Genetic Risk Underlying Psychiatric and Cognitive Symptoms in Huntington’s Disease

Abstract

BACKGROUND: Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene. It is diagnosed following a standardized examination of motor control and often presents with cognitive decline and psychiatric symptoms. Recent studies have detected genetic loci modifying the age at onset of motor symptoms in HD, but genetic factors influencing cognitive and psychiatric presentations are unknown. METHODS: We tested the hypothesis that psychiatric and cognitive symptoms in HD are influenced by the same common genetic variation as in the general population by 1) constructing polygenic risk scores from large genomewide association studies of psychiatric and neurodegenerative disorders and of intelligence and 2) testing for correlation with the presence of psychiatric and cognitive symptoms in a large sample (n = 5160) of patients with HD. RESULTS: Polygenic risk score for major depression was associated specifically with increased risk of depression in HD, as was schizophrenia risk score with psychosis and irritability. Cognitive impairment and apathy were associated with reduced polygenic risk score for intelligence. CONCLUSIONS: Polygenic risk scores for psychiatric disorders, particularly depression and schizophrenia, are associated with increased risk of the corresponding psychiatric symptoms in HD, suggesting a common genetic liability. However, the genetic liability to cognitive impairment and apathy appears to be distinct from other psychiatric symptoms in HD. No associations were observed between HD symptoms and risk scores for other neurodegenerative disorders. These data provide a rationale for treatments effective in depression and schizophrenia to be used to treat depression and psychotic symptoms in HD.

The timing and impact of psychiatric, cognitive and motor abnormalities in Huntington’s disease

“…Cognitive impairment measured by SDMT or Stroop correlated most strongly with lifetime history of cognitive impairment in HD-CCQ, as expected, but also showed significant correlations with motor symptoms and apathy. These results fit with other studies showing that these symptoms track together in the disease trajectory 29,30 . There was also a significant association between cognitive impairment and psychosis, which fits the cognitive deficits observed in schizophrenia 31 (table 2), much more prevalent than in non-HD populations 5,10,32,33 , and likely underestimated due to pathological unawareness of these traits by HD patients 34 .…”

“…HD-CCQ provides particular insight into neuropsychiatric symptoms but is not designed to capture the subtle early motor or cognitive signs found in prospective studies 7,8 . As it relies on retrospective reporting by patients and care partners the HD-CCQ is necessarily coarse, although the data it generates correlate well with more precise measures of depression, irritability and cognition (table 1) showing that these symptoms track together in the disease trajectory 39,41 . There was also a significant association between cognitive impairment and psychosis, which fits the cognitive deficits observed in schizophrenia 42 .…”

“…This is a much higher figure than previously reported based on clinician estimates of first HD manifestation (figure 1) 9 , most likely because it is difficult to confidently attribute early psychiatric symptoms to HD. The overlap between HD and psychiatric disorders has been demonstrated by the recent finding that polygenic risk scores for psychiatric diseases, particularly depression and schizophrenia, are associated with increased risk of corresponding psychiatric symptoms in HD 29 . This suggests that the expanded HTT CAG repeat might lower the genetic threshold for manifestation of typical psychiatric symptoms 29 .…”

“…The differences in ages between first motor symptoms and each of the psychiatric symptoms were approximately normally distributed, with a wide range of at least +/-20 years in each case (figures 2 and e-2, doi:10.5061/dryad.pk0p2ngkz). In those patients reporting depression, onset occurred before motor symptoms in 39 We next assessed whether there were any patterns in the mean ages of onset of the -25 ). Depression was significantly associated with lower total motor scores (indicating fewer motor symptoms or signs), fitting with its prevalence early in the disease course.…”

Phosphodiesterase 9A Inhibition Facilitates Corticostriatal Transmission in Wild-Type and Transgenic Rats That Model Huntington’s Disease

“…Hallmark pathological features of HD include progressive motor dysfunction characterized by an initial hyperkinetic phase (uncontrolled dance-like movements termed chorea), and a subsequent hypokinetic phase associated with dystonia and rigidity (Berardelli et al, 1999;Zuccato et al, 2010). Decline in motor control is often accompanied by cognitive, emotional, and psychiatric disturbances (Walker, 2007;Bates et al, 2015;Espinoza et al, 2019;Ellis et al, 2020). Neuropathological studies point to preferential degeneration of striatopallidal medium-sized spiny neurons (MSNs) and dysfunction of corticostriatal projection neurons (Wong et al, 1982;Reiner et al, 1988;Vonsattel et al, 2008).…”