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.