2024
The overarching goal of this project is to identify genes on the X chromosome that affect the risk for Alzheimer’s disease or Parkinson’s disease in a sex-specific manner. Together, these two diseases are the most common neurodegenerative disorders across the globe, and strikingly, both display well-established sex differences, with about 2/3 of Alzheimer’s disease patients being women and about 2/3 of Parkinson’s disease patients being men. While many factors may contribute to these sex biases, genetics has been proposed as an important role player. The study of human genetics is pivotal to identifying genes that can be targeted for drug development, but sex-specific genetic risk factors in Alzheimer’s disease and Parkinson’s disease remain understudied, impeding advances in sex-specific precision medicine. The sex chromosomes (XY in men, XX in women) may represent an obvious source of sex-specific risk factors, but because of various technical and analytical challenges, they have been excluded in virtually most genetic studies to date. We have recently developed a state-of-the-art pipeline to perform the first large-scale genetic association studies on the X chromosome in both Parkinson’s and Alzheimer’s disease and have started making compelling novel discoveries. We, however, still face challenges in terms of having enough sample sizes (i.e., power) and simply having access to appropriate data to help clearly identify relevant genes on the X chromosome. This is exactly what the current project will address. We will apply our expertise and pipelines to process X chromosome genetic data and then determine how genetic variants regulate X chromosome protein levels as well as biomarkers of Parkinson’s and Alzheimer’s disease. We will then use innovative strategies to integrate this wealth of data to increase our power and prioritize important X chromosome genes. Ultimately, we believe this study will identify drug targets to improve treatment in men and women, respectively.
Michael Belloy, Ph.D.
