title: Genome-wide significance for a modifier of age at neurological onset in Huntington's disease at 6q23-24: the HD MAPS study.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA, USA. jlli@alum.bu.edu
authors.forename: Jian-Liang
authors.initials: JL
authors.lastname: Li
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Simon C
authors.initials: SC
authors.lastname: Warby
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Morrison
authors.forename: Martha
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authors.lastname: Nance
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.forename: Russell L
authors.initials: RL
authors.lastname: Margolis
authors.forename: Adam
authors.initials: A
authors.lastname: Rosenblatt
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Squitieri
authors.forename: Luigi
authors.initials: L
authors.lastname: Frati
authors.forename: Estrella
authors.initials: E
authors.lastname: Gómez-Tortosa
authors.forename: Carmen Ayuso
authors.initials: CA
authors.lastname: García
authors.forename: Oksana
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authors.lastname: Suchowersky
authors.forename: Mary Lou
authors.initials: ML
authors.lastname: Klimek
authors.forename: Ronald J A
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authors.lastname: Trent
authors.forename: Elizabeth
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authors.lastname: McCusker
authors.forename: Andrea
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authors.lastname: Novelletto
authors.forename: Marina
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authors.lastname: Frontali
authors.forename: Jane S
authors.initials: JS
authors.lastname: Paulsen
authors.forename: Randi
authors.initials: R
authors.lastname: Jones
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ashizawa
authors.forename: Alice
authors.initials: A
authors.lastname: Lazzarini
authors.forename: Vanessa C
authors.initials: VC
authors.lastname: Wheeler
authors.forename: Ranjana
authors.initials: R
authors.lastname: Prakash
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
authors.forename: Luc
authors.initials: L
authors.lastname: Djoussé
authors.forename: Jayalakshmi Srinidhi
authors.initials: JS
authors.lastname: Mysore
authors.forename: Tammy
authors.initials: T
authors.lastname: Gillis
authors.forename: Michael
authors.initials: M
authors.lastname: Hakky
authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
authors.forename: Marie H
authors.initials: MH
authors.lastname: Saint-Hilaire
authors.forename: Jang-Ho J
authors.initials: JH
authors.lastname: Cha
authors.forename: Steven M
authors.initials: SM
authors.lastname: Hersch
authors.forename: John B
authors.initials: JB
authors.lastname: Penney
authors.forename: Madaline B
authors.initials: MB
authors.lastname: Harrison
authors.forename: Susan L
authors.initials: SL
authors.lastname: Perlman
authors.forename: Andrea
authors.initials: A
authors.lastname: Zanko
authors.forename: Ruth K
authors.initials: RK
authors.lastname: Abramson
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Lechich
authors.forename: Ayana
authors.initials: A
authors.lastname: Duckett
authors.forename: Karen
authors.initials: K
authors.lastname: Marder
authors.forename: P Michael
authors.initials: PM
authors.lastname: Conneally
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.forename: Marcy E
authors.initials: ME
authors.lastname: MacDonald
authors.forename: Richard H
authors.initials: RH
authors.lastname: Myers
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002896:Chromosomes, Human, Pair 6; D008040:Genetic Linkage; D005819:Genetic Markers; D015894:Genome, Human; D006801:Humans; D006816:Huntington Disease / Q000235:genetics*; D008875:Middle Aged; D008957:Models, Genetic; D040641:Quantitative Trait Loci; D018911:Trinucleotide Repeats / Q000235:genetics*
chemical_list: D005819:Genetic Markers