Mendelian randomization confirms the role of Y-chromosome loss in Alzheimer’s Disease etiopathogenesis in males

Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event occurring exclusively in men 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 randomization to construct an age-independent polygenic risk score of mLOY (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per SD 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 males with mild cognitive impairment (HR=1.23; p=0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group. The male-specificity of the observed effects suggests that these associations of mLOY with AD are caused by the inherent loss of the Y chromosome, and not by the increased genomic instability underlying mLOY risk. Additionally, we found that blood mLOY phenotype was associated with increased CSF 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. Furthermore, we encourage researchers to use this mloy-PRS instrument to find unbiased associations between mLOY and ageing-related diseases. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement P.G. is supported by CIBERNED employment plan CNV-304-PRF-866. CIBERNED is integrated into ISCIII (Instituto de Salud Carlos III). I. de Rojas is supported by a national grant from the Instituto de Salud Carlos III FI20/00215. A. Cano acknowledges the support of the Spanish Ministry of Science, Innovation and Universities under the grant Juan de la Cierva (FJC2018-036012-I). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240 and PI19/01301. The Genome Research @ Fundacio ACE project (GR@ACE) is supported by Grifols SA, Fundacion bancaria La Caixa, Fundacio ACE, and CIBERNED. Accion Estrategica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III) Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER Una manera de hacer Europa). Some control samples and data from patients included in this study were provided in part by the National DNA Bank Carlos III (www.bancoadn.org, University of Salamanca, Spain) and Hospital Universitario Virgen de Valme (Sevilla, Spain); they were processed following standard operating procedures with the appropriate approval of the Ethical and Scientific Committee. Genotyping of the ACE MCI-EADB samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). This work was supported by a grant (European Alzheimer DNA BioBank, EADB) from the EU Joint Program Neurodegenerative Disease Research (JPND). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Written informed consent was obtained from all participants. The Ethics and Scientific Committees have approved this research protocol (Acta 25/2016, Ethics Committee. H., Clinic I Provincial, Barcelona, Spain) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.