孟德尔随机化
生物
发病机制
蛋白质组
疾病
全基因组关联研究
计算生物学
遗传关联
人类基因组
遗传学
基因
生物信息学
基因组
单核苷酸多态性
免疫学
基因型
病理
遗传变异
医学
作者
Aliza P. Wingo,Yue Liu,Ekaterina S. Gerasimov,Jake Gockley,Benjamin A. Logsdon,Duc M. Duong,Eric B. Dammer,Chloe Robins,Thomas G. Beach,Eric M. Reiman,Michael P. Epstein,Philip L. De Jager,James J. Lah,David A. Bennett,Nicholas T. Seyfried,Aĺlan I. Levey
出处
期刊:Nature Genetics
[Springer Nature]
日期:2021-01-28
卷期号:53 (2): 143-146
被引量:155
标识
DOI:10.1038/s41588-020-00773-z
摘要
Genome-wide association studies (GWAS) have identified many risk loci for Alzheimer’s disease (AD)1,2, but how these loci confer AD risk is unclear. Here, we aimed to identify loci that confer AD risk through their effects on brain protein abundance to provide new insights into AD pathogenesis. To that end, we integrated AD GWAS results with human brain proteomes to perform a proteome-wide association study (PWAS) of AD, followed by Mendelian randomization and colocalization analysis. We identified 11 genes that are consistent with being causal in AD, acting via their cis-regulated brain protein abundance. Nine replicated in a confirmation PWAS and eight represent new AD risk genes not identified before by AD GWAS. Furthermore, we demonstrated that our results were independent of APOE e4. Together, our findings provide new insights into AD pathogenesis and promising targets for further mechanistic and therapeutic studies. Integrating human brain proteomes with genome-wide association data followed by Mendelian randomization identifies 11 genes with potentially causal roles in Alzheimer’s disease pathogenesis.
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