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...
| Authors: | ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; |
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| Format: | Article |
| Status: | Published version |
| Publication date: | 2023 |
| Country: | España |
| Institution: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repository: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:10459.1/464458 |
| Online Access: | https://doi.org/10.3390/ijms24020898 https://hdl.handle.net/10459.1/464458 |
| Access Level: | Open access |
| Keyword: | Alzheimer’s disease Mosaic loss of chromosome Y Disease progression GWAS Mendelian randomization |
| _version_ | 1878736570340605952 |
|---|---|
| author | García-González, Pablo |
| 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 |
| author_browse | Alarcón-Martin, Emilio Andrade, Victor Diez Fairen, Mónica García Ribas, Guillermo García-González, Pablo Gomez-Garre, Pilar Heilmann-Heimbach, Stefanie Martino Adami, Pamela V. Montrreal, Laura Moreno-Grau, S. Nuñez Llaves, Raul Olivé Roig, Claudia Orellana, Adelina Periñán, María Teresa Piñol Ripoll, Gerard Puerta, Raquel Quintela, Inés de Rojas, Itziar Álvarez, Ignacio |
| 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 |
| collection | Recercat. Dipósit de la Recerca de Catalunya |
| 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_9155eeedda40f15549ff4e76cb308eb0 |
| institution | 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) |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:recercat.cat:10459.1/464458 |
| publishDate | 2023 |
| publishDateSort | 2023 |
| publisher | MDPI |
| publisherStr | MDPI |
| reponame_str | Recercat. Dipósit de la Recerca de Catalunya |
| spelling | Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in Men 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 Alzheimer’s disease Mosaic loss of chromosome Y Disease progression GWAS Mendelian randomization 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. MDPI https://doi.org/10.3390/ijms24020898 https://hdl.handle.net/10459.1/464458 |
| 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 |
| status_str | publishedVersion |
| title | 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_short | 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 |
| topic | Alzheimer’s disease Mosaic loss of chromosome Y Disease progression GWAS Mendelian randomization |
| topic_facet | Alzheimer’s disease Mosaic loss of chromosome Y Disease progression GWAS Mendelian randomization |
| url | https://doi.org/10.3390/ijms24020898 https://hdl.handle.net/10459.1/464458 |