Abstract
BackgroundAge at onset of Huntington's disease (HD) is correlated with the size of the abnormal CAG repeat expansion in the HD gene; however, several studies have indicated that other genetic factors also contribute to the variability in HD age at onset. To identify modifier genes, we recently reported a whole-genome scan in a sample of 629 affected sibling pairs from 295 pedigrees, in which six genomic regions provided suggestive evidence for quantitative trait loci (QTL), modifying age at onset in HD.MethodsIn order to test the replication of this finding, eighteen microsatellite markers, three from each of the six genomic regions, were genotyped in 102 newly recruited sibling pairs from 69 pedigrees, and data were analyzed, using a multipoint linkage variance component method, in the follow-up sample and the combined sample of 352 pedigrees with 753 sibling pairs.ResultsSuggestive evidence for linkage at 6q23-24 in the follow-up sample (LOD = 1.87, p = 0.002) increased to genome-wide significance for linkage in the combined sample (LOD = 4.05, p = 0.00001), while suggestive evidence for linkage was observed at 18q22, in both the follow-up sample (LOD = 0.79, p = 0.03) and the combined sample (LOD = 1.78, p = 0.002). Epistatic analysis indicated that there is no interaction between 6q23-24 and other loci.ConclusionIn this replication study, linkage for modifier of age at onset in HD was confirmed at 6q23-24. Evidence for linkage was also found at 18q22. The demonstration of statistically significant linkage to a potential modifier locus opens the path to location cloning of a gene capable of altering HD pathogenesis, which could provide a validated target for therapeutic development in the human patient.
Highlights
Age at onset of Huntington's disease (HD) is correlated with the size of the abnormal CAG repeat expansion in the HD gene; several studies have indicated that other genetic factors contribute to the variability in HD age at onset
Our recent studies [7] and those of others [5,6] suggest that the remaining variation in HD age at onset is strongly heritable and about 56% [8] of the variance remaining in age at onset is attributable to genes other than the HD gene, supporting the existence of genes capable of modifying HD pathogenesis
One of the interesting features of NEDD4L is that it may mediate degradation of the product of SGK, the above mentioned candidate gene located at 6q23 [25]. This replication study confirms evidence for linkage in the 6q23-24 region observed in our original genome scan
Summary
Age at onset of Huntington's disease (HD) is correlated with the size of the abnormal CAG repeat expansion in the HD gene; several studies have indicated that other genetic factors contribute to the variability in HD age at onset. Our recent studies [7] and those of others [5,6] suggest that the remaining variation in HD age at onset is strongly heritable and about 56% [8] of the variance remaining in age at onset is attributable to genes other than the HD gene, supporting the existence of genes capable of modifying HD pathogenesis. Wexler et al [5] suggest that 60% of the variance may be attributable to environmental factors, remarkable similarity for onset age in monozygotic twins [3] support primarily genetic modifiers for this trait
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