Genes That Escape X Chromosome Inactivation Are Associated with Alzheimer’s Disease Endophenotypes: Findings from ROSMAP

AbstractBackgroundWomen are disproportionately affected by Alzheimer’s disease (AD) and exhibit greater AD neuropathology than men. Women possess two X chromosomes, with one randomly silenced across each cell for dosage compensation. X chromosome inactivation (XCI) is not complete, and XCI‐escaping genes provide a promising avenue of discovery for biological pathways driving sex‐specific AD risk. Our objective was to examine XCI‐escaping genes in association with β‐amyloid (Aβ) and tau tangle density, and cognitive decline.MethodsUsing bulk RNAseq from dorsolateral prefrontal cortex tissue, Aβ plaque and tau tangle pathology, and antemortem longitudinal cognition data from ROSMAP, we investigated whether XCI‐escaping genes explain significant variance in AD endophenotypes. Propensity scoring based on age‐at‐death, postmortem interval, race, latency‐to‐death, education, and APOEε4 status resulted in a matched sample (N = 648, age‐at‐deathmean(SD) = 87.5(6.5)). Linear regression and mixed‐effects models assessed the association between 216 reported XCI‐escaping genes and Aβ and tau at autopsy, and a longitudinal global cognitive composite. Analyses were sex‐stratified and FDR‐corrected. Differential expression analyses assessed sex‐biased mean gene expression.Results22 XCI‐escaping genes were associated with Aβ (20 female‐specific, 2 male‐specific), 49 genes with tau (43 female‐specific, 6 male‐specific), and 48 genes with cognitive decline (46 female‐specific, 2 male‐specific). In women, 40%(8/20) were negatively associated with Aβ, 56%(24/43) negatively associated with tauopathy, and 43%(20/46) were negatively associated with cognitive decline. Of note, higher GRIPAP1 expression was associated with lower Aβ (β = ‐0.18, pFDR = 0.02) and tau (β = ‐0.21, pFDR = 0.001), and slower cognitive decline (β = 0.02, pFDR = 0.04) in women. By contrast, ATP11C expression was associated with higher Aβ (β = 0.19, pFDR = 0.03) and tau (β = 0.15, pFDR = 0.03), and faster cognitive decline (β = ‐0.02, pFDR = 0.03) in women. Unexpectedly, of 216 XCI‐escaping genes tested, only 4% were expressed more highly in females than males.ConclusionGRIPAP1 and ATP11C are implicated in endosomal recycling and inflammation, respectively, supporting two pathways associated with AD. Both GRIPAP1 and ATP11C exhibited sex‐parity in gene expression suggesting that single‐cell RNAseq will be necessary to further characterize XCI‐escapism in relation to AD risk. Altogether, this study presents evidence that studying the X chromosome is integral to understanding female resistance, resilience, and vulnerability to AD pathology.