A genetic association study of glutamine-encoding DNA sequence structures, somatic CAG expansion, and DNA repair gene variants, with Huntington disease clinical outcomes
| Autor: | Ciosi, M., Maxwell, A., Cumming, S.A., Moss, D.J.H., Alshammari, A.M., Flower, M.D., Durr, A., Leavitt, B.R., Roos, R.A.C., Holmans, P., Jones, L., Langbehn, D.R., Kwak, S., Tabrizi, S.J., Monckton, D.G., TRACK-HD Team, Enroll-HD Team |
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| Přispěvatelé: | University of Glasgow, University College of London [London] (UCL), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), University of British Columbia (UBC), Leiden University Medical Center (LUMC), MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University-Medical Research Council, Cardiff University, University of Iowa [Iowa City], UK Dementia Research Institute (UK DRI) |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Adult
Male 0301 basic medicine Candidate gene Research paper Adolescent Genotype Somatic cell [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology Quantitative Trait Loci lcsh:Medicine DNA repair MLH3 Biology Polymorphism Single Nucleotide General Biochemistry Genetics and Molecular Biology Young Adult 03 medical and health sciences 0302 clinical medicine Somatic expansion Humans Genetic Predisposition to Disease Child Alleles Aged Genetic association Genetic association study Aged 80 and over Genetics Huntingtin Protein lcsh:R5-920 lcsh:R Exons General Medicine Middle Aged Polyglutamine tract Huntington disease 3. Good health 030104 developmental biology MSH3 [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics 030220 oncology & carcinogenesis Female Trinucleotide Repeat Expansion Trinucleotide repeat expansion lcsh:Medicine (General) |
| Zdroj: | EBioMedicine, Vol 48, Iss, Pp 568-580 (2019) EBioMedicine, 48, 568-580 EBioMedicine EBioMedicine, Elsevier, 2019, 48, pp.568-580. ⟨10.1016/j.ebiom.2019.09.020⟩ |
| ISSN: | 2352-3964 |
| DOI: | 10.1016/j.ebiom.2019.09.020⟩ |
| Popis: | 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: Genetic association study, Somatic expansion, DNA repair, Huntington disease |
| Databáze: | OpenAIRE |
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