Lobanov, Sergey ORCID: https://orcid.org/0000-0002-3126-1903, McAllister, Branduff, McDade-Kumar, Mia, Landwehrmeyer, Bernhard, Orth, Michael, Rosser, Anne ORCID: https://orcid.org/0000-0002-4716-4753, Paulsen, Jane, Lee, Jong-Min, MacDonald, Marcy, Gusella, James, Long, Jeffrey, Ryten, Mina, Williams, Nigel ORCID: https://orcid.org/0000-0003-1177-6931, Holmans, Peter ORCID: https://orcid.org/0000-0003-0870-9412, Massey, Thomas ORCID: https://orcid.org/0000-0002-9804-2131 and Jones, Lesley ORCID: https://orcid.org/0000-0002-3007-4612 2022. Huntington’s disease age at motor onset is modified by the tandem hexamer repeat in TCERG1. npj Genomic Medicine 7 , 53. 10.1038/s41525-022-00317-w |
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Abstract
Huntington’s disease is caused by an expanded CAG tract in HTT. The length of the CAG tract accounts for over half the variance in age at onset of disease, and is influenced by other genetic factors, mostly implicating the DNA maintenance machinery. We examined a single nucleotide variant, rs79727797, on chromosome 5 in the TCERG1 gene, previously reported to be associated with Huntington’s disease and a quasi-tandem repeat (QTR) hexamer in exon 4 of TCERG1 with a central pure repeat. We developed a method for calling perfect and imperfect repeats from exome-sequencing data, and tested association between the QTR in TCERG1 and residual age at motor onset (after correcting for the effects of CAG length in the HTT gene) in 610 individuals with Huntington’s disease via regression analysis. We found a significant association between age at onset and the sum of the repeat lengths from both alleles of the QTR (p = 2.1 × 10−9), with each added repeat hexamer reducing age at onset by one year (95% confidence interval [0.7, 1.4]). This association explained that previously observed with rs79727797. The association with age at onset in the genome-wide association study is due to a QTR hexamer in TCERG1, translated to a glutamine/alanine tract in the protein. We could not distinguish whether this was due to cis-effects of the hexamer repeat on gene expression or of the encoded glutamine/alanine tract in the protein. These results motivate further study of the mechanisms by which TCERG1 modifies onset of HD.
Item Type: | Article |
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Date Type: | Publication |
Status: | Published |
Schools: | Advanced Research Computing @ Cardiff (ARCCA) MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Medicine |
Additional Information: | This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
Publisher: | Nature Research |
ISSN: | 2056-7944 |
Funders: | Medical Research Council, Alzheimer’s Research UK, Brain Research Trust, Health and Care Research Wales, Horizon 2020 Framework Programme, CHDI Foundation |
Date of First Compliant Deposit: | 18 July 2022 |
Date of Acceptance: | 15 July 2022 |
Last Modified: | 22 Jul 2024 16:09 |
URI: | https://orca.cardiff.ac.uk/id/eprint/151348 |
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