Year: 2024
Type: conference-paper
Abstract: Huntington’s disease (HD) is caused by an expanded CAG repeat in the huntingtin gene (HTT). Beyond this primary causative gene, other genetic factors also modify the disease processes, as the age at which clinical symptoms manifest in this monogenic disorder is not entirely determined by the CAG repeat length alone. Notably, approximately 65% of the variance in the age of onset for motor symptoms can be attributed to the CAG repeat length, while the remaining variance exhibits heritability, indicating the involvement of genetic modifiers in HD. Importantly, identifying the genetic modifiers can uncover fundamental disease mechanisms and guide therapeutic strategies, providing the rationale for the genome-wide searches for such modifiers. Therefore, the Genetic Modifiers of HD (GeM-HD) Consortium conducted a series of genome-wide association studies (GWAS) to identify genetic modifiers of HD, revealing that the uninterrupted HTT CAG repeat sequence, rather than the polyglutamine segment in the huntingtin protein, influences the rate of HD pathogenesis. The latter is further modulated by polymorphic variations in multiple DNA repair genes. Subsequent GWAS leveraging the genotype and phenotype data from the ENROLL-HD platform have further revealed that HD modification is driven by complex, cell type-specific DNA repair pathways that impact clinical landmarks and somatic repeat instability phenotypes. Additionally, the genotype data within ENROLL-HD can facilitate the identification of suitable subjects for gene-targeting approaches. The ENROLL-HD platform, by supporting the discovery of genetic modifiers and enabling genotype-based research, provides a valuable resource for underpinning the development of effective treatments for HD.
Author: Jong-Min Lee
Institutions: Harvard University, Massachusetts General Hospital
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4402374129