants and genes at 11p11.2 may contribute to AD risk. This finding provides new insights into the mechanistic and therapeutic challenges of AD.
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