TY - JOUR
T1 - Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset
AU - Wexler, Nancy S.
AU - Lorimer, Judith
AU - Porter, Julie
AU - Gomez, Fidela
AU - Moskowitz, Carol
AU - Shackell, Edith
AU - Marder, Karen
AU - Penchaszadeh, Graciela
AU - Roberts, Simone A.
AU - Gayán, Javier
AU - Brocklebank, Denise
AU - Cherny, Stacey S.
AU - Cardon, Lon R.
AU - Gray, Jacqueline
AU - Dlouhy, Stephen R.
AU - Wiktorski, Sandra
AU - Hodes, Marion E.
AU - Conneally, P. Michael
AU - Penney, Jack B.
AU - Gusella, James
AU - Cha, Jang Ho
AU - Irizarry, Michael
AU - Rosas, Diana
AU - Hersch, Steven
AU - Hollingsworth, Zane
AU - MacDonald, Marcy
AU - Young, Anne B.
AU - Andresen, J. Michael
AU - Housman, David E.
AU - Mieja De Young, Margot
AU - Bonilla, Ernesto
AU - Stillings, Theresa
AU - Negrette, Americo
AU - Snodgrass, S. Robert
AU - Martinez-Jaurrieta, Maria Dolores
AU - Ramos-Arroyo, Maria A.
AU - Bickham, Jacqueline
AU - Ramos, Juan Sanchez
AU - Marshall, Frederick
AU - Shoulson, Ira
AU - Rey, Gustavo J.
AU - Feigin, Andrew
AU - Arnheim, Norman
AU - Acevedo-Cruz, Amarilis
AU - Acosta, Leticia
AU - Alvir, Jose
AU - Fischbeck, Kenneth
AU - Thompson, Leslie M.
AU - Young, Angela
AU - Dure, Leon
AU - O'Brien, Christopher J.
AU - Paulsen, Jane
AU - Brickman, Adam
AU - Krch, Denise
AU - Peery, Shelley
AU - Hogarth, Penelope
AU - Higgins, Donald S.
AU - Landwehrmeyeri, Bernhard
PY - 2004/3/9
Y1 - 2004/3/9
N2 - 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 ≈40% of the variance remaining in onset age is attributable to genes other than the HD gene and 60% is environmental.
AB - 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 ≈40% of the variance remaining in onset age is attributable to genes other than the HD gene and 60% is environmental.
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U2 - 10.1073/pnas.0308679101
DO - 10.1073/pnas.0308679101
M3 - Article
C2 - 14993615
AN - SCOPUS:12144288251
SN - 0027-8424
VL - 101
SP - 3498
EP - 3503
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 10
ER -