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

Article type: Research Article

Authors: Hong, Eun Pyo^{a; b; c; 1} | Chao, Michael J.^{a; b; 1} | Massey, Thomas^d | McAllister, Branduff^d | Lobanov, Sergey^d | Jones, Lesley^{d; 2} | Holmans, Peter^{d; 2} | Kwak, Seung^{e; 2} | Orth, Michael^{f; 2} | Ciosi, Marc^g | Monckton, Darren G.^{g; 2} | Long, Jeffrey D.^{h; 2} | Lucente, Diane^a | Wheeler, Vanessa C.^{a; b; c; 2} | MacDonald, Marcy E.^{a; b; c; 2} | Gusella, James F.^{a; c; i; 2} | Lee, Jong-Min^{a; b; c; 2; *}

Affiliations: [a] Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA | [b] Department of Neurology, Harvard Medical School, Boston, MA, USA | [c] Medical and Population Genetics Program, the Broad Institute of M.I.T. and Harvard, Cambridge, MA, USA | [d] Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK | [e] CHDI Foundation, Princeton, NJ, USA | [f] Department of Old Age Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland | [g] Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK | [h] Department of Psychiatry, Carver College of Medicine and Department of Biostatistics, College of Public Health, and Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA | [i] Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA

Correspondence: [*] Correspondence to: Jong-Min Lee, Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. Tel.: +1 617 643 9714; Fax: +1 617 726 5735; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Note: [2] GeM-HD Consortium investigators

Abstract: 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 https://www.hdinhd.org/ for browsing, pathway analysis, and data download.

Keywords: Genetic modifier, Huntington’s disease, residual age-at-onset, XWAS

DOI: 10.3233/JHD-210485

Journal: Journal of Huntington's Disease, vol. 10, no. 3, pp. 367-375, 2021