Structural variants linked to Alzheimer's disease and other common age-related clinical and neuropathologic traits
Ricardo A Vialle, Katia de Paiva Lopes, Yan Li, Bernard Ng, Julie A Schneider, Aron S Buchman, Yanling Wang, Jose M Farfel et al.. Genome medicine, 2025-03-04
Topic: Genetics and APOE
First, we mapped SVs across 81 AD risk loci and discovered 22 SVs in linkage disequilibrium (LD) with GWAS lead variants and directly associated with the phenotypes tested. The strongest association was a deletion of an Alu element in the 3'UTR of the TMEM106B gene, in high LD with the respective AD GWAS locus and associated with multiple AD and AD-related disorders (ADRD) phenotypes, including tangles density, TDP-43, and cognitive resilience. The deletion of this element was also linked to lower TMEM106B protein abundance. We also found a 22-kb deletion associated with depression in ROS/MAP and bearing similar association patterns as GWAS SNPs at the IQCK locus. In addition, we leveraged our catalog of SV-GWAS to replicate and characterize independent findings in SV-based GWAS for AD and five other neurodegenerative diseases. Among these findings, we highlight the replication of genome-wide significant SVs for progressive supranuclear palsy (PSP), including markers for the 17q21.31 MAPT locus inversion and a 1483-bp deletion at the CYP2A13 locus, along with other suggestive associations, such as a 994-bp duplication in the LMNTD1 locus, suggestively linked to AD and a 3958-bp deletion at the DOCK5 locus linked to Lewy body disease (LBD) (P = 3.36 × 10-4). While still limited in sample size, this study highlights the utility of including analysis of SVs for elucidating mechanisms underlying GWAS loci and provides a valuable resource for the characterization of the effects of SVs in neurodegenerative disease pathogenesis.
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APA 7th
Vialle, R. A., Lopes, K. d. P., Li, Y., Ng, B., Schneider, J. A., Buchman, A. S., et al. (2025). Structural variants linked to Alzheimer's disease and other common age-related clinical and neuropathologic traits. Genome medicine. https://doi.org/10.1186/s13073-025-01444-6
Vancouver
Vialle RA, Lopes KdP, Li Y, Ng B, Schneider JA, Buchman AS, et al. Structural variants linked to Alzheimer's disease and other common age-related clinical and neuropathologic traits. Genome medicine. 2025. doi:10.1186/s13073-025-01444-6. PMID: 40038788.
BibTeX
@article{vialle2025-40038788,
author = {Vialle, Ricardo A and Lopes, Katia de Paiva and Li, Yan and Ng, Bernard and Schneider, Julie A and Buchman, Aron S and Wang, Yanling and Farfel, Jose M and others},
title = {{Structural variants linked to Alzheimer's disease and other common age-related clinical and neuropathologic traits}},
journal = {Genome medicine},
year = {2025},
doi = {10.1186/s13073-025-01444-6},
pmid = {40038788},
url = {https://doi.org/10.1186/s13073-025-01444-6}
}
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Key findings
- First, we mapped SVs across 81 AD risk loci and discovered 22 SVs in linkage disequilibrium (LD) with GWAS lead variants and directly associated with the phenotypes tested.
- The strongest association was a deletion of an Alu element in the 3'UTR of the TMEM106B gene, in high LD with the respective AD GWAS locus and associated with multiple AD and AD-related disorders (ADRD) phenotypes, including tangles density, TDP-43, and cognitive resilience.
- The deletion of this element was also linked to lower TMEM106B protein abundance.
- We also found a 22-kb deletion associated with depression in ROS/MAP and bearing similar association patterns as GWAS SNPs at the IQCK locus.
- In addition, we leveraged our catalog of SV-GWAS to replicate and characterize independent findings in SV-based GWAS for AD and five other neurodegenerative diseases.
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Study details
- Study designcohort study
- Participants1,088
- Evidence strengthModerate
How this study scored 70/100
Published in a peer-reviewed journal, and it is a cohort study following people over time. Scored zero for 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 39 of the 56 points we could judge it on, which is 70 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Genome medicine) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 7 / 12 | A cohort study following people over time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 3 / 4 | 1,088 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 40038788) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 39 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 39 of the 56 points we could judge it on is 70 out of 100. |
| Total | 70 / 100 | — |
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