SWHR Emerging Scholars in Women’s Health Research Awardee
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Dr. Mabel Seto is a postdoctoral fellow in the Department of Neurology at Brigham and Women’s Hospital. She received her Ph.D. in Pharmacology from Vanderbilt University, where she utilized multi-omic analyses to identify genetic and molecular modifiers of Alzheimer’s disease risk. Since her Ph.D., she has largely focused on using computational approaches to perform AD research with the goal of identifying new targets for AD drug discovery. She is currently in the lab of Dr. Rachel Buckley, and her present work and interests are related to sex differences in AD, particularly how genes expressed on the X chromosome affects AD endophenotypes. She was also recently awarded an Alzheimer’s Association Research Fellowship to study how parental history of dementia influences offspring AD risk.

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

Mabel Seto [1],[2], Michelle J. Clifton [2], Gillian T. Coughlan [1], Ting-Chen Wang [2], Reisa A. Sperling [1], Yanling Wang [4], David A. Bennett, Timothy J. Hohman [2], Hyun-Sik Yang [1], Logan Dumitrescu [2], Rachel F. Buckley [1]  

[1] MGH 

[2] Vanderbilt University 

[4] Rush University  

 Alzheimer’s disease (AD) disproportionately affects women. 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. Using bulk RNAseq from dorsolateral prefrontal cortex tissue, Aβ plaque and tau tangle pathology, and antemortem longitudinal cognition data in a matched sample from ROSMAP (N=648, age-at-deathmean(SD)=87.5(6.5)), we assessed the association between 216 reported XCI-escaping genes and Aβ and tau at autopsy, and longitudinal cognition in linear regression and mixed-effects models. Analyses were sex-stratified and FDR-corrected. 22 genes were associated with Aβ (20 female-specific, 2 male-specific), 49 genes with tau (43 female, 6 male), and 48 genes with cognitive decline (46 female, 2 male). In women, 40% (8/20) were protective against Aβ, 56% (24/43) against tauopathy, and 43% (20/46) against cognitive decline. Of note, higher GRIPAP1 expression was associated with lower Aβ (β=-0.18, p=0.02) and tau (β=-0.21, p=0.001), and slower cognitive decline (β=0.02, p=0.04) in women whereas ATP11C expression was associated with higher Aβ (β=0.19, p=0.03) and tau (β=0.15, p=0.03), and faster cognitive decline (β =-0.02, p=0.03). Altogether, this study presents evidence that studying the X chromosome is integral to understanding female resilience and vulnerability to AD pathology. This study was supported by the NIH New Innovator Award (DP2AG082342). 

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