This project aims to investigate the genetic and epigenetic mechanisms underlying neurodegenerative disorders, with a particular focus on polyglutamine (PolyQ) diseases such as Huntington’s disease and Spinocerebellar ataxias, as well as Amyotrophic Lateral Sclerosis (ALS). Although these disorders are clinically distinct, they may share overlapping pathways or diverging molecular processes that contribute to neurodegeneration. Understanding these patterns is critical for improving disease classification and identifying potential therapeutic targets (Li Gan et al., 2018).
The study will primarily use UK Biobank’s whole genome sequencing (WGS) and methylation array data to explore the convergence and divergence of genetic risk factors across these diseases. We will perform genotype-first analyses of known or suspected pathogenic variants in key neurodegenerative genes (such as HTT, ATXN1, C9orf72), and examine the downstream phenotypic and clinical profiles of variant carriers compared to non-carriers. These analyses will include assessments of disease status, cognitive function, and age-related traits.
A second key component of this project involves integrating findings from external single-nucleus RNA sequencing (snRNA-seq) studies to guide the selection of candidate genes and regions of interest. We aim to conduct both genome-wide and targeted analyses, including rare variant burden testing, polygenic risk scoring, and sequence alignment at loci associated with trinucleotide repeat expansions.
All analyses will be conducted through the Research Analysis Platform (RAP). The project is led by graduate student Rivka Masar as part of her academic research, under the supervision of the Principal Investigator, who will ensure compliance with UK Biobank requirements. We request access to sequencing, methylation, clinical, cognitive, and mortality data, and seek approval under the student fee structure.