Genetic modifiers of somatic expansion and clinical phenotypes in Huntington’s disease reveal shared and tissue-specific effects

An inherited, expanded CAG repeat in HTT undergoes further somatic
expansion to cause Huntington’s disease (HD).  To gain insights
into this molecular mechanism, we compared genome-wide association studies
of somatic expansion in blood and somatic expansion-driven HD clinical
phenotypes.  Here, we show that somatic expansion is driven by a
mismatch repair-related process whose genetic modification and
consequences show unexpected complexity, including cell-type
specificity.  The HD clinical trajectory is further modified by
non-DNA repair genes that differentially influence measures of cognitive
and motor dysfunction.  In addition to shared (DNA repair genes
MSH3, PMS2, and FAN1) and distinct trans-modifiers, a synonymous
CAG-adjacent variant in HTT dramatically hastens motor onset without
increasing somatic expansion, while a cis-acting 5’-UTR variant promotes
blood repeat expansion without influencing clinical HD.  Our
findings are directly relevant to the therapeutic suppression of expansion
in DNA repeat disorders and provide additional clues to HD pathogenic
mechanisms beyond somatic expansion.