X Chromosome Genetic Overlap of Hormone, Lipid, and Brain Imaging Traits with Alzheimer’s Disease Reveals Novel Risk Genes

Motivation: The X chromosome represents 5% of the genome and plays an obvious role in driving sex dimorphism yet has remained largely understudied in genome-wide association studies. Goal(s): Leverage a recent large-scale X chromosome-wide association study of Alzheimer's disease to integrate X chromosome genetic data from AD-related traits, including lipid, hormone, and brain imaging phenotypes, to identify shared genetic signals. Approach: Genetic colocalization analyses across AD-trait pairs. Results: We identified 20 loci with potential links to AD, including 15 novel risk loci, some showing female-specific effects. The findings enhance our understanding of sex-specific AD pathways and may inform future drug targets and treatment strategies. Impact: Integrating X chromosome genetic data for Alzheimer's disease (AD) with related traits, we uncovered 20 AD risk loci, including several showing sex-specific effects. These findings provide new biological insights into AD and highlight potential sex-agnostic and sex-specific AD drug targets.