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Now published in The Lancet

A Genetic Association Study of Glutamine-Encoding DNA Sequence Structures, Somatic CAG Expansion, and DNA Repair Gene Variants, with Huntington Disease Clinical Outcomes

33 Pages Posted: 10 Sep 2019

See all articles by Marc Ciosi

Marc Ciosi

University of Glasgow - Institute of Molecular, Cell and Systems Biology

Alastair Maxwell

University of Glasgow - Institute of Molecular, Cell and Systems Biology

Sarah A. Cumming

University of Glasgow - Institute of Molecular, Cell and Systems Biology

Davina J. Hensman Moss

University College London

Asma M. Alshammari

University of Glasgow - Institute of Molecular, Cell and Systems Biology

Michael D. Flower

University College London

Alexandra Durr

Hôpital de la Pitié-Salpêtrière - Sorbonne Université, Paris Brain Institute (ICM Institut du Cerveau)

Blair R. Leavitt

University of British Columbia (UBC)

Raymund A. C. Roos

Leiden University

The TRACK-HD Team

Independent

The Enroll-HD Team

Independent

Peter Holmans

Cardiff University

Lesley Jones

Cardiff University

Douglas R. Langbehn

University of Iowa

Seung Kwak

CHDI Management/CHDI Foundation

Sarah J. Tabrizi

University College London

Darren Monckton

University of Glasgow - Institute of Molecular, Cell and Systems Biology

More...

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 x 10-6). We also show that individual-specific somatic expansion scores are associated with variants in FAN1 (pFDR = 4·8 x 10 6), MLH3 (pFDR = 8·0 x 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 Statement: This work was supported by an award to DGM from CHDI Foundation. TRACK-HD and Enroll-HD are supported by CHDI Foundation, a non-profit biomedical research organization exclusively dedicated to developing therapeutics for HD. SJT receives funding from the Medical Research Council UK, Wellcome Trust, Rosetrees Trust, Takeda Pharmaceuticals, Cantervale Limited, NIHR North Thames Local Clinical Research Network, UK Dementia Research Institute at UCL and CHDI Foundation. LJ and PH receive support from the MRC (MR/L010305/1) and CHDI.

Declaration of Interests: MC, AM, SAC, DJHM, AMA, MDF, AD, BRL, PH, and LJ have nothing to disclose. RAR reports personal fees from UniQure, outside the submitted work. DRL reports personal fees from Roche Pharmaceutical, Voyager, Teva Pharmaceutical, Wave Life Sciences, Takeda Pharmaceutical Company and Axon Advisors, and other from CHDI, outside the submitted work. SK reports and is employed by CHDI Management, Inc., as an advisor to the CHDI Foundation. SJT reports personal fees from Alnylam Pharmaceuticals, DDF Discovery, F. Hoffmann-La Roche, Genentech, GSK, Heptares Therapeutics, Takeda Pharmaceuticals, Teva Pharmaceuticals, Triplet Therapeutics, UCB Pharma and Vertex Pharmaceuticals, outside the submitted work. DGM reports other from CHDI Foundation, during the conduct of the study and personal fees from Vertex Pharmaceuticals, LoQus23 Therapeutics and Triplet Therapeutics, outside the submitted work.

Ethics Approval Statement: This study complies with all relevant ethical regulations. All participants were recruited with informed consent and all collaborating clinical sites are required to obtain and maintain local ethics committee approvals. The study was approved by TRACK-HD and Enroll-HD.

Keywords: genetic association study; somatic expansion; DNA repair; Huntington disease

Suggested Citation

Ciosi, Marc and Maxwell, Alastair and Cumming, Sarah A. and Moss, Davina J. Hensman and Alshammari, Asma M. and Flower, Michael D. and Durr, Alexandra and Leavitt, Blair R. and Roos, Raymund A. C. and Team, The TRACK-HD and Team, The Enroll-HD and Holmans, Peter and Jones, Lesley and Langbehn, Douglas R. and Kwak, Seung and Tabrizi, Sarah J. and Monckton, Darren, A Genetic Association Study of Glutamine-Encoding DNA Sequence Structures, Somatic CAG Expansion, and DNA Repair Gene Variants, with Huntington Disease Clinical Outcomes (08/29/2019 20:02:03). Available at SSRN: https://ssrn.com/abstract=3445535 or http://dx.doi.org/10.2139/ssrn.3445535

Marc Ciosi

University of Glasgow - Institute of Molecular, Cell and Systems Biology

Glasgow
United Kingdom

Alastair Maxwell

University of Glasgow - Institute of Molecular, Cell and Systems Biology

Glasgow
United Kingdom

Sarah A. Cumming

University of Glasgow - Institute of Molecular, Cell and Systems Biology

Glasgow
United Kingdom

Davina J. Hensman Moss

University College London

Gower Street
London, WC1E 6BT
United Kingdom

Asma M. Alshammari

University of Glasgow - Institute of Molecular, Cell and Systems Biology

Glasgow
United Kingdom

Michael D. Flower

University College London

Gower Street
London, WC1E 6BT
United Kingdom

Alexandra Durr

Hôpital de la Pitié-Salpêtrière - Sorbonne Université, Paris Brain Institute (ICM Institut du Cerveau)

175 Rue du Chevaleret
Paris, 75013
France

Blair R. Leavitt

University of British Columbia (UBC)

2329 West Mall
Vancouver, British Columbia BC V6T 1Z4
Canada

Raymund A. C. Roos

Leiden University

Postbus 9500
Leiden, Zuid Holland 2300 RA
Netherlands

The TRACK-HD Team

Independent

The Enroll-HD Team

Independent

Peter Holmans

Cardiff University

Aberconway Building
Colum Drive
Cardiff, Wales CF10 3EU
United Kingdom

Lesley Jones

Cardiff University

Aberconway Building
Colum Drive
Cardiff, Wales CF10 3EU
United Kingdom

Douglas R. Langbehn

University of Iowa

341 Schaeffer Hall
Iowa City, IA 52242-1097
United States

Seung Kwak

CHDI Management/CHDI Foundation

United States

Sarah J. Tabrizi

University College London

Gower Street
London, WC1E 6BT
United Kingdom

Darren Monckton (Contact Author)

University of Glasgow - Institute of Molecular, Cell and Systems Biology ( email )

Glasgow
United Kingdom