Disease-predominant loci across Alzheimer's disease, Parkinson's disease and Lewy body dementia: evidence from the UK Biobank prospective cohort, conditional GWAS and colocalization.

Overview

1. Department of Pharmacy, Beidahuang Industry Group General Hospital, Harbin, China
2. Center for Bioinformatics, Faculty of Computing, Harbin Institute of Technology, Harbin, China

Abstract

Background: Alzheimer’s disease (AD), Parkinson’s disease (PD) and Lewy body dementia (LBD) overlap clinically, pathologically and genetically, complicating interpretation of cross-disorder genome-wide association study (GWAS) signals.

Methods: We analysed 322,963 UK Biobank participants with bidirectional time-varying Cox models, one-year and two-year lag analyses, and competing-risk sensitivity models to quantify AD-PD clinical co-occurrence. We then analysed European-ancestry AD, PD and LBD GWAS summary statistics using linkage disequilibrium score regression (LDSC), GCTA-mtCOJO/GSMR, MAGMA, stratified LDSC, brain eQTL/mQTL SMR with HEIDI filtering, and Bayesian colocalization for selected methylation probes. Conditional loci were compared with original GWAS loci to separate shared liability from retained disorder-predominant associations.

Results: PD was associated with subsequent AD (fully adjusted HR 2.27, 95% CI 1.94–2.65; P = 6.40E-25), and AD was associated with subsequent PD (HR 3.14, 95% CI 2.56–3.85; P = 2.10E-28). Lag and competing-risk sensitivity analyses remained concordant. LDSC estimated positive genetic correlations for AD-PD (rg = 0.20; P = 0.0086) and PD-LBD (rg = 0.61; P = 0.0005). Conditioning reduced genome-wide significant loci from 14 to 9 for AD, from 24 to 21 for PD and from 5 to 2 for LBD. Retained loci included AD signals near CR1, BIN1, CLU, SPI1, MS4A, PICALM, ABCA7 and APOE; PD signals near GBA, NUCKS1, TMEM163, STK39, GAK/TMEM175, BST1, SNCA, LRRK2, MAPT and RIT2; and LBD signals near SNCA/MMRN1 and APOE. MAGMA and S-LDSC highlighted amyloid, lipid, immune, synaptic-vesicle and brain-tissue enrichment patterns. Brain QTL analyses prioritized retained eQTL and mQTL signals, and colocalization supported shared PD-GWAS/mQTL signals at HLA-DRB5, ARHGAP27, CRHR1, MAPT and KANSL1.

Conclusion: AD and PD show bidirectional clinical co-occurrence, whereas conditional genetic analyses retain a smaller set of disease-predominant loci and regulatory signals across AD, PD and LBD. These findings refine cross-disorder interpretation and nominate loci for independent genetic and functional validation.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

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• zenodo:20714624, at Zenodo; found in “Data availability statement”

Data availability statement

The original contributions presented in the study are publicly available. This data can be found in Zenodo with the DOI https://doi.org/10.5281/zenodo.20714624.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 4 authors, 7 keywords, 58 references.

Cite

This paper

Zhang, Y., Zhang, Z., Qiu, S., & Hu, Y. (2026). Disease-predominant loci across Alzheimer's disease, Parkinson's disease and Lewy body dementia: evidence from the UK Biobank prospective cohort, conditional GWAS and colocalization. Frontiers in genetics, 17, 1865257. https://doi.org/10.3389/fgene.2026.1865257

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