Genetic risk underlying psychiatric and cognitive symptoms in Huntington’s Disease

Abstract

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 exam 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. 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 constructing polygenic risk scores from large genome-wide association studies of psychiatric and neurodegenerative disorders, and of intelligence, and testing for correlation with the presence of psychiatric and cognitive symptoms in a large sample (n=5160) of HD patients. 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. In general, 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.

Psychosis as a Treatment Target in Dementia: A Roadmap for Designing Interventions

“…In the aforementioned GWAS, depressive symptoms were positively genetically correlated with psychosis, while bipolar disorder was negatively correlated. No genetic correlation was found with schizophrenia, but previous studies using schizophrenia polygenic risk scores to evaluate shared genetic liability have reported associations with psychosis in AD and in Huntington's disease, and with psychotic experiences in the general population [120][121][122][123].…”

Psychosis-associated DNA methylomic variation in Alzheimer's disease cortex

“…There are several converging lines of evidence to suggest that psychotic symptoms across the life span have some common mechanisms. Recent genomic research has linked polygenic risk for SZ to psychotic symptoms in Huntington's disease (Ellis et al, 2019) and AD (Creese et al, 2019), as well as psychotic experiences in the general population (Legge et al, 2019), while neuropsychological testing implicates similar deficits in processing speed and executive function in individuals with very-late-onset SZ-like psychosis and AD þ P (Van Assche et al, 2019). Our findings that top-ranked AD þ P-associated DMPs are enriched for SZ loci extend this evidence base into molecular-level mechanistic similarities for the first time.…”

What is the Pathogenic CAG Expansion Length in Huntington’s Disease?

“…The differences in disease manifestation in people are not reflected in mice, because laboratory mice are much less genetically diverse and live in a more uniform environment. Genetic variation in HD subjects influences the presentation of many non-motor symptoms for instance [106]. Most HD mouse models, despite possession of a repeat length that would give juvenile HD with its different clinical presentation, show a similar motor phenotype (though this may be an artefact of how this is measured) ( Table 1) [47].…”