Genome-wide significance for a modifier of age at neurological onset in Huntington's disease at 6q23-24: the HD MAPS study.
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.
Li
Jian-Liang
JL
Department of Neurology, Boston University School of Medicine, Boston, MA, USA. jlli@alum.bu.edu
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
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*
D005819:Genetic Markers