Common SNP-Based Haplotype Analysis of the 4p16.3 Huntington Disease Gene Region

Center for Human Genetic Research, Massachusetts General Hospital, Boston, 02114, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 03/2012; 90(3):434-44. DOI: 10.1016/j.ajhg.2012.01.005
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Age at the onset of motor symptoms in Huntington disease (HD) is determined largely by the length of a CAG repeat expansion in HTT but is also influenced by other genetic factors. We tested whether common genetic variation near the mutation site is associated with differences in the distribution of expanded CAG alleles or age at the onset of motor symptoms. To define disease-associated single-nucleotide polymorphisms (SNPs), we compared 4p16.3 SNPs in HD subjects with population controls in a case:control strategy, which revealed that the strongest signals occurred at a great distance from the HD mutation as a result of "synthetic association" with SNP alleles that are of low frequency in population controls. Detailed analysis delineated a prominent ancestral haplotype that accounted for ∼50% of HD chromosomes and extended to at least 938 kb on about half of these. Together, the seven most abundant haplotypes accounted for ∼83% of HD chromosomes. Neither the extended shared haplotype nor the individual local HTT haplotypes were associated with altered CAG-repeat length distribution or residual age at the onset of motor symptoms, arguing against modification of these disease features by common cis-regulatory elements. Similarly, the 11 most frequent control haplotypes showed no trans-modifier effect on age at the onset of motor symptoms. Our results argue against common local regulatory variation as a factor influencing HD pathogenesis, suggesting that genetic modifiers be sought elsewhere in the genome. They also indicate that genome-wide association analysis with a small number of cases can be effective for regional localization of genetic defects, even when a founder effect accounts for only a fraction of the disorder.

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    • "This major HD haplotype seems to correspond to the most frequent HD haplotype defined in earlier studies and it is extremely similar, if not exactly the same, to the extended haplotype ( " Ext_Hap_1 " ) found to account for about 25% of a set of 699 European HD chromosomes. [Lee et al., 2012] Indeed, by comparing the common SNPs and corresponding haplotypes between the two studies (Fig. S2), we observed that our extended haplotype 1 includes, among other low frequency Western European HD haplotypes, the " Ext_Hap_1 " . The frequency of this haplotype (Fig. S3) among Portuguese HD chromosomes (23%) is thus lower than in the Western European HD chromosomes (38%), indicating that other haplotypes (extended haplotypes 2, 3, and 4) have contributed to a greater extent to HD in Portugal than in European chromosomes overall. "
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    ABSTRACT: Huntington's disease (HD) is a neurodegenerative disorder characterized by involuntary choreic movements, cognitive impairment, and behavioral changes, caused by the expansion of an unstable CAG repeat in HTT. We characterized the genetic diversity of the HD mutation by performing an extensive haplotype analysis of ∼1Mb region flanking HTT in over 300 HD families of Portuguese origin. We observed that haplotype A, marked by HTT delta2642, was enriched in HD chromosomes and carried the two largest expansions reported in the Portuguese population. However, the most frequent HD haplotype B carried one of the largest (+12 CAGs) expansions, which resulted in an allele class change to full penetrance. Despite having a normal CAG distribution skewed to the higher end of the range, these two core haplotypes had similar expanded CAG repeat sizes compared to the other major core haplotypes (C and D) and there was no statistical difference in transmitted repeat instability across haplotypes. We observed a diversity of HTT region haplotypes in both normal and expanded chromosomes, representative of more than one ancestral chromosome underlying HD in Portugal, where multiple independent events on distinct chromosome 4 haplotypes have given rise to expansion into the pathogenic range. © 2015 Wiley Periodicals, Inc. © 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 02/2015; 168(2). DOI:10.1002/ajmg.b.32289 · 3.42 Impact Factor
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    • "Two studies showed that targeting three SNP would be sufficient to treat 75% of their respective HD cohort [13]. Note that a large proportion of patients of European origin clusters in a single haplotype with a specific set of SNPs [16]–[18]. "
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    ABSTRACT: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder resulting from polyglutamine expansion in the huntingtin (HTT) protein and for which there is no cure. Although suppression of both wild type and mutant HTT expression by RNA interference is a promising therapeutic strategy, a selective silencing of mutant HTT represents the safest approach preserving WT HTT expression and functions. We developed small hairpin RNAs (shRNAs) targeting single nucleotide polymorphisms (SNP) present in the HTT gene to selectively target the disease HTT isoform. Most of these shRNAs silenced, efficiently and selectively, mutant HTT in vitro. Lentiviral-mediated infection with the shRNAs led to selective degradation of mutant HTT mRNA and prevented the apparition of neuropathology in HD rat's striatum expressing mutant HTT containing the various SNPs. In transgenic BACHD mice, the mutant HTT allele was also silenced by this approach, further demonstrating the potential for allele-specific silencing. Finally, the allele-specific silencing of mutant HTT in human embryonic stem cells was accompanied by functional recovery of the vesicular transport of BDNF along microtubules. These findings provide evidence of the therapeutic potential of allele-specific RNA interference for HD.
    PLoS ONE 06/2014; 9(6):e99341. DOI:10.1371/journal.pone.0099341 · 3.23 Impact Factor
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    • "Indeed, only a small number of genes have been firmly identified as modifiers of aggregation diseases by either candidate or association approaches [15,24]. Furthermore, these modifiers are often not replicated in different populations, and replicated modifiers account for only a small fraction of the heritable variation [15,58-60]. Genetic tractability of model animals, together with the ability to control the contribution of the environment, offers a unique opportunity to examine how natural variation in the genetic background of individuals affects their ability to resist protein aggregation; what is the nature of the genetic variants that modify proteostasis; whether these are distinct from the spectrum of induced mutations; and whether natural variation can predict/modify the susceptibility to protein conformation diseases. "
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    ABSTRACT: Monogenic gain-of-function protein aggregation diseases, including Huntington's disease, exhibit substantial variability in age of onset, penetrance, and clinical symptoms, even among individuals with similar or identical mutations. This difference in phenotypic expression of proteotoxic mutations is proposed to be, at least in part, due to the variability in genetic background. To address this, we examined the role of natural variation in defining the susceptibility of genetically diverse individuals to protein aggregation and toxicity, using C. elegans polyglutamine model. Introgression of polyQ40 into three wild genetic backgrounds uncovered wide variation in onset of aggregation and corresponding toxicity, as well as alteration in the cell-specific susceptibility to aggregation. To further dissect these relationships, we established a panel of 21 recombinant inbred lines that showed a broad range of aggregation phenotypes independent of differences in expression levels. We found that aggregation is a transgressive trait and does not always correlate with measures of toxicity, such as early onset of muscle dysfunction, egg laying deficits, and reduced lifespan. Moreover, distinct measures of proteotoxicity were independently modified by the genetic background. Resistance to protein aggregation and the ability to restrict its associated cellular dysfunction are independently controlled by the natural variation in genetic background, revealing important new considerations in the search for targets for therapeutic intervention in conformational diseases. Thus, our C. elegans model can serve as a powerful tool to dissect the contribution of natural variation to individual susceptibility to proteotoxicity.Please see related commentary by Kaeberlein,
    BMC Biology 09/2013; 11(1):100. DOI:10.1186/1741-7007-11-100 · 7.98 Impact Factor
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