Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer's Disease Aetiopathogenesis in Men

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; CSF biomarkers; EADB; GR@ACE/DEGESCO; GWAS; Mendelian randomization; disease progression; mild cognitive impairment; mosaic loss of chromosome Y; polygenic risk score.

Figure 1

mLRR-y variation with age in the GR@ACE-DEGESCO cohort. (a) Age and mLRR-Y distribution in the case and control groups. The dots represent mLRR-Y values for individual samples, and the histogram represents the age distribution across the case and control groups. (b) Proportion of individuals with mLOY in the different age groups based on age at blood sampling. (c,d) mLRR-Y distribution for the different age groups based on age at blood sampling in control and AD individuals, respectively.

Figure 2

Association of mLOY phenotypes with risk of conversion to dementia and AD dementia over time for men with MCI in the GR@ACE-DEGESCO cohort. Kaplan–Meier plots showing survival time in years for conversion to (a) dementia or (b) AD for prospective MCI men with LOY (blue) or without LOY (red) in the GR@ACE-DEGESCO cohort.

Figure 3

mLRR-Y associations with CSF protein levels. (a–c) Forest plots showing the effect size obtained in linear regression models for mLRR-Y on (a) Abeta-42, (b) phospho-tau, and (c) total tau in men with MCI or dementia, along with the meta-analysis results. (d–g) Volcano plots showing association of CSF proteins in the Olink inflammation and neurology panels with (d) mLRR-Y, (e) mLRR-Y adjusted by total tau, (f) APOE genotype, and (g) total tau. (h–k) QQ plots obtained in the models for (h) mLRR-Y, (i) mLRR-Y adjusted by total tau, (j) APOE genotype, and (k) total tau. We adjusted the models by age, the time window between CSF and DNA sampling, and APOE genotype.