Integrative Analysis to Understand the Contribution of the X Chromosome to Alzheimer's Disease

The X chromosome constitutes about ~5% of the human genome and harbors approximately 800 protein-coding genes, many of which have important immune and brain-related functions. Recently, we and others have demonstrated that the X chromosome is involved in Alzheimer’s disease (AD) risk. However, X chromosome genetics have not been comprehensively studies in large heterogeneous populations representative of the U.S. Furthermore, the process of X chromosome inactivation (XCI) balances gene expression across sexes. However, about 15% of genes on the inactive X chromosome consistently escaping inactivation and an additional 10% show variable escape patterns among individuals. The complexity in X chromosome requires careful analytical strategies that integrates epigenetics and multi-omics data. Unfortunately, large-scale population-based genetic and epigenetic studies in AD often ignore the X chromosome because of the analytical complexity, leaving a gap in our understanding of its influence on AD. This proposal seeks to fill this knowledge gap by conducting integrative analyses focused on the X chromosome and its relationship with AD, by leveraging a large number of genetic, DNA methylation and multi-omics population cohorts datasets. Specifically, in Aim 1, we will expand and confirm our knowledge of X chromosome genetic architecture in relation to risk and protection for AD in heterogenous large cohort studies. In Aim 2, we will identify DNA methylation (DNAm) differences on the X chromosome that are associated with AD in both brain and blood. In Aim 3, we will perform integrative multi- omics analysis to decipher the functional basis of X chr variants associated with AD. Our study will substantially improve the current understanding of the contribution of X chromosome genetics and epigenetics to AD, thus facilitating more targeted prevention, diagnostic, and treatment strategies. Project Number: 1RF1AG099026-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Brian Kunkle (+3 co-PIs) | Institution: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE, CORAL GABLES, FL | Award Amount: $3,232,914 | Activity Code: RF1 | Study Section: Neurological, Mental and Behavioral Health Study Section[NMBH] View on NIH RePORTER: https://reporter.nih.gov/project-details/11301304