Topic: Amyloid, tau and blood-test diagnosis
Genome-wide association studies (GWAS) typically represent Alzheimers disease (AD) risk loci by a single lead SNP, although the lead SNP may capture only part of the genetic variation at a locus. We asked what genetic architectures underlie AD GWAS associations and how much information is obscured when a locus is reduced to a single lead SNP. We integrated AD GWAS summary statistics with long-read whole-genome sequencing of 493 individuals, phased DNA methylation, chromatin annotations, and structural variant (SV) imputation. Across 98 established AD loci, linkage disequilibrium (LD)-based clumping and conditional analysis identified 280 independent AD-haplotypes, of which 207 (74%) harbored linked structural variants, yielding 2,000 haplotype-linked SVs comprising intronic transposable elements and multiallelic tandem repeats within regulatory regions. Integration of methylation, chromatin annotations, and genomic context prioritized 52 AD haplotypes with candidate regulatory SVs, revealing that lead SNPs often capture only part of the underlying structural and regulatory architecture. At the SHARPIN/PLEC locus, long-read fine-mapping resolved an independent regulatory PLEC haplotype carrying a CpG-rich tandem repeat associated with enhancer methylation and reduced microglial expression. Extending these findings to population scale, we imputed 83% of haplotype-linked SVs into SNP-genotyped cohorts (median imputation R2 = 0.76). In exploratory model comparisons, lead-SNP-only models were favored at just 10% of loci, whereas models incorporating multiple haplotypes, SVs, or both were favored at the remaining 90%. Our findings show that AD GWAS loci frequently comprise structurally and regulatorily heterogeneous haplotypes that cannot be fully interpreted through the lead SNP alone. Rather than the lead SNP, the haplotype represents the fundamental unit for resolving the biological mechanisms driving AD genetic risk.
Key findings
- At the SHARPIN/PLEC locus, long-read fine-mapping resolved an independent regulatory PLEC haplotype carrying a CpG-rich tandem repeat associated with enhancer methylation and reduced microglial expression.
- Extending these findings to population scale, we imputed 83% of haplotype-linked SVs into SNP-genotyped cohorts (median imputation R2 = 0.76).
- Our findings show that AD GWAS loci frequently comprise structurally and regulatorily heterogeneous haplotypes that cannot be fully interpreted through the lead SNP alone.
Why it matters
Long-read sequencing showed that many Alzheimer's disease GWAS loci contain structural variants and regulatory complexity that a single lead SNP does not capture. This refines understanding of genetic risk architecture and does not test any treatment or cure.
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Study details
- Participants493
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 26 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, effect reported and randomised / blinded because the record does not state it. We have no data on impact for its field and year, so that was left out: it earned 24 of the 94 points we could judge it on, which is 26 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (medRxiv (preprint)) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| 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 | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 2 / 4 | 493 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 | 0 / 7 | Cited 0 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.0 citations a year over 2 year(s) since 2026 |
| 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 | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 0 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Henne H. Holstege: h-index 43 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Delft University of Technology: institution h-index 811 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 1 country |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 2 / 2 | Free to read |
| Points | 24 / 94 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 24 of the 94 points we could judge it on is 26 out of 100. |
| Total | 26 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Tesi, N., Salazar, A., Bouland, G., Alvarez, D., Zhang, Y., Knoop, L., et al. (2026). Long-read sequencing reveals hidden structural complexity within Alzheimers disease-associated GWAS loci. medRxiv (preprint). https://doi.org/10.64898/2026.03.16.26348487
Vancouver
Tesi N, Salazar A, Bouland G, Alvarez D, Zhang Y, Knoop L, et al. Long-read sequencing reveals hidden structural complexity within Alzheimers disease-associated GWAS loci. medRxiv (preprint). 2026. doi:10.64898/2026.03.16.26348487.
BibTeX
@article{tesi2026-d8615865,
author = {Tesi, N. and Salazar, A. and Bouland, G. and Alvarez, D. and Zhang, Y. and Knoop, L. and van Schoor, N. M. and Huisman and others},
title = {{Long-read sequencing reveals hidden structural complexity within Alzheimers disease-associated GWAS loci}},
journal = {medRxiv (preprint)},
year = {2026},
doi = {10.64898/2026.03.16.26348487},
url = {https://doi.org/10.64898/2026.03.16.26348487}
}
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