Determine frequency of systemic and psychiatric comorbidities in Huntington disease gene expansion carriers (HDGECs) and compare them with non-carrier controls in Enroll-HD cohort.

Enroll-HD is a multi-center longitudinal natural history study with 15300 participants (11581 HDGECs and 3719 controls) until last dataset. Systemic involvement in Huntington Disease (HD) has not been studied in detail; literature suggests cardiac, muscle and/or liver involvement. Therapies aimed at decreasing systemic and CNS expression of both mutant and normal HTT gene are being developed. HTT, being ubiquitously expressed, understanding systemic involvement in HD is vital. 

We classified comorbidity data with ICD10 codes and collated it using PheWAS for medical and MEDRA for surgical codes. Data was analyzed for occurrence and relative frequency of specific systemic and psychiatric disorders and compared between the HDGECs and controls.  

Of all participants 10,191 (86%) HDGECS (average age 49.6 years, M:F::44:56) and 2956 (79.5%) controls (average age 49 years, M:F::38:62) reported 57,605 co-morbidities. Reported frequencies of cardiac, gastrointestinal, kidney, thyroid and endocrine, respiratory, hematologic, vascular and oncologic co-morbidities was comparable among the two groups. Hypertension was reported in 13.8% HDGECs versus 19.4% controls, type II diabetes 4.4% versus 6.9% and hyperlipidemia 10.5% versus 12.7% respectively. Mood disorders was reported in 44% HDGECs versus 25.6% controls, behavior/personality change in 6.5% versus 1%, psychosis 4.5% versus 1.7% and sleep disorders in 8.3% versus 3.2%, fracture 13% versus 6%, falls 6.4% versus 2.8% respectively.

In contrast to current literature, frequency of systemic co-morbidities is similar in occurrence between HDGECs and controls; not unexpectedly, falls and orthopedic complications are more frequent. Diabetes and hypertension are less frequent in HDGECs than controls and general population. Depression and anxiety are more frequent in HDGECs; however, disorders of behavior and personality may be specific indicators of HD related psychological change. Sleep disorders deserve to be further investigated.