Data from: CAG repeat not polyglutamine length determines timing of Huntington’s disease onset

Variable, glutamine-encoding, CAA interruptions indicate that a property
of the uninterrupted HTT CAG repeat sequence, distinct from the length of
huntingtin’s polyglutamine segment, dictates the rate at which
Huntington’s disease (HD) develops. The timing of onset shows no
significant association with HTT cis-eQTLs but is influenced, sometimes in
a sex-specific manner, by polymorphic variation at multiple DNA
maintenance genes, suggesting that the special onset-determining property
of the uninterrupted CAG repeat is a propensity for length instability
that leads to its somatic expansion. Additional naturally occurring
genetic modifier loci, defined by GWAS, may influence HD pathogenesis
through other mechanisms. These findings have profound implications for
the pathogenesis of HD and other repeat diseases and question the
fundamental premise that polyglutamine length determines the rate of
pathogenesis in the “polyglutamine disorders.”