Genomewide linkage analysis of age of onset of Huntington's Disease

Abstract

The age of onset of Huntington’s disease (HD) is highly correlated with the number of CAG repeats in the gene coding for the hungtingtin protein. However, there remains substantial unexplained variance in age of onset, since this relationship is only moderate for individuals with between 40 to 50 repeats, which make the majority of individuals with expanded repeats. Once the effect of the CAG repeat has been accounted for, the residual variance in age of onset is a heritable trait. Targeted candidate gene studies and a genome scan have suggested some loci as potential modifiers of the age of onset of HD. In this study, we have used the large Venezuelan pedigrees, which were used to locate the original HD gene, which offer much greater power than a standard sib-pair design. We have developed and applied near-optimal pedigree-member selection procedures to maximize power in the pedigrees. In this manner, we have carried out a genomewide linkage analysis employing a 6000-SNP marker panel. We have identified a novel locus at chromosome 2p25 (LOD = 4.29) that may modify the age of onset of HD. There is a second linkage peak (LOD = 3.39 at 2q35), which is consistent for sub-pedigrees of different complexities. A third linkage peak (LOD = 2.48 at 6q22) may confirm the most promising locus from a previous genome scan. Two other candidate loci are suggested on chromosome 5 (LOD = 3.31 at 5p14 and LOD = 3.14 at 5q32). All these regions harbor candidate genes that are promising HD modifier genes. The identification of these new genes may provide an invaluable help to improve our understanding of HD and develop new therapies.