Eun Pyo Hong1,2,3, Michael J Chao1,2, Thomas Massey4, Branduff McAllister4, Sergey Lobanov4, Lesley Jones4, Peter Holmans4, Seung Kwak5, Michael Orth6, Marc Ciosi7, Darren G Monckton7, Jeffrey D Long8, Diane Lucente1, Vanessa C Wheeler1,2,3, Marcy E MacDonald1,2,3, James F Gusella1,3,9, Jong-Min Lee1,2,3. 1. Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. 2. Department of Neurology, Harvard Medical School, Boston, MA, USA. 3. Medical and Population Genetics Program, the Broad Institute of M.I.T. and Harvard, Cambridge, MA, USA. 4. Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK. 5. CHDI Foundation, Princeton, NJ, USA. 6. Department of Old Age Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland. 7. Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. 8. 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. 9. Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
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.
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.
Authors: Fernando Morales; Melissa Vásquez; Carolina Santamaría; Patricia Cuenca; Eyleen Corrales; Darren G Monckton Journal: DNA Repair (Amst) Date: 2016-03-08
Authors: S E Andrew; Y P Goldberg; B Kremer; H Telenius; J Theilmann; S Adam; E Starr; F Squitieri; B Lin; M A Kalchman Journal: Nat Genet Date: 1993-08 Impact factor: 38.330
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Authors: Gillian P Bates; Ray Dorsey; James F Gusella; Michael R Hayden; Chris Kay; Blair R Leavitt; Martha Nance; Christopher A Ross; Rachael I Scahill; Ronald Wetzel; Edward J Wild; Sarah J Tabrizi Journal: Nat Rev Dis Primers Date: 2015-04-23 Impact factor: 52.329
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Authors: Eun Pyo Hong; Marcy E MacDonald; Vanessa C Wheeler; Lesley Jones; Peter Holmans; Michael Orth; Darren G Monckton; Jeffrey D Long; Seung Kwak; James F Gusella; Jong-Min Lee Journal: J Huntingtons Dis Date: 2021
Authors: Marc Ciosi; Alastair Maxwell; Sarah A Cumming; Davina J Hensman Moss; Asma M Alshammari; Michael D Flower; Alexandra Durr; Blair R Leavitt; Raymund A C Roos; Peter Holmans; Lesley Jones; Douglas R Langbehn; Seung Kwak; Sarah J Tabrizi; Darren G Monckton Journal: EBioMedicine Date: 2019-10-10 Impact factor: 8.143
Authors: Xiaofeng Gu; Jeffrey Richman; Peter Langfelder; Nan Wang; Shasha Zhang; Monica Bañez-Coronel; Huei-Bin Wang; Lucia Yang; Lalini Ramanathan; Linna Deng; Chang Sin Park; Christopher R Choi; Jeffrey P Cantle; Fuying Gao; Michelle Gray; Giovanni Coppola; Gillian P Bates; Laura P W Ranum; Steve Horvath; Christopher S Colwell; X William Yang Journal: Neuron Date: 2022-02-02 Impact factor: 18.688