Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in Men

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 asso...

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Detalles Bibliográficos
Autores: García-González, Pablo, de Rojas, Itziar, Moreno-Grau, S., Montrreal, Laura, Puerta, Raquel, Alarcón-Martin, Emilio, Quintela, Inés, Orellana, Adelina, Andrade, Victor, Martino Adami, Pamela V., Heilmann-Heimbach, Stefanie, Gomez-Garre, Pilar, Periñán, María Teresa, Álvarez, Ignacio, Diez Fairen, Mónica, Nuñez Llaves, Raul, Olivé Roig, Claudia, García Ribas, Guillermo, Piñol Ripoll, Gerard
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Universitat de Lleida (UdL)
Repositorio:Repositori Obert UdL
OAI Identifier:oai:repositori.udl.cat:10459.1/464458
Acceso en línea:https://doi.org/10.3390/ijms24020898
https://hdl.handle.net/10459.1/464458
Access Level:acceso abierto
Palabra clave:Alzheimer’s disease
Mosaic loss of chromosome Y
Disease progression
GWAS
Mendelian randomization
Descripción
Sumario: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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