Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

Association analysis of chromosome X to identify genetic modifiers of Huntington's disease

Hong, Eun Pyo, Chao, Michael J., Massey, Thomas, McAllister, Branduff, Lobanov, Sergey, Jones, Lesley, Holmans, Peter, Kwak, Seung, Orth, Michael, Ciosi, Marc, Monckton, Darren G., Long, Jeffrey D., Lucente, Diane, Wheeler, Vanessa C., MacDonald, Marcy E., Gusella, James F. and Lee, Jong-Min 2021. Association analysis of chromosome X to identify genetic modifiers of Huntington's disease. Journal of Huntington's Disease 10 (3) , pp. 367-375. 10.3233/JHD-210485

[thumbnail of GWA12345.XWAS.Accepted.Author.Manuscript.pdf] PDF - Accepted Post-Print Version
Download (811kB)


Background:Huntington’s disease (HD) is caused by an expanded (>35) CAG trinucleotide repeat in huntingtin (HTT). Age-at-onset of motor symptoms is inversely correlated with the size of the inherited CAG repeat, which expands further in brain regions due to somatic repeat instability. Our recent genetic investigation focusing on autosomal SNPs revealed that age-at-onset is also influenced by genetic variation at many loci, the majority of which encode genes involved in DNA maintenance/repair processes and repeat instability. Objective:We performed a complementary association analysis to determine whether variants in the X chromosome modify HD. Methods:We imputed SNPs on chromosome X for ∼9,000 HD subjects of European ancestry and performed an X chromosome-wide association study (XWAS) to test for association with age-at-onset corrected for inherited CAG repeat length. Results:In a mixed effects model XWAS analysis of all subjects (males and females), assuming random X-inactivation in females, no genome-wide significant onset modification signal was found. However, suggestive significant association signals were detected at Xq12 (top SNP, rs59098970; p-value, 1.4E-6), near moesin (MSN), in a region devoid of DNA maintenance genes. Additional suggestive signals not involving DNA repair genes were observed in male- and female-only analyses at other locations. Conclusion:Although not genome-wide significant, potentially due to small effect size compared to the power of the current study, our data leave open the possibility of modification of HD by a non-DNA repair process. Our XWAS results are publicly available at the updated GEM EURO 9K website hosted at for browsing, pathway analysis, and data download.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: IOS Press
ISSN: 1879-6397
Date of First Compliant Deposit: 7 September 2021
Date of Acceptance: 3 June 2021
Last Modified: 30 Aug 2022 17:09

Citation Data

Cited 1 time in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item


Downloads per month over past year

View more statistics