Age at motor onset and disease progression in HD have a genetic contribution. Psychiatric symptoms are more frequent in HD compared with the general population and there is some evidence that these symptoms are heritable.Aims
To test for shared genetic liability between neuropsychiatric disorders and the presence of psychiatric symptoms (psychosis, irritability, depression, apathy, violence/aggression, obsessive behaviour, cognitive dysfunction) in the REGISTRY HD cohort.Methods/techniques
The presence of psychiatric phenotypes in HD was determined using the HD clinical characteristics questionnaire (HDCC). GWAS summary statistics for schizophrenia, bipolar disorder, ADHD, major depression (MDD) and autism were obtained from the Psychiatric Genomics Consortium and used to construct polygenic risk scores (PRS) in 4065 unrelated HD individuals from REGISTRY. Association between PRS and phenotype was carried out via logistic regression, correcting for CAG length and ethnicity.Results
Significant associations (after correcting for multiple testing) were observed between schizophrenia PRS and increased risk of psychosis (OR=1.24, p=2.45×10–5), violence/aggression (OR=1.21, p=5.74×10–7), irritability (OR=1.17, p=1.94×10–6) and depression (OR=1.16, p=5.88×10–5). Each phenotypic association remained significant after conditioning on the others. Further significant associations were observed for depression with MDD (OR=1.11, p=2.07×10–3) and bipolar (OR=1.14, p=4.51×10–4) PRS and between violence/aggression and ADHD PRS (OR=1.12, p=1.24×10–3). The associations between depression and each of the schizophrenia, MDD and bipolar risk scores remained significant when tested simultaneously.Conclusions
There is significant, though complex, association between genetic liability to neuropsychiatric disorders and psychiatric symptoms in HD. Further work is needed to ascertain which combinations of symptoms and risk scores correlate best and to understand their biological and clinical importance.