A genetic association study of glutamine-encoding DNA sequence structures, somatic CAG expansion, and DNA repair gene variants, with Huntington disease clinical outcomes

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

doi:10.1016/j.ebiom.2019.09.020

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A genetic association study of glutamine-encoding DNA sequence structures, somatic CAG expansion, and DNA repair gene variants, with Huntington disease clinical outcomes

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A genetic association study of glutamine-encoding DNA sequence structures, somatic CAG expansion, and DNA repair gene variants, with Huntington disease clinical outcomes

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, …

EBioMedicine, Vol.48, pp.568-580

10/2019

DOI: 10.1016/j.ebiom.2019.09.020

PMCID: PMC6838430

PMID: 31607598

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Abstract

Huntington disease (HD) is caused by an unstable CAG/CAA repeat expansion encoding a toxic polyglutamine tract. Here, we tested the hypotheses that HD outcomes are impacted by somatic expansion of, and polymorphisms within, the HTT CAG/CAA glutamine-encoding repeat, and DNA repair genes. The sequence of the glutamine-encoding repeat and the proportion of somatic CAG expansions in blood DNA from participants inheriting 40 to 50 CAG repeats within the TRACK-HD and Enroll-HD cohorts were determined using high-throughput ultra-deep-sequencing. Candidate gene polymorphisms were genotyped using kompetitive allele-specific PCR (KASP). Genotypic associations were assessed using time-to-event and regression analyses. Using data from 203 TRACK-HD and 531 Enroll-HD participants, we show that individuals with higher blood DNA somatic CAG repeat expansion scores have worse HD outcomes: a one-unit increase in somatic expansion score was associated with a Cox hazard ratio for motor onset of 3·05 (95% CI = 1·94 to 4·80, p = 1·3 × 10−6). We also show that individual-specific somatic expansion scores are associated with variants in FAN1 (pFDR = 4·8 × 10-6), MLH3 (pFDR = 8·0 × 10−4), MLH1 (pFDR = 0·004) and MSH3 (pFDR = 0·009). We also show that HD outcomes are best predicted by the number of pure CAGs rather than total encoded-glutamines. These data establish pure CAG length, rather than encoded-glutamine, as the key inherited determinant of downstream pathophysiology. These findings have implications for HD diagnostics, and support somatic expansion as a mechanistic link for genetic modifiers of clinical outcomes, a driver of disease, and potential therapeutic target in HD and related repeat expansion disorders. CHDI Foundation.

Genetic association study

DNA repair

Somatic expansion

Huntington disease

Details

Title: Subtitle: A genetic association study of glutamine-encoding DNA sequence structures, somatic CAG expansion, and DNA repair gene variants, with Huntington disease clinical outcomes
Creators: Marc Ciosi - Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
Alastair Maxwell - Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
Sarah A Cumming - Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
Davina J Hensman Moss - Huntington's Disease Centre, Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK
Asma M Alshammari - Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
Michael D Flower - Huntington's Disease Centre, Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK
Alexandra Durr - APHP Department of Genetics, Pitié-Salpêtrière University Hospital, Paris, France
Blair R Leavitt - Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada
Raymund A.C Roos - Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands
Peter Holmans - Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
Lesley Jones - Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK
Douglas R Langbehn - Departments of Psychiatry and Biostatistics, University of Iowa, Iowa City, IA, USA
Seung Kwak - CHDI Management/CHDI Foundation, Princeton, NJ, USA
Sarah J Tabrizi - Huntington's Disease Centre, Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK
Darren G Monckton - Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
Resource Type: Journal article
Publication Details: EBioMedicine, Vol.48, pp.568-580
DOI: 10.1016/j.ebiom.2019.09.020
PMID: 31607598
PMCID: PMC6838430
NLM abbreviation: EBioMedicine
ISSN: 2352-3964
eISSN: 2352-3964
Publisher: Elsevier B.V
Grant note: CHDI Foundation (https://doi.org/10.13039/100005725)
Language: English
Date published: 10/2019
Academic Unit: Psychiatry; Iowa Neuroscience Institute
Record Identifier: 9984066142402771

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