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, Víctor Andrade, Pamela V. Martino Adami, Stefanie Heilmann‐Heimbach, Pilar Gómez‐Garre, María Teresa Periñán, Ignacio Álvarez, Mónica Díez-Fairén, Raúl Núñez‐Llaves, Clàudia Olivé, Guillermo García‐Ribas, Manuel Menéndez‐González, Carmen Martı́nez, Miquel Aguilar, Maríateresa Buongiorno, Emilio Franco‐Macías, María Eugenia Sáez, Amanda Cano, María J. Bullido, Luís Miguel Real, Eloy Rodríguez‐Rodríguez, José Luís Royo, Victoria Álvarez, Pau Pástor, Gerard Piñol‐Ripoll, Pablo Mir, Miguel Calero, Miguel Medina, Pascual Sánchez‐Juan, Ãngel Carracedo, Sergi Valero, Isabel Hernández, Lluís Tárraga, Alfredo Ramı́rez, Merçé Boada, Agustı́n Ruiz
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.