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.
Wexler
Nancy S
NS
Columbia University, 1051 Riverside Drive, New York, NY 10032, USA. wexlern@pi.cpmc.columbia.edu
Lorimer
Judith
J
Porter
Julie
J
Gomez
Fidela
F
Moskowitz
Carol
C
Shackell
Edith
E
Marder
Karen
K
Penchaszadeh
Graciela
G
Roberts
Simone A
SA
Gayán
Javier
J
Brocklebank
Denise
D
Cherny
Stacey S
SS
Cardon
Lon R
LR
Gray
Jacqueline
J
Dlouhy
Stephen R
SR
Wiktorski
Sandra
S
Hodes
Marion E
ME
Conneally
P Michael
PM
Penney
Jack B
JB
Gusella
James
J
Cha
Jang-Ho
JH
Irizarry
Michael
M
Rosas
Diana
D
Hersch
Steven
S
Hollingsworth
Zane
Z
MacDonald
Marcy
M
Young
Anne B
AB
Andresen
J Michael
JM
Housman
David E
DE
De Young
Margot Mieja
MM
Bonilla
Ernesto
E
Stillings
Theresa
T
Negrette
Americo
A
Snodgrass
S Robert
SR
Martinez-Jaurrieta
Maria Dolores
MD
Ramos-Arroyo
Maria A
MA
Bickham
Jacqueline
J
Ramos
Juan Sanchez
JS
Marshall
Frederick
F
Shoulson
Ira
I
Rey
Gustavo J
GJ
Feigin
Andrew
A
Arnheim
Norman
N
Acevedo-Cruz
Amarilis
A
Acosta
Leticia
L
Alvir
Jose
J
Fischbeck
Kenneth
K
Thompson
Leslie M
LM
Young
Angela
A
Dure
Leon
L
O'Brien
Christopher J
CJ
Paulsen
Jane
J
Brickman
Adam
A
Krch
Denise
D
Peery
Shelley
S
Hogarth
Penelope
P
Higgins
Donald S
DS
Landwehrmeyer
Bernhard
B
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