Genetic modifiers of psychiatric, motor, and cognitive symptoms in Huntington’s disease

The Enroll-HD natural history platform provides rich longitudinal phenotypes enabling genome-wide analyses across diverse clinical domains. Psychiatric symptoms are a major source of morbidity in Huntington’s disease (HD), yet the genetic architecture underlying their onset is poorly understood. We analyzed ∼18,000 people with HD (PwHD) to define genetic determinants of ages at psychiatric, motor, and cognitive symptom onset, and HD diagnosis. GWAS meta-analysis recapitulated 11 established modifiers of motor onset and identified a novel locus spanning RAB3B / ZFYVE9 associated with age at violent/aggressive behavior onset. Exome-wide analyses in Enroll-HD participants implicated rare variants in FAN1 , PMS1 , POLD1 , and HTT . Several HD modifiers of motor and cognitive symptom onset ( MSH3 , FAN1 , HTT ) also influenced psychiatric symptom onset, whereas PMS1 and POLD1 showed significant association with motor symptom onset. Psychiatric polygenic scores predicted psychiatric symptom onset, revealing a hybrid architecture combining psychiatric liability in general population with HD- or repeat expansion disease (RED)-specific pathways.