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Post‐GWAS multiomic functional investigation of the TNIP1 locus in Alzheimer's disease highlights a potential role for GPX3
Abstract
INTRODUCTION: Recent genome‐wide association studies (GWAS) have reported a genetic association with Alzheimer's disease (AD) at the TNIP1/GPX3 locus, but the mechanism is unclear. METHODS: We used cerebrospinal fluid (CSF) proteomics data to test ( n = 137) and replicate ( n = 446) the association of glutathione peroxidase 3 (GPX3) with CSF biomarkers (including amyloid and tau) and the GWAS‐implicated variants (rs34294852 and rs871269). RESULTS: CSF GPX3 levels decreased with amyloid and tau positivity (analysis of variance P = 1.5 × 10 −5 ) and higher CSF phosphorylated tau (p‐tau) levels ( P = 9.28 × 10 −7 ). The rs34294852 minor allele was associated with decreased GPX3 ( P = 0.041). The replication cohort found associations of GPX3 with amyloid and tau positivity ( P = 2.56 × 10 −6 ) and CSF p‐tau levels ( P = 4.38 × 10 −9 ). DISCUSSION: These results suggest variants in the TNIP1 locus may affect the oxidative stress response in AD via altered GPX3 levels. Highlights: Cerebrospinal fluid (CSF) glutathione peroxidase 3 (GPX3) levels decreased with amyloid and tau positivity and higher CSF phosphorylated tau. The minor allele of rs34294852 was associated with lower CSF GPX3. levels when also controlling for amyloid and tau category. GPX3 transcript levels in the prefrontal cortex were lower in Alzheimer's disease than controls. rs34294852 is an expression quantitative trait locus for GPX3 in blood, neutrophils, and microglia.
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“GPX3 is an enzyme involved in the antioxidant system and its expression is altered in AD [49].”
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Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease
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Self-citationMicroglia Heterogeneity in the Single-Cell Era
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Di Caro, V., Cho, E., Thiel, J., Lizama, B. N., Koel-Simmelink, M. J. A., Pandey, K., Duong, D., Seyfried, N. T., Grundman, M., Teunissen, C. E., et al. (2026) · Alzheimer's Research & Therapy · doi:10.1186/s13195-026-02025-4 · Cited by 1
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Metadata
- Authors
- Panyard, D. J., Reus, L. M., Ali, M., Liu, J., Deming, Y. K., Lu, Q., Kollmorgen, G., Carboni, M., Wild, N., Visser, P. J., Bertram, L., Zetterberg, H., Blennow, K., Gobom, J., Western, D., Sung, Y. J., Carlsson, C. M., Johnson, S. C., Asthana, S., Cruchaga, C., Tijms, B. M., Engelman, C. D., & Snyder, M. P.
- Affiliations
- Department of Genetics Stanford University School of Medicine Stanford University Stanford California USA
- Alzheimer Center Amsterdam, Neurology Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc Amsterdam The Netherlands
- Department of Psychiatry Washington University School of Medicine St. Louis Missouri USA
- Department of Biostatistics and Medical Informatics University of Wisconsin‐Madison Madison Wisconsin USA
- Department of Population Health Sciences University of Wisconsin‐Madison Madison Wisconsin USA
- Roche Diagnostics GmbH Penzberg Germany
- Roche Diagnostics International Ltd Rotkreuz Switzerland
- Lübeck Interdisciplinary Platform for Genome Analytics Institutes of Neurogenetics and Cardiogenetics University of Lübeck Lübeck Germany
- Institute of Neuroscience and Physiology The Sahlgrenska Academy at the University of Gothenburg Mölndal Sweden
- Wisconsin Alzheimer's Disease Research Center University of Wisconsin‐Madison Madison Wisconsin USA
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2024-05-29
- Volume
- 20
- Issue
- 7
- Pages
- 5044-5053
- ISSN
- 1552-5260
- 1552-5279
- PMC
- PMC11247664
- Cited by
- 14
- References
- 8
- Language
- en
- Funders
- National Institute on Aging (R01AG044546, R01AG064877, RF1AG053303, U01AG058922, R01AG064614, 1RF1AG074007, P30AG066444, P01AG003991, R01AG27161, R21AG067092, R01AG037639, R01AG021155, P30AG017266, T32AG000213)
- National Institutes of Health (R01AG054047, RF1AG058501, P41GM108538)
- University of Wisconsin-Madison (P2CHD047873)
- European Commission (115952, 806999, 101034344)
- Vetenskapsrådet (#2018‐02532, #2017‐00915)
- European Research Council (#101053962)
- Familjen Erling-Perssons Stiftelse (#EP2019‐02)
- Stiftelsen för Gamla Tjänarinnor (#SGT2021‐09‐Zetterberg)
- UK Dementia Research Institute (#UKDRI‐1003)
- Hjärnfonden (#FO2019‐0228, #FO2017‐0243, #ALZ2022‐0006)
- Alzheimerfonden (#AF‐930934)
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