期刊
NATURE GENETICS
卷 53, 期 2, 页码 143-+出版社
NATURE RESEARCH
DOI: 10.1038/s41588-020-00773-z
关键词
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资金
- National Institutes of Health (NIH) [P30 AG066511, P30 AG10161, P30 NS055077, P50 AG025688, R01 AG015819, R01 AG017917, R01 AG053960, R01 AG056533, R01 AG057911, R01 AG061800, R56 AG060757, R56 AG062256, RC2 AG036547, RF1 AG057470, U01 AG046152, U01 AG046161, U01 AG061356, U01 AG061357, U01 MH115484]
- NIH
- Veterans Administration [I01 BX003853, IK4 BX005219]
- Arizona Department of Health Services
- Arizona Biomedical Research Commission
- Michael J. Fox Foundation for Parkinson's Research
- Alzheimer's Association
- Alzheimer's Research UK
- Weston Brain Institute Biomarkers Across Neurodegenerative Diseases Grant [11060]
This study identified 11 genes that may play a role in Alzheimer's disease (AD) by affecting brain protein abundance, through a proteome-wide association study. Eight of these genes are new AD risk genes not identified before by AD GWAS, providing new insights into AD pathogenesis. This research offers promising targets for further mechanistic and therapeutic studies on AD.
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.
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