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Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer's disease
Rajabli F, Benchek P, Tosto G, Kushch N, Sha J, Bazemore K, Zhu C, Lee WP et al.. Genome biology, 2025-07-17
Topic: Amyloid, tau and blood-test diagnosis
Plain-language summary
Background Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer's Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer's disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. Results We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). We additionally identify three population-specific loci with genome-wide significance at/near PTPRK and GRB14 in HIS and KIAA0825 in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). Conclusions Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near LRRC4C and LHX5-AS1, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the SHARPIN locus with only 13.7% of the sample size of the NHW GWAS study (n = 409,589) in which this locus was first observed. Continued expansion into larger multi-ancestry studies will provide even more power for further elucidating the genomics of late-onset Alzheimer's disease.
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APA 7th
Rajabli, F., Benchek, P., Tosto, G., Kushch, N., Sha, J., Bazemore, K., et al. (2025). Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer's disease. Genome biology. https://doi.org/10.1186/s13059-025-03564-z
Vancouver
Rajabli F, Benchek P, Tosto G, Kushch N, Sha J, Bazemore K, et al. Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer's disease. Genome biology. 2025. doi:10.1186/s13059-025-03564-z. PMID: 40676597.
BibTeX
@article{rajabli2025-40676597,
author = {Rajabli, F. and Benchek, P. and Tosto, G. and Kushch, N. and Sha, J. and Bazemore, K. and Zhu, C. and Lee, W. P. and others},
title = {{Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer's disease}},
journal = {Genome biology},
year = {2025},
doi = {10.1186/s13059-025-03564-z},
pmid = {40676597},
url = {https://doi.org/10.1186/s13059-025-03564-z}
}
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Key findings
- Results We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1).
Why it matters
Pooling genetic data from 56,241 people of White, African American, Hispanic and East Asian ancestry, this study found 13 gene regions linked to late-onset Alzheimer's across populations, including two new ones near LRRC4C and LHX5-AS1, plus population-specific regions near PTPRK, GRB14 and KIAA0825. The authors say including diverse ancestries boosts the power to find risk genes, which can point to new biological pathways to study.
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Study details
- Study designmeta-analysis
- Participants409,589
- Effect size13.7%
- Evidence strengthHigh
How this study scored 77/100
Published in a peer-reviewed journal, and it is a meta-analysis pooling many studies.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Genome biology) |
| Journal's citation record | 3 / 4 | Genome biology: journal h-index 389 (OpenAlex, 2026-10-29) |
| Study design | 12 / 12 | A meta-analysis pooling many studies |
| Strength of evidence | 5 / 5 | Rated “high” 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 | 4 / 4 | 409,589 participants |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomized / blinded | 0 / 2 | A review of other studies — randomization is not credited here |
| Times cited | 3 / 7 | Cited 24 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 8.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 4.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 3 other studies in this library |
| Still being cited | 2 / 4 | Cited 24 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Martin Rhys Farlow: h-index 118 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | University of Washington: institution h-index 3,540 (OpenAlex) |
| Multicenter collaboration | 3 / 3 | OpenAlex lists 53 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40676597) |
| Free to read | 2 / 2 | Free to read |
| Total | 77 / 100 | — |
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