Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer's Disease Aetiopathogenesis in Men
Por:
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, Llaves, RN, Olive, RC, 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, Alvarez, 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 and Ruiz, A
Publicada:
1 ene 2023
Resumen:
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 x 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.
Filiaciones:
García-González, P:
Univ Int Catalunya, Res Ctr, Ace Alzheimer Ctr Barcelona, Barcelona 08017, Spain
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, Memory Clin, Barcelona 08017, Spain
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid 28220, Spain
de Rojas, I:
Univ Int Catalunya, Res Ctr, Ace Alzheimer Ctr Barcelona, Barcelona 08017, Spain
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, Memory Clin, Barcelona 08017, Spain
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid 28220, Spain
Moreno-Grau, S:
Univ Int Catalunya, Res Ctr, Ace Alzheimer Ctr Barcelona, Barcelona 08017, Spain
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, Memory Clin, Barcelona 08017, Spain
Galatea Bio Inc, Hialeah, FL 33010 USA
Montrreal, L:
Univ Int Catalunya, Res Ctr, Ace Alzheimer Ctr Barcelona, Barcelona 08017, Spain
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, Memory Clin, Barcelona 08017, Spain
Puerta, R:
Univ Int Catalunya, Res Ctr, Ace Alzheimer Ctr Barcelona, Barcelona 08017, Spain
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, Memory Clin, Barcelona 08017, Spain
Alarcón-Martín, E:
Univ Int Catalunya, Res Ctr, Ace Alzheimer Ctr Barcelona, Barcelona 08017, Spain
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, Memory Clin, Barcelona 08017, Spain
Quintela, I:
Univ Santiago de Compostela, Ctr Nacl Genotipado CEGEN PRB3 ISCIII, Grp Med Xen, Santiago De Compostela 15705, Spain
Orellana, A:
Univ Int Catalunya, Res Ctr, Ace Alzheimer Ctr Barcelona, Barcelona 08017, Spain
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, Memory Clin, Barcelona 08017, Spain
Andrade, V:
Univ Cologne, Med Fac, Dept Psychiat & Psychotherapy, Div Neurogenet & Mol Psychiat, D-50937 Cologne, Germany
Univ Clin Bonn, Dept Neurodegenerat Dis & Geriatr Psychiat, D-53127 Bonn, Germany
Adami, PVM:
Univ Cologne, Med Fac, Dept Psychiat & Psychotherapy, Div Neurogenet & Mol Psychiat, D-50937 Cologne, Germany
Heilmann-Heimbach, S:
Univ Bonn, Sch Med, Inst Human Genet, D-53127 Bonn, Germany
Univ Bonn, Univ Hosp Bonn, D-53127 Bonn, Germany
Gomez-Garre, P:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid 28220, Spain
Univ Seville, Hosp Univ Virgen Rocio, Serv Neurol & Neurofisiol,CSIC, Unidad Trastornos Movimiento,Inst Biomed Sevilla, Seville 41013, Spain
Periñán, MT:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid 28220, Spain
Univ Seville, Hosp Univ Virgen Rocio, Serv Neurol & Neurofisiol,CSIC, Unidad Trastornos Movimiento,Inst Biomed Sevilla, Seville 41013, Spain
Alvarez, I:
Fundacio Docencia & Recerca MutuaTerrassa, Terrassa 08221, TX, Spain
Hosp Univ Mutua Terrassa, Dept Neurol, Memory Disorders Unit, Terrassa 08221, Spain
Diez-Fairen, M:
Fundacio Docencia & Recerca MutuaTerrassa, Terrassa 08221, TX, Spain
Hosp Univ Mutua Terrassa, Dept Neurol, Memory Disorders Unit, Terrassa 08221, Spain
Llaves, RN:
Univ Int Catalunya, Res Ctr, Ace Alzheimer Ctr Barcelona, Barcelona 08017, Spain
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, Memory Clin, Barcelona 08017, Spain
Olive, RC:
Univ Int Catalunya, Res Ctr, Ace Alzheimer Ctr Barcelona, Barcelona 08017, Spain
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, Memory Clin, Barcelona 08017, Spain
Garcia-Ribas, G:
Hosp Univ Ramon & Cajal, IRYCIS, Madrid 28034, Spain
Menéndez-González, M:
Hosp Univ Cent Asturias, Serv Neurol, Oviedo 33011, Spain
Inst Invest Sanitaria Principado Asturias ISPA, Asturias 33011, Spain
Univ Oviedo, Dept Med, Oviedo 33011, Spain
Martínez, C:
Inst Invest Sanitaria Principado Asturias ISPA, Asturias 33011, Spain
Hosp Univ Cabuenes, Serv Neurol, Gijon 33394, Spain
Aguilar, M:
Fundacio Docencia & Recerca MutuaTerrassa, Terrassa 08221, TX, Spain
Hosp Univ Mutua Terrassa, Dept Neurol, Memory Disorders Unit, Terrassa 08221, Spain
Buongiorno, M:
Fundacio Docencia & Recerca MutuaTerrassa, Terrassa 08221, TX, Spain
Hosp Univ Mutua Terrassa, Dept Neurol, Memory Disorders Unit, Terrassa 08221, Spain
Franco-Macías, E:
Univ Seville, Hosp Univ Virgen Rocio, Serv Neurol & Neurofisiol, Unidad Demencias,Inst Biomed Sevilla IBiS,CSIC, Seville 41013, Spain
Saez, ME:
CAEBI Ctr Andaluz Estudios Bioinformat, Seville 41013, Spain
Cano, A:
Univ Int Catalunya, Res Ctr, Ace Alzheimer Ctr Barcelona, Barcelona 08017, Spain
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, Memory Clin, Barcelona 08017, Spain
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid 28220, Spain
Bullido, MJ:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid 28220, Spain
UAM, Ctr Biol Mol Severo Ochoa, CSIC, Madrid 28049, Spain
Inst Invest Sanitaria Hosp la Paz IdIPaz, Madrid 28029, Spain
Real, LM:
Hosp Univ Valme, Unidad Clin Enfermedades Infecciosas & Microbiol, Seville 41013, Spain
Univ Malaga, Fac Med, Dept Especial Quirurg Bioquim & Inmunol, Malaga 29016, Spain
Rodríguez-Rodríguez, E:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid 28220, Spain
Univ Cantabria, Marques Valdecilla Univ Hosp, Neurol Serv, Santander 39008, Spain
IDIVAL, Santander 39008, Spain
Royo, JL:
Univ Malaga, Fac Med, Dept Especial Quirurg Bioquim & Inmunol, Malaga 29016, Spain
Alvarez, V:
Hosp Univ Cent Asturias, Lab Genet, Oviedo 33011, Spain
:
Fundacio Docencia & Recerca MutuaTerrassa, Terrassa 08221, TX, Spain
Hosp Univ Mutua Terrassa, Dept Neurol, Memory Disorders Unit, Terrassa 08221, Spain
Piñol-Ripoll, G:
Hosp Univ Santa Maria Lleida, Unitat Trastorns Cognitius, Lleida 25198, Spain
Inst Recerca Biomed Lleida IRBLLeida, Lleida 25198, Spain
Mir, P:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid 28220, Spain
Univ Seville, Hosp Univ Virgen Rocio, Serv Neurol & Neurofisiol,CSIC, Unidad Trastornos Movimiento,Inst Biomed Sevilla, Seville 41013, Spain
Univ Seville, Fac Med, Dept Med, Seville 41009, Spain
Lara, MC:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid 28220, Spain
Inst Salud Carlos III, Majadahonda 28222, Spain
Padilla, MM:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid 28220, Spain
Queen Sofia Fdn Alzheimer Ctr, CIEN Fdn, Madrid 28220, Spain
Sánchez-Juan, P:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid 28220, Spain
Univ Cantabria, Marques Valdecilla Univ Hosp, Neurol Serv, Santander 39008, Spain
IDIVAL, Santander 39008, Spain
Queen Sofia Fdn Alzheimer Ctr, CIEN Fdn, Madrid 28220, Spain
Carracedo, A:
Univ Santiago de Compostela, Ctr Nacl Genotipado CEGEN PRB3 ISCIII, Grp Med Xen, Santiago De Compostela 15705, Spain
CIBERER, Fdn Publ Galega Med Xen, IDIS, Santiago De Compostela 15705, Spain
Valero, S:
Univ Int Catalunya, Res Ctr, Ace Alzheimer Ctr Barcelona, Barcelona 08017, Spain
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, Memory Clin, Barcelona 08017, Spain
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid 28220, Spain
:
Univ Int Catalunya, Res Ctr, Ace Alzheimer Ctr Barcelona, Barcelona 08017, Spain
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, Memory Clin, Barcelona 08017, Spain
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid 28220, Spain
Tàrraga, L:
Univ Int Catalunya, Res Ctr, Ace Alzheimer Ctr Barcelona, Barcelona 08017, Spain
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, Memory Clin, Barcelona 08017, Spain
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid 28220, Spain
Ramirez, A:
Univ Cologne, Med Fac, Dept Psychiat & Psychotherapy, Div Neurogenet & Mol Psychiat, D-50937 Cologne, Germany
Univ Clin Bonn, Dept Neurodegenerat Dis & Geriatr Psychiat, D-53127 Bonn, Germany
German Ctr Neurodegenerat Dis DZNE, D-53127 Bonn, Germany
Dept Psychiat, San Antonio, TX 78229 USA
Glenn Biggs Inst Alzheimers & Neurodegenerat Dis, San Antonio, TX 78229 USA
Univ Cologne, Excellence Cluster Cellular Stress Responses Agin, D-50931 Cologne, Germany
Boada, M:
Univ Int Catalunya, Res Ctr, Ace Alzheimer Ctr Barcelona, Barcelona 08017, Spain
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, Memory Clin, Barcelona 08017, Spain
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid 28220, Spain
:
Univ Int Catalunya, Res Ctr, Ace Alzheimer Ctr Barcelona, Barcelona 08017, Spain
Univ Int Catalunya, Ace Alzheimer Ctr Barcelona, Memory Clin, Barcelona 08017, Spain
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid 28220, Spain
Green Published, gold
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