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Mendelian randomisation confirms the role of Y-chromosome loss in Alzheimer's disease aetiopathogenesis in men

Abstract: 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.

 Fuente: International Journal of Molecular Sciences, 2023, 24, 898

 Editorial: Multidisciplinary Digital Publishing Institute (MDPI)

 Año de publicación: 2023

 Nº de páginas: 17

 Tipo de publicación: Artículo de Revista

 DOI: 10.3390/ijms24020898

 ISSN: 1661-6596,1422-0067

Autoría

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

PASCUAL SANCHEZ JUAN