A genome scan for modifiers of age at onset in Huntington disease: The HD MAPS study.
Huntington disease (HD) is caused by the expansion of a CAG repeat within the coding region of a novel gene on 4p16.3. Although the variation in age at onset is partly explained by the size of the expanded repeat, the unexplained variation in age at onset is strongly heritable (h2=0.56), which suggests that other genes modify the age at onset of HD. To identify these modifier loci, we performed a 10-cM density genomewide scan in 629 affected sibling pairs (295 pedigrees and 695 individuals), using ages at onset adjusted for the expanded and normal CAG repeat sizes. Because all those studied were HD affected, estimates of allele sharing identical by descent at and around the HD locus were adjusted by a positionally weighted method to correct for the increased allele sharing at 4p. Suggestive evidence for linkage was found at 4p16 (LOD=1.93), 6p21-23 (LOD=2.29), and 6q24-26 (LOD=2.28), which may be useful for investigation of genes that modify age at onset of HD.
Li
Jian-Liang
JL
Department of Neurology, Boston University School of Medicine, and Bioinformatics Program, School of Public Health, Boston University, Boston, MA, USA.
Hayden
Michael R
MR
Almqvist
Elisabeth W
EW
Brinkman
Ryan R
RR
Durr
Alexandra
A
Dodé
Catherine
C
Morrison
Patrick J
PJ
Suchowersky
Oksana
O
Ross
Christopher A
CA
Margolis
Russell L
RL
Rosenblatt
Adam
A
Gómez-Tortosa
Estrella
E
Cabrero
David Mayo
DM
Novelletto
Andrea
A
Frontali
Marina
M
Nance
Martha
M
Trent
Ronald J A
RJ
McCusker
Elizabeth
E
Jones
Randi
R
Paulsen
Jane S
JS
Harrison
Madeline
M
Zanko
Andrea
A
Abramson
Ruth K
RK
Russ
Ana L
AL
Knowlton
Beth
B
Djoussé
Luc
L
Mysore
Jayalakshmi S
JS
Tariot
Suzanne
S
Gusella
Michael F
MF
Wheeler
Vanessa C
VC
Atwood
Larry D
LD
Cupples
L Adrienne
LA
Saint-Hilaire
Marie
M
Cha
Jang-Ho J
JH
Hersch
Steven M
SM
Koroshetz
Walter J
WJ
Gusella
James F
JF
MacDonald
Marcy E
ME
Myers
Richard H
RH
D017668:Age of Onset; D002874:Chromosome Mapping; D016678:Genome; D006801:Humans; D006816:Huntington Disease / Q000235:genetics*; D018911:Trinucleotide Repeats