Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a triplet (CAG) expansion mutation. The length of the triplet repeat is the most important factor in determining age of onset of HD, although substantial variability remains after controlling for repeat length. The Venezuelan HD kindreds encompass 18,149 individuals spanning 10 generations, 15,409 of whom are living. Of the 4,384 immortalized lymphocyte lines collected, 3,989 DNAs were genotyped for their HD alleles, representing a subset of the population at greatest genetic risk. There are 938 heterozygotes, 80 people with variably penetrant alleles, and 18 homozygotes. Analysis of the 83 kindreds that comprise the Venezuelan HD kindreds demonstrates that residual variability in age of onset has both genetic and environmental components. We created a residual age of onset phenotype from a regression analysis of the log of age of onset on repeat length. Familial correlations (correlation +/- SE) were estimated for sibling (0.40 +/- 0.09), parent-offspring (0.10 +/- 0.11), avuncular (0.07 +/- 0.11), and cousin (0.15 +/- 0.10) pairs, suggesting a familial origin for the residual variance in onset. By using a variance-components approach with all available familial relationships, the additive genetic heritability of this residual age of onset trait is 38%. A model, including shared sibling environmental effects, estimated the components of additive genetic (0.37), shared environment (0.22), and nonshared environment (0.41) variances, confirming that approximately 40% of the variance remaining in onset age is attributable to genes other than the HD gene and 60% is environmental.
Columbia University, 1051 Riverside Drive, New York, NY 10032, USA. wexlern@pi.cpmc.columbia.edu
Nancy S
NS
Wexler
Judith
J
Lorimer
Julie
J
Porter
Fidela
F
Gomez
Carol
C
Moskowitz
Edith
E
Shackell
Karen
K
Marder
Graciela
G
Penchaszadeh
Simone A
SA
Roberts
Javier
J
Gayán
Denise
D
Brocklebank
Stacey S
SS
Cherny
Lon R
LR
Cardon
Jacqueline
J
Gray
Stephen R
SR
Dlouhy
Sandra
S
Wiktorski
Marion E
ME
Hodes
P Michael
PM
Conneally
Jack B
JB
Penney
James
J
Gusella
Jang-Ho
JH
Cha
Michael
M
Irizarry
Diana
D
Rosas
Steven
S
Hersch
Zane
Z
Hollingsworth
Marcy
M
MacDonald
Anne B
AB
Young
J Michael
JM
Andresen
David E
DE
Housman
Margot Mieja
MM
De Young
Ernesto
E
Bonilla
Theresa
T
Stillings
Americo
A
Negrette
S Robert
SR
Snodgrass
Maria Dolores
MD
Martinez-Jaurrieta
Maria A
MA
Ramos-Arroyo
Jacqueline
J
Bickham
Juan Sanchez
JS
Ramos
Frederick
F
Marshall
Ira
I
Shoulson
Gustavo J
GJ
Rey
Andrew
A
Feigin
Norman
N
Arnheim
Amarilis
A
Acevedo-Cruz
Leticia
L
Acosta
Jose
J
Alvir
Kenneth
K
Fischbeck
Leslie M
LM
Thompson
Angela
A
Young
Leon
L
Dure
Christopher J
CJ
O'Brien
Jane
J
Paulsen
Adam
A
Brickman
Denise
D
Krch
Shelley
S
Peery
Penelope
P
Hogarth
Donald S
DS
Higgins
Bernhard
B
Landwehrmeyer
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002648:Child; D002675:Child, Preschool; D004777:Environment; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D010641:Phenotype; D019680:Trinucleotide Repeat Expansion; D014687:Venezuela / Q000453:epidemiology