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Association Analysis of Chromosome X to Identify Genetic Modifiers of Huntington's Disease
Journal article   Open access   Peer reviewed

Association Analysis of Chromosome X to Identify Genetic Modifiers of Huntington's Disease

Eun Pyo Hong, Michael J Chao, Thomas Massey, Branduff McAllister, Sergey Lobanov, Lesley Jones, Peter Holmans, Seung Kwak, Michael Orth, Marc Ciosi, …
Journal of Huntington's disease, Vol.10(3), pp.367-375
2021
DOI: 10.3233/JHD-210485
PMCID: PMC8860147
PMID: 34180418
url
https://eprints.gla.ac.uk/view/journal_volume/Journal_of_Huntington=27s_Disease.html>,View
Open Access

Abstract

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. We performed a complementary association analysis to determine whether variants in the X chromosome modify HD. 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. 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. 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 https://www.hdinhd.org/ for browsing, pathway analysis, and data download.
 Age of Onset Female Genes, Modifier Genome-Wide Association Study Humans Huntingtin Protein - genetics Huntington Disease - genetics Male X Chromosome

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