Genetic modifiers of Huntington’s disease differentially influence motor and cognitive domains

Genome-wide association studies (GWAS) of Huntington’s disease (HD) have
identified six DNA maintenance gene loci (among others) as modifiers and
implicated a two step-mechanism of pathogenesis: somatic instability of
the causative HTT CAG repeat with subsequent triggering of neuronal
damage. The largest studies have been limited to HD individuals with a
rater-estimated age at motor onset. To capitalize on the wealth of
phenotypic data in several large HD natural history studies, we have
performed algorithmic prediction using common motor and cognitive measures
to predict age at other disease landmarks as additional phenotypes for
GWAS.  Combined with imputation using the Trans-Omics for
Precision Medicine reference panel, predictions using integrated measures
provided objective landmark phenotypes with greater power to detect most
modifier loci.  Importantly, substantial differences in the
relative modifier signal across loci, highlighted by comparing common
modifiers at MSH3 and FAN1, revealed that individual modifier effects can
act preferentially in the motor or cognitive domains. Individual
components of the DNA maintenance modifier mechanisms may therefore act
differentially on the neuronal circuits underlying the corresponding
clinical measures. In addition, we identified new modifier effects at the
PMS1 and PMS2 loci and implicated a potential new locus on chromosome 7.
These findings indicate that broadened discovery and characterization of
HD genetic modifiers based on additional quantitative or qualitative
phenotypes offers not only the promise of in-human validated therapeutic
targets, but also a route to dissecting the mechanisms and cell types
involved in both the somatic instability and toxicity components of HD
pathogenesis.