C005 Identification of genetic modifiers of HTT CAG repeat somatic expansion in blood: a genome-wide association study in a large cohort of Huntington disease expansion-carriers

<h3>Background</h3> The Huntington disease (HD) CAG repeat is genetically unstable, and its somatic expansion plays a critical role in the manifestation of HD. Understanding the factors that influence these somatic expansions can thus provide insights into the development and progression of the disease. It can also allow the identification of therapeutic targets with the aim of slowing somatic expansions and consequently HD progression. <h3>Aim</h3> Identification of genetic modifiers of somatic expansions of the HTT CAG repeat. <h3>Methods/Techniques</h3> We have quantified somatic CAG expansions of HD-causing alleles in nearly 4,000 blood DNA samples from Enroll-HD participants using ultra-deep MiSeq sequencing (~10,000 sequencing reads per allele on average). The CAG and age-adjusted quantity of somatic CAG expansions was then used as a phenotype in a genome-wide association study. <h3>Results/Outcome</h3> We identified genome-wide significant genetic modifier effects at the DNA mismatch repair genes MSH2, MSH6, MSH3, PMS2, MLH3, and FAN1. Some of these genes have previously been identified as genetic modifiers of HD clinical phenotypes and have been involved with somatic repeat expansions in animal model of HD and other repeat expansion disorders. <h3>Conclusions</h3> These findings suggest that some genetic modifiers of HD operate via their effects on the somatic expansion of the HTT CAG repeat, supporting the latter as a potential therapeutic target in HD. Since somatic expansion is a common feature of multiple repeat expansion disorders, the identified genetic modifiers may also be potential targets in these disorders.