International Journal of Molecular Sciences (Jan 2023)
Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in Men
- Pablo García-González,
- Itziar de Rojas,
- Sonia Moreno-Grau,
- Laura Montrreal,
- Raquel Puerta,
- Emilio Alarcón-Martín,
- Inés Quintela,
- Adela Orellana,
- Victor Andrade,
- Pamela V. Martino Adami,
- Stefanie Heilmann-Heimbach,
- Pilar Gomez-Garre,
- María Teresa Periñán,
- Ignacio Alvarez,
- Monica Diez-Fairen,
- Raul Nuñez Llaves,
- Claudia Olivé Roig,
- Guillermo Garcia-Ribas,
- Manuel Menéndez-González,
- Carmen Martínez,
- Miquel Aguilar,
- Mariateresa Buongiorno,
- Emilio Franco-Macías,
- Maria Eugenia Saez,
- Amanda Cano,
- Maria J. Bullido,
- Luis Miguel Real,
- Eloy Rodríguez-Rodríguez,
- Jose Luís Royo,
- Victoria Álvarez,
- Pau Pastor,
- Gerard Piñol-Ripoll,
- Pablo Mir,
- Miguel Calero Lara,
- Miguel Medina Padilla,
- Pascual Sánchez-Juan,
- Angel Carracedo,
- Sergi Valero,
- Isabel Hernandez,
- Lluis Tàrraga,
- Alfredo Ramirez,
- Mercé Boada,
- Agustín Ruiz
Affiliations
- Pablo García-González
- Research Center and Memory Clinic, Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, 08017 Barcelona, Spain
- Itziar de Rojas
- Research Center and Memory Clinic, Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, 08017 Barcelona, Spain
- Sonia Moreno-Grau
- Research Center and Memory Clinic, Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, 08017 Barcelona, Spain
- Laura Montrreal
- Research Center and Memory Clinic, Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, 08017 Barcelona, Spain
- Raquel Puerta
- Research Center and Memory Clinic, Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, 08017 Barcelona, Spain
- Emilio Alarcón-Martín
- Research Center and Memory Clinic, Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, 08017 Barcelona, Spain
- Inés Quintela
- Grupo de Medicina Xenómica, Centro Nacional de Genotipado (CEGEN-PRB3-ISCIII), Universidade de Santiago de Compostela, 15705 Santiago de Compostela, Spain
- Adela Orellana
- Research Center and Memory Clinic, Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, 08017 Barcelona, Spain
- Victor Andrade
- Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, 50937 Cologne, Germany
- Pamela V. Martino Adami
- Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, 50937 Cologne, Germany
- Stefanie Heilmann-Heimbach
- Institute of Human Genetics, School of Medicine & University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
- Pilar Gomez-Garre
- CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, 28220 Madrid, Spain
- María Teresa Periñán
- CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, 28220 Madrid, Spain
- Ignacio Alvarez
- Fundació Docència i Recerca MútuaTerrassa, 08221 Terrassa, Spain
- Monica Diez-Fairen
- Fundació Docència i Recerca MútuaTerrassa, 08221 Terrassa, Spain
- Raul Nuñez Llaves
- Research Center and Memory Clinic, Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, 08017 Barcelona, Spain
- Claudia Olivé Roig
- Research Center and Memory Clinic, Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, 08017 Barcelona, Spain
- Guillermo Garcia-Ribas
- Hospital Universitario Ramon y Cajal, IRYCIS, 28034 Madrid, Spain
- Manuel Menéndez-González
- Servicio de Neurología, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain
- Carmen Martínez
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Asturias, Spain
- Miquel Aguilar
- Fundació Docència i Recerca MútuaTerrassa, 08221 Terrassa, Spain
- Mariateresa Buongiorno
- Fundació Docència i Recerca MútuaTerrassa, 08221 Terrassa, Spain
- Emilio Franco-Macías
- Unidad de Demencias, Servicio de Neurología y Neurofisiología, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, 41013 Sevilla, Spain
- Maria Eugenia Saez
- CAEBI, Centro Andaluz de Estudios Bioinformáticos, 41013 Sevilla, Spain
- Amanda Cano
- Research Center and Memory Clinic, Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, 08017 Barcelona, Spain
- Maria J. Bullido
- CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, 28220 Madrid, Spain
- Luis Miguel Real
- Unidad Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario de Valme, 41013 Sevilla, Spain
- Eloy Rodríguez-Rodríguez
- CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, 28220 Madrid, Spain
- Jose Luís Royo
- Depatamento de Especialidades Quirúrgicas, Bioquímica e Inmunología, Facultad de Medicina, Universidad de Málaga, 29016 Málaga, Spain
- Victoria Álvarez
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Asturias, Spain
- Pau Pastor
- Fundació Docència i Recerca MútuaTerrassa, 08221 Terrassa, Spain
- Gerard Piñol-Ripoll
- Unitat Trastorns Cognitius, Hospital Universitari Santa Maria de Lleida, 25198 Lleida, Spain
- Pablo Mir
- CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, 28220 Madrid, Spain
- Miguel Calero Lara
- CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, 28220 Madrid, Spain
- Miguel Medina Padilla
- CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, 28220 Madrid, Spain
- Pascual Sánchez-Juan
- CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, 28220 Madrid, Spain
- Angel Carracedo
- Grupo de Medicina Xenómica, Centro Nacional de Genotipado (CEGEN-PRB3-ISCIII), Universidade de Santiago de Compostela, 15705 Santiago de Compostela, Spain
- Sergi Valero
- Research Center and Memory Clinic, Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, 08017 Barcelona, Spain
- Isabel Hernandez
- Research Center and Memory Clinic, Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, 08017 Barcelona, Spain
- Lluis Tàrraga
- Research Center and Memory Clinic, Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, 08017 Barcelona, Spain
- Alfredo Ramirez
- Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, 50937 Cologne, Germany
- Mercé Boada
- Research Center and Memory Clinic, Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, 08017 Barcelona, Spain
- Agustín Ruiz
- Research Center and Memory Clinic, Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, 08017 Barcelona, Spain
- DOI
- https://doi.org/10.3390/ijms24020898
- Journal volume & issue
-
Vol. 24,
no. 2
p. 898
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.
Keywords
- Alzheimer’s disease
- mosaic loss of chromosome Y
- disease progression
- GWAS
- Mendelian randomization
- GR@ACE/DEGESCO