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EBioMedicine. 2019 Oct;48:568-580. doi: 10.1016/j.ebiom.2019.09.020. Epub 2019 Oct 10.

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

Author information

1
Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
2
Huntington's Disease Centre, Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK.
3
APHP Department of Genetics, Pitié-Salpêtrière University Hospital, Paris, France; ICM, Institut du Cerveau et de la Moelle, INSERM U1127, CNRS UMR7225, Sorbonne Université, Paris, France.
4
Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada.
5
Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands.
6
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK.
7
Departments of Psychiatry and Biostatistics, University of Iowa, Iowa City, IA, USA.
8
CHDI Management/CHDI Foundation, Princeton, NJ, USA.
9
Huntington's Disease Centre, Department of Neurodegenerative Disease, Institute of Neurology, University College London, London, UK; UK Dementia Research Institute at UCL, London, UK.
10
Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK. Electronic address: darren.monckton@glasgow.ac.uk.

Abstract

BACKGROUND:

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.

METHODS:

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.

FINDINGS:

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.

INTERPRETATION:

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.

FUNDING:

CHDI Foundation.

KEYWORDS:

DNA repair; Genetic association study; Huntington disease; Somatic expansion

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