C016 Genetic basis of cognitive/psychiatric/behavioural phenotypes in Huntington’s disease

<h3>Background</h3> Genetic modifiers outside the expanded CAG repeat in HTT have been identified for HD age at onset and progression in recent genome wide association studies (GWAS). However, HD patients also show cognitive, psychiatric, and behavioural phenotypes, and it is therefore of interest to identify genetic modifier loci for these. <h3>Aims</h3> To characterise the genetic determinants of these phenotypes, and their underlying biology, using polygenic scores (PS) for common neuropsychiatric disorders, GWAS and post-GWAS analyses. <h3>Methods</h3> 9,040 patients from the ENROLL-HD PDS6 database were genome-wide genotyped, passed genetic quality control and had data for 46 phenotypes. PS for 11 neuropsychiatric measures were constructed using PRS-CS and assessed for association with the phenotypes using linear/logistic regression. Linear mixed model GWAS analysis in GENESIS, gene/pathway and FUSION based transcriptome-wide association (TWAS) analyses were performed on baseline values of each phenotype, along with 5 composite phenotypes derived using principal component analysis. Analyses adjusted for age, sex and CAG length. <h3>Results</h3> PS for the cognitive and non-cognitive aspects of educational attainment were associated with several HD phenotypes, notably with measures of verbal fluency. The MSH3 and FAN1 loci showed strong associations with several phenotypes and composite measures. TWAS indicated differential gene expression. Novel loci contained genes associated with neuronal development and plasticity, and the schizophrenia risk locus 22q11.2. <h3>Conclusions</h3> We have shown genetic overlap of behavioural, cognitive and psychiatric phenotypes in HD with educational attainment and neuropsychiatric traits, and also identified individual loci influencing these phenotypes.