Genetic overlap between psychiatric disorders and neuropsychiatric symptoms in HD

Abstract Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in HTT. It is diagnosed following a standardized exam of motor control and often presents with cognitive decline and neuropsychiatric signs and symptoms. Recent studies have indicated genetic loci modifying the age at onset of motor symptoms, and it is therefore of interest to determine whether the neuropsychiatric symptoms in HD are influenced by the same genetic variation that mediates risk for psychiatric disorders in the wider population. This hypothesis was investigated by constructing polygenic risk scores from large recent genetic association studies of psychiatric and neurodegenerative disorders and of intelligence, and testing for association with the presentation of signs and symptoms in a large sample (n=5160) of HD patients. Multiple associations of psychiatric disease polygenic risk scores were observed with neuropsychiatric and cognitive symptoms in HD, of which the most striking were those between schizophrenia and psychosis in HD. Interestingly, polygenic risk score for increased intelligence was protective for cognitive decline and apathy in HD. Consistent with previous studies, no associations were seen between polygenic risk scores for the other major neurodegenerative disorders and neuropsychiatric or cognitive symptoms in HD.