Journal article
Genome-wide significance for a modifier of age at neurological onset in Huntington's Disease at 6q23-24: the HD MAPS study
BMC medical genetics, Vol.7(1), pp.71-71
08/17/2006
DOI: 10.1186/1471-2350-7-71
PMCID: PMC1586197
PMID: 16914060
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.
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.
Details
- Title: Subtitle
- Genome-wide significance for a modifier of age at neurological onset in Huntington's Disease at 6q23-24: the HD MAPS study
- Creators
- Jian-Liang Li - Boston UniversityMichael R Hayden - University of British ColumbiaSimon C Warby - University of British ColumbiaAlexandra Durr - InsermPatrick J Morrison - Belfast City HospitalMartha Nance - Hennepin County Medical CenterChristopher A Ross - University of IowaRussell L Margolis - University of BaltimoreAdam Rosenblatt - Johns Hopkins UniversityFerdinando Squitieri - Istituto Neurologico MediterraneoLuigi Frati - Sapienza University of RomeEstrella Gómez-Tortosa - Hospital Universitario Fundación Jiménez DíazCarmen Ayuso García - Hospital Universitario Fundación Jiménez DíazOksana Suchowersky - University of CalgaryMary Lou Klimek - University of CalgaryRonald JA Trent - The University of SydneyElizabeth McCusker - Westmead HospitalAndrea Novelletto - University of Rome Tor VergataMarina Frontali - Institute of Neurobiology and Molecular MedicineJane S Paulsen - University of IowaRandi Jones - Emory UniversityTetsuo Ashizawa - The University of Texas Medical Branch at GalvestonAlice Lazzarini - Rutgers, The State University of New JerseyVanessa C Wheeler - Massachusetts General HospitalRanjana Prakash - Boston UniversityGang Xu - Boston UniversityLuc Djoussé - Boston UniversityJayalakshmi Srinidhi Mysore - Massachusetts General HospitalTammy Gillis - Massachusetts General HospitalMichael Hakky - Massachusetts General HospitalL Adrienne Cupples - Boston UniversityMarie H Saint-Hilaire - Boston UniversityJang-Ho J Cha - Massachusetts General HospitalSteven M Hersch - Massachusetts General HospitalJohn B Penney - Massachusetts General HospitalMadaline B Harrison - University of VirginiaSusan L Perlman - University of California, Los AngelesAndrea Zanko - University of California, San FranciscoRuth K Abramson - William S. Hall Psychiatric InstituteAnthony J Lechich - Columbia UniversityAyana Duckett - Columbia UniversityKaren Marder - Columbia UniversityP Michael Conneally - Indiana UniversityJames F Gusella - Massachusetts General HospitalMarcy E MacDonald - Massachusetts General HospitalRichard H Myers - Boston University
- Resource Type
- Journal article
- Publication Details
- BMC medical genetics, Vol.7(1), pp.71-71
- DOI
- 10.1186/1471-2350-7-71
- PMID
- 16914060
- PMCID
- PMC1586197
- NLM abbreviation
- BMC Med Genet
- ISSN
- 1471-2350
- eISSN
- 1471-2350
- Publisher
- BioMed Central
- Language
- English
- Date published
- 08/17/2006
- Academic Unit
- Psychiatry; Psychological and Brain Sciences
- Record Identifier
- 9984383300702771