GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia
Lincoln M P Shade, Yuriko Katsumata, Erin L Abner, Khine Zin Aung, Steven A Claas, Qi Qiao, Bernardo Aguzzoli Heberle, J Anthony Brandon et al.. Nature genetics, 2024-10-08
Topic: Genetics and APOE
Genome-wide association studies (GWAS) have identified >80 Alzheimer's disease and related dementias (ADRD)-associated genetic loci. However, the clinical outcomes used in most previous studies belie the complex nature of underlying neuropathologies. Here we performed GWAS on 11 ADRD-related neuropathology endophenotypes with participants drawn from the following three sources: the National Alzheimer's Coordinating Center, the Religious Orders Study and Rush Memory and Aging Project, and the Adult Changes in Thought study (n = 7,804 total autopsied participants). We identified eight independent significantly associated loci, of which four were new (COL4A1, PIK3R5, LZTS1 and APOC2). Separately testing known ADRD loci, 19 loci were significantly associated with at least one neuropathology after false-discovery rate adjustment. Genetic colocalization analyses identified pleiotropic effects and quantitative trait loci. Methylation in the cerebral cortex at two sites near APOC2 was associated with cerebral amyloid angiopathy. Studies that include neuropathology endophenotypes are an important step in understanding the mechanisms underlying genetic ADRD risk.
Key findings
- We identified eight independent significantly associated loci, of which four were new (COL4A1, PIK3R5, LZTS1 and APOC2).
- Separately testing known ADRD loci, 19 loci were significantly associated with at least one neuropathology after false-discovery rate adjustment.
- Methylation in the cerebral cortex at two sites near APOC2 was associated with cerebral amyloid angiopathy.
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Study details
- Participants7,804
- Evidence strengthLow
How this study scored 57/100
Published in a leading specialty journal. Scored zero for study design, effect reported 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 32 of the 56 points we could judge it on, which is 57 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Nature 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 | 3 / 4 | 7,804 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| 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 39379761) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 32 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 32 of the 56 points we could judge it on is 57 out of 100. |
| Total | 57 / 100 | — |
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APA 7th
Shade, L. M. P., Katsumata, Y., Abner, E. L., Aung, K. Z., Claas, S. A., Qiao, Q., et al. (2024). GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia. Nature genetics. https://doi.org/10.1038/s41588-024-01939-9
Vancouver
Shade LMP, Katsumata Y, Abner EL, Aung KZ, Claas SA, Qiao Q, et al. GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia. Nature genetics. 2024. doi:10.1038/s41588-024-01939-9. PMID: 39379761.
BibTeX
@article{shade2024-39379761,
author = {Shade, Lincoln M P and Katsumata, Yuriko and Abner, Erin L and Aung, Khine Zin and Claas, Steven A and Qiao, Qi and Heberle, Bernardo Aguzzoli and Brandon, J Anthony and others},
title = {{GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia}},
journal = {Nature genetics},
year = {2024},
doi = {10.1038/s41588-024-01939-9},
pmid = {39379761},
url = {https://doi.org/10.1038/s41588-024-01939-9}
}
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