RT Journal Article
T1 Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in Men
A1 García-González, Pablo
A1 Rojas, Itziar  de
A1 Moreno-Grau, Sonia
A1 Montrreal, Laura
A1 Puerta, Raquel
A1 Alarcón-Martín, Emilio
A1 Quintela, Inés
A1 Orellana, Adela
A1 Andrade, Victor
A1 Martino Adami, Pamela V.
A1 Heilmann-Heimbach, Stefanie
A1 Gómez-Garre, Pilar
A1 Periñán, María Teresa
A1 Alvarez, Ignacio
A1 Díez-Fairen, Mónica
A1 Nuñez Llaves, Raul
A1 Olivé Roig, Claudia
A1 García-Ribas, Guillermo
A1 Menéndez-González, Manuel
A1 Martínez, Carmen
A1 Aguilar, Miquel
A1 Buongiorno, Mariateresa
A1 Franco-Macías, Emilio
A1 Saez, Maria Eugenia
A1 Cano, Amanda
A1 Bullido Gómez-Heras, Maria Jesús
A1 Real-Navarrete, Luis Miguel
A1 Rodríguez-Rodríguez, Eloy
A1 Royo-Sánchez-Palencia, José Luis
A1 Álvarez, Victoria
A1 Pastor, Pau
A1 Piñol-Ripoll, Gerard
A1 Mir, Pablo
A1 Calero Lara, Miguel
A1 Medina Padilla, Miguel
A1 Sánchez-Juan, Pascual
A1 Carracedo Álvarez, Ángel María
A1 Valero, Sergi
A1 Hernández, Isabel
A1 Tàrraga, Lluis
A1 Ramirez, Alfredo
A1 Boada, Mercé
A1 Ruiz Laza, Agustín
K1 Alzheimer, Enfermedad de
AB 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.
PB IOAP-MDPI
YR 2023
FD 2023-01-04
LK https://hdl.handle.net/10630/25996
UL https://hdl.handle.net/10630/25996
LA eng
NO García-González P, de Rojas I, Moreno-Grau S, Montrreal L, Puerta R, Alarcón-Martín E, Quintela I, Orellana A, Andrade V, Adami PVM, Heilmann-Heimbach S, Gomez-Garre P, Periñán MT, Alvarez I, Diez-Fairen M, Nuñez Llaves R, Olivé Roig C, Garcia-Ribas G, Menéndez-González M, Martínez C, Aguilar M, Buongiorno M, Franco-Macías E, Saez ME, Cano A, Bullido MJ, Real LM, Rodríguez-Rodríguez E, Royo JL, Álvarez V, Pastor P, Piñol-Ripoll G, Mir P, Lara MC, Padilla MM, Sánchez-Juan P, Carracedo A, Valero S, Hernandez I, Tàrraga L, Ramirez A, Boada M, Ruiz A. Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in Men. International Journal of Molecular Sciences. 2023; 24(2):898. https://doi.org/10.3390/ijms24020898
NO P.G.-G. (Pablo García-González) is supported by CIBERNED employment plan CNV-304-PRF-866. CIBERNED is integrated into ISCIII (Instituto de Salud Carlos III). I.d.R is supported by a national grant from the Instituto de Salud Carlos III FI20/00215. A.C. (Amanda Cano) acknowledges the support of the Spanish Ministry of Science, Innovation, and Universities under the grant Juan de la Cierva (FJC2018-036012-I). M.B. (Mercé Boada) and A.R. (Agustín Ruiz) are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240, and PI19/01301. The Genome Research @ Fundació ACE project (GR@ACE) is supported by Grifols SA, Fundación bancaria “La Caixa”, Fundació ACE, and CIBERNED. Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)—Subdirección General de Evaluación—and the Fondo Europeo de Desarrollo Regional (FEDER—“Una manera de hacer Europa”). Genotyping of the ACE MCI-EADB samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). This work was supported by a grant (European Alzheimer DNA BioBank, EADB) from the EU Joint Program—Neurodegenerative Disease Research (JPND). Partial funding for open access charge: Universidad de Málaga
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 19 ene 2026