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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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 documento: artigo
Estado:Versão publicada
Data de publicação:2023
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositório:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10459.1/464458
Acesso em linha:https://doi.org/10.3390/ijms24020898
https://hdl.handle.net/10459.1/464458
Access Level:Acceso aberto
Palavra-chave:Alzheimer’s disease
Mosaic loss of chromosome Y
Disease progression
GWAS
Mendelian randomization
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spelling Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in MenGarcía-González, Pablode Rojas, ItziarMoreno-Grau, S.Montrreal, LauraPuerta, RaquelAlarcón-Martin, EmilioQuintela, InésOrellana, AdelinaAndrade, VictorMartino Adami, Pamela V.Heilmann-Heimbach, StefanieGomez-Garre, PilarPeriñán, María TeresaÁlvarez, IgnacioDiez Fairen, MónicaNuñez Llaves, RaulOlivé Roig, ClaudiaGarcía Ribas, GuillermoPiñol Ripoll, GerardAlzheimer’s diseaseMosaic loss of chromosome YDisease progressionGWASMendelian randomizationMosaic 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.MDPI2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://doi.org/10.3390/ijms24020898https://hdl.handle.net/10459.1/464458reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a https://doi.org/10.3390/ijms24020898International Journal of Molecular Sciences, 2023, vol. 24, núm. 2, 898cc-by (c) Pablo García-González et al., 2023Attribution 4.0 Internationalinfo:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/4.0/oai:recercat.cat:10459.1/4644582026-05-29T05:05:01Z
dc.title.none.fl_str_mv Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in Men
title Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in Men
spellingShingle Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in Men
García-González, Pablo
Alzheimer’s disease
Mosaic loss of chromosome Y
Disease progression
GWAS
Mendelian randomization
title_short Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in Men
title_full Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in Men
title_fullStr Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in Men
title_full_unstemmed Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in Men
title_sort Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in Men
dc.creator.none.fl_str_mv 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
author García-González, Pablo
author_facet 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
author_role author
author2 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
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Alzheimer’s disease
Mosaic loss of chromosome Y
Disease progression
GWAS
Mendelian randomization
topic Alzheimer’s disease
Mosaic loss of chromosome Y
Disease progression
GWAS
Mendelian randomization
description 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.
publishDate 2023
dc.date.none.fl_str_mv 2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://doi.org/10.3390/ijms24020898
https://hdl.handle.net/10459.1/464458
url https://doi.org/10.3390/ijms24020898
https://hdl.handle.net/10459.1/464458
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a https://doi.org/10.3390/ijms24020898
International Journal of Molecular Sciences, 2023, vol. 24, núm. 2, 898
dc.rights.none.fl_str_mv cc-by (c) Pablo García-González et al., 2023
Attribution 4.0 International
info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/4.0/
rights_invalid_str_mv cc-by (c) Pablo García-González et al., 2023
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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