Omnibus proteome-wide association study identifies 43 risk genes for Alzheimer disease dementia
Tingyang Hu, Randy L Parrish, Qile Dai, Aron S Buchman, Shinya Tasaki, David A Bennett, Nicholas T Seyfried, Michael P Epstein et al.. American journal of human genetics, 2024-07-29
Topic: Genetics and APOE
Transcriptome-wide association study (TWAS) tools have been applied to conduct proteome-wide association studies (PWASs) by integrating proteomics data with genome-wide association study (GWAS) summary data. The genetic effects of PWAS-identified significant genes are potentially mediated through genetically regulated protein abundance, thus informing the underlying disease mechanisms better than GWAS loci. However, existing TWAS/PWAS tools are limited by considering only one statistical model. We propose an omnibus PWAS pipeline to account for multiple statistical models and demonstrate improved performance by simulation and application studies of Alzheimer disease (AD) dementia. We employ the Aggregated Cauchy Association Test to derive omnibus PWAS (PWAS-O) p values from PWAS p values obtained by three existing tools assuming complementary statistical models-TIGAR, PrediXcan, and FUSION. Our simulation studies demonstrated improved power, with well-calibrated type I error, for PWAS-O over all three individual tools. We applied PWAS-O to studying AD dementia with reference proteomic data profiled from dorsolateral prefrontal cortex of postmortem brains from individuals of European ancestry. We identified 43 risk genes, including 5 not identified by previous studies, which are interconnected through a protein-protein interaction network that includes the well-known AD risk genes TOMM40, APOC1, and APOC2. We also validated causal genetic effects mediated through the proteome for 27 (63%) PWAS-O risk genes, providing insights into the underlying biological mechanisms of AD dementia and highlighting promising targets for therapeutic development. PWAS-O can be easily applied to studying other complex diseases.
Key findings
- The genetic effects of PWAS-identified significant genes are potentially mediated through genetically regulated protein abundance, thus informing the underlying disease mechanisms better than GWAS loci.
- Our simulation studies demonstrated improved power, with well-calibrated type I error, for PWAS-O over all three individual tools.
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Study details
- Evidence strengthLow
How this study scored 43/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record, multi-centre collaboration and free to read, so those were left out: it earned 24 of the 56 points we could judge it on, which is 43 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (American journal of human genetics) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2024 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 39079537) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 24 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 24 of the 56 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | — |
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APA 7th
Hu, T., Parrish, R. L., Dai, Q., Buchman, A. S., Tasaki, S., Bennett, D. A., et al. (2024). Omnibus proteome-wide association study identifies 43 risk genes for Alzheimer disease dementia. American journal of human genetics. https://doi.org/10.1016/j.ajhg.2024.07.001
Vancouver
Hu T, Parrish RL, Dai Q, Buchman AS, Tasaki S, Bennett DA, et al. Omnibus proteome-wide association study identifies 43 risk genes for Alzheimer disease dementia. American journal of human genetics. 2024. doi:10.1016/j.ajhg.2024.07.001. PMID: 39079537.
BibTeX
@article{hu2024-39079537,
author = {Hu, Tingyang and Parrish, Randy L and Dai, Qile and Buchman, Aron S and Tasaki, Shinya and Bennett, David A and Seyfried, Nicholas T and Epstein, Michael P and others},
title = {{Omnibus proteome-wide association study identifies 43 risk genes for Alzheimer disease dementia}},
journal = {American journal of human genetics},
year = {2024},
doi = {10.1016/j.ajhg.2024.07.001},
pmid = {39079537},
url = {https://doi.org/10.1016/j.ajhg.2024.07.001}
}
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