Mendelian randomisation confirms the role of Y-chromosome loss in Alzheimer’s disease aetiopathogenesis in men
Entity
UAM. Departamento de Biología MolecularPublisher
MDPIDate
2023-01-04Citation
10.3390/ijms24020898
International Journal of Molecular Sciences 24.2 (2023): 898
ISSN
1661-6596 (print); 1422-0067 (online)DOI
10.3390/ijms24020898Editor's Version
https://doi.org/10.3390/ijms24020898Subjects
CSF biomarkers; EADB; GR@ACE/DEGESCO; GWAS; Mendelian randomization; Alzheimer’s Disease; Disease Progression; Mild Cognitive Impairment; Mosaic Loss of Chromosome Y; Polygenic Risk Score; Biología y Biomedicina / BiologíaNote
Artículo escrito por un elevado número de autores, solo se referencian el que aparece en primer lugar, los autores pertenecientes a la UAM y el nombre del grupo de colaboración, si lo hubiereRights
© 2023 by the authors. Licensee MDPI, Basel, SwitzerlandAbstract
Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event and has been previously associated with Alzheimer’s disease (AD). However, mLOY estimation from genotype microarray data only reflects the mLOY degree of subjects at the moment of DNA sampling. Therefore, mLOY phenotype associations with AD can be severely age-confounded in the context of genome-wide association studies. Here, we applied Mendelian randomisation to construct an age-independent mLOY polygenic risk score (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per standard deviation unit (p = 4.22 × 10−20) and was orthogonal with age. We found that a higher genetic risk for mLOY was associated with faster progression to AD in men with mild cognitive impairment (hazard ratio (HR) = 1.23, p = 0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group, suggesting that these associations are caused by the inherent loss of the Y chromosome. Additionally, the blood mLOY phenotype in men was associated with increased cerebrospinal fluid levels of total tau and phosphorylated tau181 in subjects with mild cognitive impairment and dementia. Our results strongly suggest that mLOY is involved in AD pathogenesis
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Google Scholar:García-González, Pablo
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Bullido Gómez-Heras, María Jesús
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