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...

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Detalhes bibliográficos
Autores: García-González, Pablo, Rojas, Itziar de, Moreno-Grau, Sonia, Montrreal, Laura, Puerta, Raquel, Alarcón-Martín, Emilio, Quintela, Inés, Orellana, Adela, Andrade, Víctor, Martino Adami, Pamela V., Heilmann-Heimbach, Stefanie, Gómez-Garre, Pilar, Periñan, María Teresa, Álvarez, Ignacio, Díez-Farien, Mónica, Núñez Llavez, Raúl, Olivé Roig, Claudia, Rodríguez Rodríguez, Eloy Manuel, Sánchez-Juan, Pascual|||0000-0002-6081-8037
Formato: artículo
Fecha de publicación:2023
País:España
Recursos:Universidad de Cantabria (UC)
Repositorio:UCrea Repositorio Abierto de la Universidad de Cantabria
Idioma:inglés
OAI Identifier:oai:repositorio.unican.es:10902/29922
Acesso em linha:https://hdl.handle.net/10902/29922
Access Level:acceso abierto
Palavra-chave:Alzheimer’s disease
Mosaic loss of chromosome Y
Disease progression
GWAS
Mendelian randomization
GR@ACE/DEGESCO
EADB
Mild cognitive impairment
Polygenic risk score
CSF biomarkers
Descrição
Resumo: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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