Genetic basis of cognitive/psychiatric/behavioural phenotypes in Huntington’s disease [Conference Abstract]

Wills, Christopher, Fitt, Danielle, Mclauchlan, Duncan, Massey, Tom ORCID: https://orcid.org/0000-0002-9804-2131 and Holmans, Peter ORCID: https://orcid.org/0000-0003-0870-9412 2026. Genetic basis of cognitive/psychiatric/behavioural phenotypes in Huntington’s disease [Conference Abstract]. Journal of Neurology, Neurosurgery and Psychiatry 97 (Supp 2) , pp. A28-A29. 10.1136/jnnp-2026-ehdn.71

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Abstract

Background: Novel genetic modifiers have been identified for HD age at onset and progression in recent genome wide association studies (GWAS). However, rates of cognitive, psychiatric, and behavioural problems are also increased in HD, and it is therefore important to identify genetic modifier loci for these. Aims: To characterise the genetic determinants of cognitive, behavioural and psychiatric phenotypes in HD, using polygenic scores (PS) for common neuropsychiatric disorders, and GWAS. Methods: 46 phenotypes were studied at baseline, and linear mixed modelling used to produce progression trajectories. Principal component analysis derived composite phenotypes for baseline and progression. PS for 28 neuropsychiatric measures were constructed and tested for association with the phenotypes in 9,040 patients from Enroll-HD PDS7. GWAS analysis was performed on each phenotype adjusted for age, sex, and CAG length. Results: Two composite phenotypes were observed in both baseline and progression. One comprised cognitive measures, alongside markers of disease severity, and the other psychiatric measures. The most significant baseline associations were with PS for depression, neuroticism, anxiety, educational attainment, and intelligence, the latter two also being protective for cognitive decline over time. Notably, the association of neuroticism PS with both baseline and progression psychiatric composite phenotype is stronger than with any of the individual phenotypes. GWAS analysis identified known HD modifier loci and novel genes associated with DNA repair and neuronal development. Conclusions: Alongside individual susceptibility loci, many phenotypic measures in HD show genetic overlap with neuropsychiatric traits. Combining multiple phenotypes into a single measure may strengthen this overlap.

Item Type:	Short Communication
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	BMJ Publishing Group
ISSN:	0022-3050
Last Modified:	28 Oct 2026 12:30
URI:	https://orca.cardiff.ac.uk/id/eprint/190500

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