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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.

ABSTRACT: 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.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.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.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.

SUBMITTER: Li JL

PROVIDER: S-EPMC1586197 | biostudies-literature | 2006 Aug

REPOSITORIES: biostudies-literature

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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.

Li Jian-Liang JL Hayden Michael R MR Warby Simon C SC Durr Alexandra A Morrison Patrick J PJ Nance Martha M Ross Christopher A CA Margolis Russell L RL Rosenblatt Adam A Squitieri Ferdinando F Frati Luigi L Gómez-Tortosa Estrella E García Carmen Ayuso CA Suchowersky Oksana O Klimek Mary Lou ML Trent Ronald J A RJ McCusker Elizabeth E Novelletto Andrea A Frontali Marina M Paulsen Jane S JS Jones Randi R Ashizawa Tetsuo T Lazzarini Alice A Wheeler Vanessa C VC Prakash Ranjana R Xu Gang G Djoussé Luc L Mysore Jayalakshmi Srinidhi JS Gillis Tammy T Hakky Michael M Cupples L Adrienne LA Saint-Hilaire Marie H MH Cha Jang-Ho J JH Hersch Steven M SM Penney John B JB Harrison Madaline B MB Perlman Susan L SL Zanko Andrea A Abramson Ruth K RK Lechich Anthony J AJ Duckett Ayana A Marder Karen K Conneally P Michael PM Gusella James F JF MacDonald Marcy E ME Myers Richard H RH

BMC medical genetics 20060817

<h4>Background</h4>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 ag ...[more]

PMID: 16914060

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Project description:Age at onset of amyotrophic lateral sclerosis (ALS) is highly variable (eg, 27-74 years in carriers of the G4C2-expansion in C9orf72). It might be influenced by environmental and genetic factors via the modulation of DNA methylation (DNAm) at CpG-sites. Hence, we combined an epigenetic and genetic approach to test the hypothesis that some common single nucleotide polymorphisms (SNPs) at CpG-sites (CpG-SNPs) could modify ALS age of onset. Our genome-wide DNAm analysis suggested three CpG-SNPs whose DNAm levels are significantly associated with age of onset in 249 ALS patients (q < 0.05). Next, genetic analysis validated the association of rs4970944 with age of onset in the discovery (n = 469; P = 0.025) and replication (n = 4160; P = 0.007) ALS cohorts. A meta-analysis of the cohorts combined showed that the median onset in AA-carriers is two years later than in GG-carriers (n = 4629; P = 0.0012). A similar association was observed with its tagging SNPs, implicating a 16 Kb region at the 1q21.3 locus as a modifier of ALS age of onset. Notably, rs4970944 genotypes are also associated with age of onset in C9orf72-carriers (n = 333; P = 0.025), suggesting that each A-allele delays onset by 1.6 years. Analysis of Genotype-Tissue Expression data revealed that the protective A-allele is linked with the reduced expression of CTSS in cerebellum (P = 0.00018), which is a critical brain region in the distributed neural circuits subserving motor control. CTSS encodes cathepsin S protein playing a key role in antigen presentation. In conclusion, we identified a 16 Kb locus tagged by rs4970944 as a modifier of ALS age of onset. Our findings support the role of antigen presenting processes in modulating age of onset of ALS and suggest potential drug targets (eg, CTSS). Future replication studies are encouraged to validate the link between the locus tagged by rs4970944 and age of onset in independent ALS cohorts, including different ethnic groups.

Dataset Information

Genome-wide significance for a modifier of age at neurological onset in Huntington's disease at 6q23-24: the HD MAPS study.

Publications

Genome-wide significance for a modifier of age at neurological onset in Huntington's disease at 6q23-24: the HD MAPS study.

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