B49 Genetic modifiers of huntington's disease progression. (13th September 2016)

• Record Type: Journal Article
• Authors: Moss, Davina J Hensman; Pardiñas, Antonio F; Flower, Michael; Miller, James; Lo, Kitty; Plagnol, Vincent; Holmans, Peter; Jones, Lesley; Langbehn, Douglas; Tabrizi, Sarah J
• Is Part Of: Journal of neurology, neurosurgery and psychiatry. Volume 87(2016)Supplement 1
• Page Start: A26
• Page End: A27
• Publication Date: 2016-09-13
• Subjects: Genetic modifiers GWAS Progression Age at onset; Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Psychiatry -- Periodicals; 616.8
• DOI: 10.1136/jnnp-2016-314597.80
• Languages: English
• ISSNs: 0022-3050

Abstract

Abstract : Background: Huntington's disease is caused by a CAG repeat expansion; ~60% onset variability is accounted for by age and CAG but studies point to ≥40% residual heritability. Disease progression offers advantages over age-at-motor onset (AAO) as an analytical phenotype which include use of multiple variables and time-points, and less inter-rater subjectivity. Aims: To define accurate stable measures of disease progression in Huntington's, and use these to identify genetic modifiers. Methods: The availability of high quality longitudinal and multivariate data in TRACK-HD enabled us to define rate of progression accurately in 218 subjects. These subjects were then genotyped; imputation then QC generated 9, 938, 174 variants in 216 subjects. Using mixed-linear models we tested for association with disease progression. To validate our findings we developed a cross-sectional measure of disease progression, and used this to stratify the EHDN REGISTRY cohort. 1, 773 subjects with valid phenotype were genotyped, mixed-linear models were used to determine association with cross sectional disease progression. Results: We find AAO and progression are correlated, but no evidence of distinct phenotypic clusters: imaging, cognitive, and quantitative-motor measures progress in parallel. In our TRACK-HD analysis we identify one significant association (P = 1.92 × 10 −8 ) and one association approaching significance in a gene previously implicated in HD mouse and cell studies (P = 5.82 × 10 −8 ). The TRACK-HD peak in a previously HD-implicated gene was replicated with P = 1.39 × 10 −5 in the REGISTRY analysis. Furthermore we found an association (P = 2.90 × 10 −7 ) between the cross sectional progression score and a Chromosome 15 locus previously associated with AAO.