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GWAS Uncovers Genetic Modifiers of Age at Huntington's Disease Onset

Note: An earlier version of this story incorrectly stated that both Huntington's disease modifiers on chromosome 15 were associated with delayed disease onset.

NEW YORK (GenomeWeb) – In Cell today, members of the Genetic Modifiers of Huntington's Disease Consortium described variants linked to earlier or later disease onset in individuals with Huntington's disease-causing trinucleotide repeats in the huntingtin gene HTT.

Through a multi-stage genome-wide association study and meta-analysis involving thousands of individuals with Huntington's disease, the researchers narrowed in on a chromosome 8 locus linked to earlier-than-usual onset, along with two chromosome 15 variants that delayed or sped up Huntington's disease symptoms by roughly a year-and-a-half or six years later, respectively.

"Figuring out the exact DNA sequence variations responsible and how they influence the disease process should provide us with a guide for developing drugs that we hope could have a much larger effect than the one to six years produced by the natural variations, possibly even preventing symptom onset altogether," corresponding author James Gusella, director of Massachusetts General Hospital's Center for Human Genetic Research, said in a statement.

Although Huntington's disease can consistently be traced back to trinucleotide expansion mutations in HTT, progressive movement problems and other disease symptoms don't always begin at the same point in an affected person's life.

For many, symptoms appear in middle age, Gusella and colleagues explained, though some cases manifest themselves as early as childhood and others develop at retirement age or beyond.

Some of this variability is due to length differences in the HTT expansion mutation. But the team reasoned that other genetic factors affecting Huntington's disease onset might provide clues to treating or staving off the condition.

"We postulated that the presence of the expanded CAG [trinucleotide expansion in HTT] in an individual provides a genetically sensitized background on which to search not for risk alleles but for genetic modifiers of the disease process," they wrote, "which may be common in the population but not have detectable effects in the absence of the [Huntington's disease] mutation."

With this in mind, the team started by doing Affymetrix 6.0 array-based genotyping on blood samples from almost 1,100 individuals with Huntington's disease.

After their quality control steps, the researchers were left with data for 977 Huntington's disease patients of European ancestry who carried between 40 and 55 repeat expansion mutations in HTT. 

They didn't see variants significantly linked to Huntington's disease onset based on directly tested and imputed SNP patterns in these individuals, though the first stage of the GWAS helped flesh out haplotype patterns in and around the HTT gene.

When the team folded in data for another 974 individuals with Huntington's disease who'd been genotyped on Illumina Omni2.5 arrays, it uncovered two chromosome 15 SNPs that were over-represented in those with early or delayed disease onset.

The researchers verified these associations using samples from 2,131 more European Huntington's disease cases as well as a meta-analysis that included samples from all three stages of the study.

In individuals with one of the chromosome 15 variants, clinical symptoms of Huntington's disease were delayed by an estimated 1.4 years. The other variant in this region was associated with a six-year acceleration in disease onset.

The combined dataset also led to a chromosome 8 site that apparently sped up the start of clinical symptoms by more than a year and a half. And still other variants showed more tenuous ties to Huntington's disease onset, including SNPs in and around the gene coding for a DNA mismatch repair gene called MLH1.

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