Scientific Discoveries

Patient Contribution is Essential for Scientific Discovery

The goal of scientific research is to find ways to improve patient quality of life and provide new therapeutic approaches. HD Biobank samples have directly contributed to:

Understanding how different populations are affected

Establishing global population specific CAG repeat length, haplotype and prevalence associations (in Africa, East Asia, North and South America, Europe and the Middle East)

  1. Kay C, Collins JA, Wright G, Baine F, Miedzybrodzka Z, Aminkeng F, Semaka A, McDonald C, Davidson M, Madore SJ, Gordon ES, Gerry N, Cornejo-Olivas M, Tishkoff S, Greenberg LJ, Krause A, Hayden MR. The molecular epidemiology of Huntington disease is related to intermediate allele frequency and haplotype in the general population. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2018 177(3):346-357 doi:10.1002/ajmg.b.32618 PMID: 29460498
  2. Kay C, Tirado-Hurtado I, Cornejo-Olivas M, Collins JA, Wright G, Inca-Martinez M, Veliz-Otani D, Ketelaar ME, Slama RA, Ross CJ, Mazzetti P, Hayden MR. The Major Targetable Huntington Disease Haplotype in Latin America has Distinct Amerindian and European Origins. Eur J Hum Genet 2017 25(3):332-340. doi:10.1038/ejhg.2016.169 PMID: 28000697
  3. Baine FK, Kay C, Ketelaar ME, Collins JA, Semaka A, Doty CN, Krause A, Greenberg JL, Hayden MR. Huntington disease in the South African population occurs on diverse and ethnically distinct genetic haplotypes. Eur J Hum Genet.  2013 21(10):1120-1127. PMID: 23463025
  4. Squitieri F, Mazza T, Maffi S, Migliore S, De Luca A, AlSalmi Q, AlHarasi S, Collins J, Kay C, Baine-Savanhu F, Landwhermeyer BG, Sabatini U, D’Alessio B, Hayden MR. Tracing the mutated Htt and haplotype of the African ancestor who spread Huntington Disease into the Middle East. Genet Med. PMID: 32661355
  5. Warby SC, Visscher H, Collins JA, Doty CN, Carter C, Butland SL, Hayden AR, Kanazawa I, Ross CJ, Hayden MR. HTT haplotypes contribute to differences in Huntington disease prevalence between Europe and East Asia. Eur J Hum Genet. 2011. 19(5):561-6 PMID: 21248742

Delineating age of onset differences

Revealing genetic modifiers of symptom onset in HD families

  1. Wright GEB, Black HF, Collins JA, Gall-Duncan T, Caron NS, Pearson CE, Hayden MR. Interrupting sequence variants and age of onset in Huntington’s disease: clinical implications and emerging therapies. Lancet Neurol. 2020 Nov;19(11):930-939. PMID: 33098802
  2. Wright GEB, Caron NS, Ng B, Casal L, Casazza W, Xu X, Ooi J, Pouladi MA, Mostafavi S, Ross CJD, Hayden MR. Gene expression profiles complement the analysis of genomic modifiers of the clinical onset of Huntington disease. Hum Mol Genet. 2020 Sep 29;29(16):2788-2802. PMID: 32898862.
  3. Wright GEB, Collins JA, Kay C, McDonald C, Dolzhenko E, Xia Q, Bečanović K, Drögemöller BI, Semaka A, Nguyen C, Trost B, Richards F, Bijlsma EK, Squitieri F, Ross CJD, Scherer SW, Eberle MA, Yuen RKC, Hayden MR. Length of uninterrupted CAG repeats, independent of polyglutamine size, results in increased somatic instability and hastens age of onset of Huntington disease. Am J Hum Genet. 2019 Jun 6;104(6):1116-1126. doi: 10.1016/j.ajhg.2019.04.007. Epub 2019 May 16. PMID: 31104771

Advancing clinical trials

Identifying new ways to measure biological markers of progression in CSF and blood

  1. Southwell AL, Smith SEP, Davis T, Caron NS, Villanueva EB, Xie Y, Collins JA, Ye E, Sturrock A, Leavitt BR, Schrum AG, Hayden MR. Ultrasensitive measurement of huntingtin protein in cerebrospinal fluid demonstrates increase with Huntington disease stage and decrease following brain huntingtin suppression. Sci Rep. 2015 15;5:12166 PMID: 26174131

Identifying potential targets for allele specific silencing trials

  1. Kay C, Collins JA, Caron NS, de Agostinho L, Findlay-Black H, Casal L, Sumathipala D, Dissanayake V, Cornejo-Olivas M, Baine F, Krause A, Greenberg JL, Paiva CLA, Squitieri F, Hayden MR. A comprehensive haplotype targeting strategy for allele-specific HTT suppression in Huntington disease. Am J Hum Genet. 2019 Dec 5;105(6):1112-1125. doi: 10.1016/j.ajhg.2019.10.011. PMID: 31708117
  2. Kay C, Collins JA, Skotte NH, Southwell AL, Warby SC, Caron NS,Doty CN, Ng B, Griguoli A, Ross C, Squitieri F, Hayden MR. Huntingtin Haplotypes are efficient target panels for allele-specific silencing in patients of european ancestry. Mol Ther. 2015. 23(11):1759-71. PMID: 26201449
  3. Warby SC, Montpetit A, Hayden A, Carroll JB, Collins J, Butland SL, Visscher H, Semaka A, Hudson TJ, Hayden MR. CAG-expansion in the Huntington disease gene is associated with a specific and targetable predisposing haplogroup. Am J Hum Genet. 2010. 84(3):351-66. PMID: 19249009

Exploring how future generations are affected

Demonstrating how instability can lead to CAG repeat expansions and new mutations

  1. Findlay Black H, Wright GEB, Collins JA, Caron N, Xia Q, Arning L, Bijlsma EK, Squitieri F, Nguyen HP, Hayden MR. Frequency of the loss of CAA interruption in the Htt CAG tract and implications for Huntington Disease penetrance in the reduced penetrance range. Genet Med. PMID: 32741964
  2. Kay C, Collins JA, Miedzybrodzka Z, Madore SJ, Gordon ES, Gerry N, Davidson M, Slama RA, Hayden MR. Huntington disease reduced penetrance alleles occur at high frequency in the general population. Neurology 2016 87:1–7 PMID: 27335115
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