Browsing by Subject "Genetic Modifier"

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    Genome-wide significance for a modifier of age at neurological onset in Huntington's Disease at 6q23-24: the HD MAPS study
    (BioMed Central, 2006-08-17) Li, Jian-Liang; Hayden, Michael R.; Warby, Simon C.; Durr, Alexandra; Morrison, Patrick J.; Nance, Martha; Ross, Christopher A.; Margolis, Russell L.; Rosenblatt, Adam; Squitieri, Ferdinando; Frati, Luigi; Gómez-Tortosa, Estrella; Ayuso García, Carmen; Suchowersky, Oksana; Klimek, Mary Lou; Trent, Ronald J.A.; McCusker, Elizabeth; Novelletto, Andrea; Frontali, Marina; Paulsen, Jane S.; Jones, Randi; Ashizawa, Tetsuo; Lazzarini, Alice; Wheeler, Vanessa C.; Prakash, Ranjana; Xu, Gang; Djoussé, Luc; Medicine, School of Medicine
    Background Age 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. Methods In 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. Results Suggestive 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. Conclusion In 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.
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    Genomewide association study for onset age in Parkinson disease
    (BioMed Central, 2009-09-22) Latourelle, Jeanne C.; Pankratz, Nathan; Dumitriu, Alexandra; Wilk, Jemma B.; Goldwurm, Stefano; Pezzoli, Gianni; Mariani, Claudio B.; DeStefano, Anita L.; Halter, Cheryl; Gusella, James F.; Nichols, William C.; Myers, Richard H.; Foroud, Tatiana; Medical and Molecular Genetics, School of Medicine
    Background Age at onset in Parkinson disease (PD) is a highly heritable quantitative trait for which a significant genetic influence is supported by multiple segregation analyses. Because genes associated with onset age may represent invaluable therapeutic targets to delay the disease, we sought to identify such genetic modifiers using a genomewide association study in familial PD. There have been previous genomewide association studies (GWAS) to identify genes influencing PD susceptibility, but this is the first to identify genes contributing to the variation in onset age. Methods Initial analyses were performed using genotypes generated with the Illumina HumanCNV370Duo array in a sample of 857 unrelated, familial PD cases. Subsequently, a meta-analysis of imputed SNPs was performed combining the familial PD data with that from a previous GWAS of 440 idiopathic PD cases. The SNPs from the meta-analysis with the lowest p-values and consistency in the direction of effect for onset age were then genotyped in a replication sample of 747 idiopathic PD cases from the Parkinson Institute Biobank of Milan, Italy. Results Meta-analysis across the three studies detected consistent association (p < 1 × 10-5) with five SNPs, none of which reached genomewide significance. On chromosome 11, the SNP with the lowest p-value (rs10767971; p = 5.4 × 10-7) lies between the genes QSER1 and PRRG4. Near the PARK3 linkage region on chromosome 2p13, association was observed with a SNP (rs7577851; p = 8.7 × 10-6) which lies in an intron of the AAK1 gene. This gene is closely related to GAK, identified as a possible PD susceptibility gene in the GWAS of the familial PD cases. Conclusion Taken together, these results suggest an influence of genes involved in endocytosis and lysosomal sorting in PD pathogenesis.