| Coexistence of Multiple Functional Variants and Genes Underlies Genetic Risk Locus 11p11.2 of Alzheimer's Disease |
| Xu, M; Liu, QJ; Bi, R; Li, Y; Li, HL; Kang, WB; Yan, ZJ; Zheng, QZ; Sun, CL; Ye, MS; Xiang, BL; Luo, XJ; Li, M; Zhang, DF ; Yao, YG
|
| 2023
|
| 发表期刊 | BIOLOGICAL PSYCHIATRY
 |
| ISSN | 0006-3223
|
| 卷号 | 94期号:9页码:743-759 |
| 摘要 | BACKGROUND: 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. METHODS: 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. RESULTS: 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-beta and phosphorylated tau changes, supporting the existence of multiple likely causal genes at 11p11.2. CONCLUSIONS: 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. |
| 收录类别 | SCI
|
| 语种 | 英语
|
| 文献类型 | 期刊论文
|
| 条目标识符 | http://ir.kiz.ac.cn/handle/152453/14029
|
| 专题 | 科研部门_疾病机理遗传学和进化医学学科组（姚永刚）
|
推荐引用方式
GB/T 7714 |
Xu, M,Liu, QJ,Bi, R,et al. Coexistence of Multiple Functional Variants and Genes Underlies Genetic Risk Locus 11p11.2 of Alzheimer's Disease[J]. BIOLOGICAL PSYCHIATRY,2023,94(9):743-759.
|
| APA |
Xu, M.,Liu, QJ.,Bi, R.,Li, Y.,Li, HL.,...&Yao, YG.(2023).Coexistence of Multiple Functional Variants and Genes Underlies Genetic Risk Locus 11p11.2 of Alzheimer's Disease.BIOLOGICAL PSYCHIATRY,94(9),743-759.
|
| MLA |
Xu, M,et al."Coexistence of Multiple Functional Variants and Genes Underlies Genetic Risk Locus 11p11.2 of Alzheimer's Disease".BIOLOGICAL PSYCHIATRY 94.9(2023):743-759.
|
修改评论