Huntington’s Disease: Common Snp-Based Haplotype Analysis

Huntington’s disease (HD) is a hereditary neurodegenerative disease for which there is no effective treatment. For its development, it is necessary to study the genetic mechanisms of the disease. It is known that the disease is associated with a mutation of the huntingtin gene, the repetition of the trinucleotide CAG in chromosome 4p16.3. It was believed that Huntington’s disease develops if the number of repeats exceeds 39, and the age of onset (AOO) is proportional to the number of these repetitions, but this is not true for all patients. It was suggested that the development of the disease is affected by cis-regulatory elements that control the expression of the huntingtin gene; this assumption requires verification. Identification of the genetic mechanism affecting the rate of HD development will help understand how to delay progress and find an effective pathogenetic therapy. Lee et al. suggested that cis-regulatory elements affect the CAG repeat length, for which they evaluated extended SNP haplotypes in the HTT gene region on mutant and normal chromosomes. The authors also studied other synthetic association signals that may be trans-regulatory elements.

First, Lee et al. studied SNP-based haplotypes in the HTT gene region. The purpose of the experiment was to check for the presence of a cis-action modifier in two areas: 1) The 938 kB area, 343 kB proximally, and 595 kB distal to the CAG repeats (NTT gene), between SNP Rs12641989 and rs11248108 associated with GH; 2) The area is 235 kB, 48 kb proximal to the NTT and 17 kB distally from the HTT, from rs2857845 to rs3095073. In the first area, the researchers identified a haplotype consisting of 62 SNPs, significantly more common in patients with HD. Then they compared patients with these haplotypes to patients with other haplotypes, according to the distribution of CAG-repeat lengths, the AOO of hyperkinesis, and the difference between the average age of onset in the population and the patient. In the second area, the authors identified 21 markers and grouped mutant chromosomes into seven haplotypes, where 83% of mutant chromosomes were placed. The authors compared these haplotypes by the same criteria. In both cases, no significant differences were found.

Further, Lee et al. studied HD GWAS underlying mechanisms of the synthetic association. The most significant signals of association with HD appeared to be from the SNP at a large distance from the NTT (rs12641989 in RGS12 and rs11248108 RNF4). The authors’ suggestion was that a combination of the extended main haplotype HTT_Hap1 and the minor alleles of some SNPs that are seldom found in the control group accounted for the signals of this association. The authors used SNP, the minor alleles of which were significantly more often represented among patients with HD. Then they calculated the frequency of these minor alleles in the control group, in all patients, in patients with a delta 2642 deletion, and finally in patients with an HD mutation and a delta 2642 deletion. Then they divided the region of chromosome 4 into a non-recombination zone and a zone of mild recombination. In both zones, the authors found that the extended major haplotype and SNP with low frequencies of minor alleles in the control group are associated with HD.

In their research, Lee et al. checked whether there are cis-modifiers for the pathogenesis of HD. The comparison between the seven most common genotypes in the distribution of the length of CAG repeats and the AOO of the disease displayed no difference. Homologous regions of normal chromosomes also do not affect these signs. Thus, the initial hypothesis of the authors was not confirmed. However, the authors found that SNPs with low frequencies of minor alleles in the control population can be used as HD markers. The research results will be useful in developing methods for localizing other genetic defects, especially in small families, where it is impossible to conduct a full-fledged genealogical analysis. For effective localization of genetic defects, SNPs should be used with low frequencies of minor alleles in the control population. It is also believed that Identifying trans-modifiers will provide targets for therapeutic effects.