Journal article
Huntington’s disease age at motor onset is modified by the tandem hexamer repeat in TCERG1
Npj genomic medicine, Vol.7, 53
09/01/2022
DOI: 10.1038/s41525-022-00317-w
PMCID: PMC9445028
PMID: 36064847
Abstract
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.
Details
- Title: Subtitle
- Huntington’s disease age at motor onset is modified by the tandem hexamer repeat in TCERG1
- Creators
- Sergey V. Lobanov - Cardiff UniversityBranduff McAllister - Cardiff UniversityMia McDade-Kumar - Cardiff UniversityG. Bernhard Landwehrmeyer - Universität UlmMichael Orth - Department of Old Age Psychiatry and Psychotherapy, Bern UniversityAnne E. Rosser - Cardiff UniversityJane S. Paulsen - Department of Neurology, University of WisconsinJong-Min Lee - Massachusetts General HospitalMarcy E. MacDonald - Massachusetts General HospitalJames F. Gusella - Massachusetts General HospitalJeffrey D. Long - University of IowaMina Ryten - Great Ormond Street Institute of Child Health, Genetics and Genomic Medicine, University, College LondonNigel M. Williams - Cardiff UniversityPeter Holmans - Cardiff UniversityThomas H. Massey - Cardiff UniversityLesley Jones - Cardiff UniversityREGISTRY Investigators of the European Huntington’s disease networkPREDICT-HD Investigators of the Huntington Study Group
- Resource Type
- Journal article
- Publication Details
- Npj genomic medicine, Vol.7, 53
- DOI
- 10.1038/s41525-022-00317-w
- PMID
- 36064847
- PMCID
- PMC9445028
- NLM abbreviation
- NPJ Genom Med
- ISSN
- 2056-7944
- Publisher
- Nature Portfolio
- Grant note
- DOI: 10.13039/501100000265, name: RCUK | Medical Research Council, award: MR/L010305/1, MR/L010305/1, MR/L010305/1; DOI: 10.13039/100005725, name: CHDI Foundation; DOI: 10.13039/501100000368, name: Brain Research Trust, award: 201617-06, 201617-06, 201617-06; DOI: 10.13039/501100002283, name: Alzheimer's Research UK, award: ARUK-PPG2018A-015; name: Alzheimer's Research UK; name: Alzheimer's Research UK; DOI: 10.13039/100010661, name: EC | Horizon 2020 Framework Programme; DOI: 10.13039/100012068, name: Health and Care Research Wales
- Language
- English
- Date published
- 09/01/2022
- Academic Unit
- Psychiatry; Psychological and Brain Sciences; Biostatistics
- Record Identifier
- 9984296033102771
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