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Identification of novel drug targets for Alzheimer’s disease by integrating genetics and proteomes from brain and blood
Genome-wide association studies (GWASs) have discovered numerous risk genes for Alzheimer’s disease (AD), but how these genes confer AD risk is challenging to decipher. To efficiently transform genetic associations into drug targets for AD, we employed an integrative analytical pipeline using proteo...
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Published in: | Molecular psychiatry 2021-10, Vol.26 (10), p.6065-6073 |
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Main Authors: | , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Genome-wide association studies (GWASs) have discovered numerous risk genes for Alzheimer’s disease (AD), but how these genes confer AD risk is challenging to decipher. To efficiently transform genetic associations into drug targets for AD, we employed an integrative analytical pipeline using proteomes in the brain and blood by systematically applying proteome-wide association study (PWAS), Mendelian randomization (MR) and Bayesian colocalization. Collectively, we identified the brain protein abundance of 7 genes (
ACE
,
ICA1L
,
TOM1L2
,
SNX32
,
EPHX2
,
CTSH
, and
RTFDC1
) are causal in AD (
P
80% for Bayesian colocalization). The proteins encoded by these genes were mainly expressed on the surface of glutamatergic neurons and astrocytes. Of them,
ACE
with its protein abundance was also identified in significant association with AD on the blood-based studies and showed significance at the transcriptomic level.
SNX32
was also found to be associated with AD at the blood transcriptomic level. Collectively, our current study results on genetic, proteomic, and transcriptomic approaches has identified compelling genes, which may provide important leads to design future functional studies and potential drug targets for AD. |
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ISSN: | 1359-4184 1476-5578 |
DOI: | 10.1038/s41380-021-01251-6 |