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

Ciosi, Marc, Maxwell, Alastair, Cumming, Sarah, Hensman Moss, Davina, Alshammari, Asma, Flower, Michael, Durr, Alexandra, Leavitt, Blair, Roos, Raymund, Holmans, Peter ORCID: https://orcid.org/0000-0003-0870-9412, Jones, Lesley ORCID: https://orcid.org/0000-0002-3007-4612, Langbehn, Douglas, Kwak, Seung, Tabrizi, Sarah and Monckton, Darren 2019. A genetic association study of glutamine-encoding DNA sequence structures, somatic CAG expansion, and DNA repair gene variants, with Huntington disease clinical outcomes. EBioMedicine 48 , pp. 568-580. 10.1016/j.ebiom.2019.09.020

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher:	Elsevier
ISSN:	2352-3964
Funders:	MRC
Date of First Compliant Deposit:	16 September 2019
Date of Acceptance:	11 September 2019
Last Modified:	22 Nov 2024 05:45
URI:	https://orca.cardiff.ac.uk/id/eprint/125434

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