The relationship between CAG repeat length and age of onset differs for Huntington's disease patients with juvenile onset or adult onset

J. Michael Andresen; Javier Gayán; Luc Djoussé; Simone Roberts; Denise Brocklebank; Stacey S. Cherny; Lon R. Cardon; James F. Gusella; Marcy E. Macdonald; Richard H. Myers; David E. Housman; Nancy S. Wexler; Judith Lorimer; Julie Porter; Fidela Gomez; Carol Moskowitz; Kelly Posner Gerstenhaber; Edith Shackell; Karen Marder; Graciela Penchaszadeh; Simone A. Roberts; Adam Brickman; Denise Brocklebank; Jacqueline Gray; Stephen R. Dlouhy; Sandra Wiktorski; Marion E. Hodes; P. Michael Conneally; John B. Penney; Jang Ho Cha; Micheal Irizarry; Diana Rosas; Steven Hersch; Zane Hollingsworth; Anne B. Young; David E. Housman; Margot Mieja de Young; Ernesto Bonilla; Theresa Stillings; Americo Negrette; S. Robert Snodgrass; Maria Dolores Martinez-Jaurrieta; Maria A. Ramos-Arroyoh; Jacqueline Bickham; Juan Sanchez Ramos; Frederick Marshall; Ira Shoulson; Gustavo J. Rey; Andrew Feigin; Norman Arnheim; Amarilis Acevedo-Cruz; Leticia Acosta; Jose Alvir; Kenneth Fischbeck; Leslie M. Thompson; Angela Young; Leon Dure; Christopher J. O'Brien; Jane Paulsen; Shelley Peery Moran; Denise Krch; Penelope Hogarth; Donald S. Higgins; Bernhard Landwehrmeyer; Michael R. Hayden; Elisabeth W. Almqvist; Ryan R. Brinkman; Oksana Suchowersky; Alexandra Durr; C. Dodé; Ferdinando Squitieri; Patrick J. Morrison; Martha Nance; Christopher A. Ross; Russell L. Margolis; Adam Rosenblatt; Gómez Tortosai Estrella; David Mayo Cabrero; Ronald J.A. Trent; Elizabeth McCusker; Andrea Novelletto; Marina Frontali; Randi Jones; Andrea Zanko; Tetsuo Ashizawa; Alice Lazzarini; Jian Liang Li; Vanessa C. Wheeler; Ana L. Russ; Gang Xu; Jayalakshmi S. Mysore; Tammy Gillis; Michael Hakky; L. Adrienne Cupples; Marie Saint-Hilaire; Steven M. Hersch

doi:10.1111/j.1469-1809.2006.00335.x

The relationship between CAG repeat length and age of onset differs for Huntington's disease patients with juvenile onset or adult onset

J. Michael Andresen, Javier Gayán, Luc Djoussé, Simone Roberts, Denise Brocklebank, Stacey S. Cherny, Lon R. Cardon, James F. Gusella, Marcy E. Macdonald, Richard H. Myers, David E. Housman, Nancy S. Wexler, Judith Lorimer, Julie Porter, Fidela Gomez, Carol Moskowitz, Kelly Posner Gerstenhaber, Edith Shackell, Karen Marder, Graciela PenchaszadehSimone A. Roberts, Adam Brickman, Denise Brocklebank, Jacqueline Gray, Stephen R. Dlouhy, Sandra Wiktorski, Marion E. Hodes, P. Michael Conneally, John B. Penney, Jang Ho Cha, Micheal Irizarry, Diana Rosas, Steven Hersch, Zane Hollingsworth, Anne B. Young, David E. Housman, Margot Mieja de Young, Ernesto Bonilla, Theresa Stillings, Americo Negrette, S. Robert Snodgrass, Maria Dolores Martinez-Jaurrieta, Maria A. Ramos-Arroyoh, Jacqueline Bickham, Juan Sanchez Ramos, Frederick Marshall, Ira Shoulson, Gustavo J. Rey, Andrew Feigin, Norman Arnheim, Amarilis Acevedo-Cruz, Leticia Acosta, Jose Alvir, Kenneth Fischbeck, Leslie M. Thompson, Angela Young, Leon Dure, Christopher J. O'Brien, Jane Paulsen, Shelley Peery Moran, Denise Krch, Penelope Hogarth, Donald S. Higgins, Bernhard Landwehrmeyer, Michael R. Hayden, Elisabeth W. Almqvist, Ryan R. Brinkman, Oksana Suchowersky, Alexandra Durr, C. Dodé, Ferdinando Squitieri, Patrick J. Morrison, Martha Nance, Christopher A. Ross, Russell L. Margolis, Adam Rosenblatt, Gómez Tortosai Estrella, David Mayo Cabrero, Ronald J.A. Trent, Elizabeth McCusker, Andrea Novelletto, Marina Frontali, Randi Jones, Andrea Zanko, Tetsuo Ashizawa, Alice Lazzarini, Jian Liang Li, Vanessa C. Wheeler, Ana L. Russ, Gang Xu, Jayalakshmi S. Mysore, Tammy Gillis, Michael Hakky, L. Adrienne Cupples, Marie Saint-Hilaire, Steven M. Hersch

School of Medicine

Research output: Contribution to journal › Article › peer-review

86 Scopus citations

Abstract

Age of onset for Huntington's disease (HD) varies inversely with the length of the disease-causing CAG repeat expansion in the HD gene. A simple exponential regression model yielded adjusted R-squared values of 0.728 in a large set of Venezuelan kindreds and 0.642 in a North American, European, and Australian sample (the HD MAPS cohort). We present evidence that a two-segment exponential regression curve provides a significantly better fit than the simple exponential regression. A plot of natural log-transformed age of onset against CAG repeat length reveals this segmental relationship. This two-segment exponential regression on age of onset data increases the adjusted R-squared values by 0.012 in the Venezuelan kindreds and by 0.035 in the HD MAPS cohort. Although the amount of additional variance explained by the segmental regression approach is modest, the two slopes of the two-segment regression are significantly different from each other in both the Venezuelan kindreds [F(2, 439) =11.13, P =2 × 10^-5] and in the HD MAPS cohort [F(2, 688) =38.27, P = 2 × 10^-16]. In both populations, the influence of each CAG repeat on age of onset appears to be stronger in the adult-onset range of CAG repeats than in the juvenile-onset range.

Original language	English (US)
Pages (from-to)	295-301
Number of pages	7
Journal	Annals of Human Genetics
Volume	71
Issue number	3
DOIs	https://doi.org/10.1111/j.1469-1809.2006.00335.x
State	Published - May 1 2007

Keywords

Huntington's disease
Multiple linear regression

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1111/j.1469-1809.2006.00335.x

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Andresen, J. M., Gayán, J., Djoussé, L., Roberts, S., Brocklebank, D., Cherny, S. S., Cardon, L. R., Gusella, J. F., Macdonald, M. E., Myers, R. H., Housman, D. E., Wexler, N. S., Lorimer, J., Porter, J., Gomez, F., Moskowitz, C., Gerstenhaber, K. P., Shackell, E., Marder, K., ... Hersch, S. M. (2007). The relationship between CAG repeat length and age of onset differs for Huntington's disease patients with juvenile onset or adult onset. Annals of Human Genetics, 71(3), 295-301. https://doi.org/10.1111/j.1469-1809.2006.00335.x

Andresen, JM, Gayán, J, Djoussé, L, Roberts, S, Brocklebank, D, Cherny, SS, Cardon, LR, Gusella, JF, Macdonald, ME, Myers, RH, Housman, DE, Wexler, NS, Lorimer, J, Porter, J, Gomez, F, Moskowitz, C, Gerstenhaber, KP, Shackell, E, Marder, K, Penchaszadeh, G, Roberts, SA, Brickman, A, Brocklebank, D, Gray, J, Dlouhy, SR, Wiktorski, S, Hodes, ME, Conneally, PM, Penney, JB, Cha, JH, Irizarry, M, Rosas, D, Hersch, S, Hollingsworth, Z, Young, AB, Housman, DE, de Young, MM, Bonilla, E, Stillings, T, Negrette, A, Snodgrass, SR, Martinez-Jaurrieta, MD, Ramos-Arroyoh, MA, Bickham, J, Ramos, JS, Marshall, F, Shoulson, I, Rey, GJ, Feigin, A, Arnheim, N, Acevedo-Cruz, A, Acosta, L, Alvir, J, Fischbeck, K, Thompson, LM, Young, A, Dure, L, O'Brien, CJ, Paulsen, J, Moran, SP, Krch, D, Hogarth, P, Higgins, DS, Landwehrmeyer, B, Hayden, MR, Almqvist, EW, Brinkman, RR, Suchowersky, O, Durr, A, Dodé, C, Squitieri, F, Morrison, PJ, Nance, M, Ross, CA , Margolis, RL, Rosenblatt, A, Estrella, GT, Cabrero, DM, Trent, RJA, McCusker, E, Novelletto, A, Frontali, M, Jones, R, Zanko, A, Ashizawa, T, Lazzarini, A, Li, JL, Wheeler, VC, Russ, AL, Xu, G, Mysore, JS, Gillis, T, Hakky, M, Cupples, LA, Saint-Hilaire, M & Hersch, SM 2007, 'The relationship between CAG repeat length and age of onset differs for Huntington's disease patients with juvenile onset or adult onset', Annals of Human Genetics, vol. 71, no. 3, pp. 295-301. https://doi.org/10.1111/j.1469-1809.2006.00335.x

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title = "The relationship between CAG repeat length and age of onset differs for Huntington's disease patients with juvenile onset or adult onset",

abstract = "Age of onset for Huntington's disease (HD) varies inversely with the length of the disease-causing CAG repeat expansion in the HD gene. A simple exponential regression model yielded adjusted R-squared values of 0.728 in a large set of Venezuelan kindreds and 0.642 in a North American, European, and Australian sample (the HD MAPS cohort). We present evidence that a two-segment exponential regression curve provides a significantly better fit than the simple exponential regression. A plot of natural log-transformed age of onset against CAG repeat length reveals this segmental relationship. This two-segment exponential regression on age of onset data increases the adjusted R-squared values by 0.012 in the Venezuelan kindreds and by 0.035 in the HD MAPS cohort. Although the amount of additional variance explained by the segmental regression approach is modest, the two slopes of the two-segment regression are significantly different from each other in both the Venezuelan kindreds [F(2, 439) =11.13, P =2 × 10-5] and in the HD MAPS cohort [F(2, 688) =38.27, P = 2 × 10-16]. In both populations, the influence of each CAG repeat on age of onset appears to be stronger in the adult-onset range of CAG repeats than in the juvenile-onset range.",

keywords = "Huntington's disease, Multiple linear regression",

author = "Andresen, {J. Michael} and Javier Gay{\'a}n and Luc Djouss{\'e} and Simone Roberts and Denise Brocklebank and Cherny, {Stacey S.} and Cardon, {Lon R.} and Gusella, {James F.} and Macdonald, {Marcy E.} and Myers, {Richard H.} and Housman, {David E.} and Wexler, {Nancy S.} and Judith Lorimer and Julie Porter and Fidela Gomez and Carol Moskowitz and Gerstenhaber, {Kelly Posner} and Edith Shackell and Karen Marder and Graciela Penchaszadeh and Roberts, {Simone A.} and Adam Brickman and Denise Brocklebank and Jacqueline Gray and Dlouhy, {Stephen R.} and Sandra Wiktorski and Hodes, {Marion E.} and Conneally, {P. Michael} and Penney, {John B.} and Cha, {Jang Ho} and Micheal Irizarry and Diana Rosas and Steven Hersch and Zane Hollingsworth and Young, {Anne B.} and Housman, {David E.} and {de Young}, {Margot Mieja} and Ernesto Bonilla and Theresa Stillings and Americo Negrette and Snodgrass, {S. Robert} and Martinez-Jaurrieta, {Maria Dolores} and Ramos-Arroyoh, {Maria A.} and Jacqueline Bickham and Ramos, {Juan Sanchez} and Frederick Marshall and Ira Shoulson and Rey, {Gustavo J.} and Andrew Feigin and Norman Arnheim and Amarilis Acevedo-Cruz and Leticia Acosta and Jose Alvir and Kenneth Fischbeck and Thompson, {Leslie M.} and Angela Young and Leon Dure and O'Brien, {Christopher J.} and Jane Paulsen and Moran, {Shelley Peery} and Denise Krch and Penelope Hogarth and Higgins, {Donald S.} and Bernhard Landwehrmeyer and Hayden, {Michael R.} and Almqvist, {Elisabeth W.} and Brinkman, {Ryan R.} and Oksana Suchowersky and Alexandra Durr and C. Dod{\'e} and Ferdinando Squitieri and Morrison, {Patrick J.} and Martha Nance and Ross, {Christopher A.} and Margolis, {Russell L.} and Adam Rosenblatt and Estrella, {G{\'o}mez Tortosai} and Cabrero, {David Mayo} and Trent, {Ronald J.A.} and Elizabeth McCusker and Andrea Novelletto and Marina Frontali and Randi Jones and Andrea Zanko and Tetsuo Ashizawa and Alice Lazzarini and Li, {Jian Liang} and Wheeler, {Vanessa C.} and Russ, {Ana L.} and Gang Xu and Mysore, {Jayalakshmi S.} and Tammy Gillis and Michael Hakky and Cupples, {L. Adrienne} and Marie Saint-Hilaire and Hersch, {Steven M.}",

year = "2007",

month = may,

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doi = "10.1111/j.1469-1809.2006.00335.x",

language = "English (US)",

volume = "71",

pages = "295--301",

journal = "Annals of Human Genetics",

issn = "0003-4800",

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number = "3",

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TY - JOUR

T1 - The relationship between CAG repeat length and age of onset differs for Huntington's disease patients with juvenile onset or adult onset

AU - Andresen, J. Michael

AU - Gayán, Javier

AU - Djoussé, Luc

AU - Roberts, Simone

AU - Brocklebank, Denise

AU - Cherny, Stacey S.

AU - Cardon, Lon R.

AU - Gusella, James F.

AU - Macdonald, Marcy E.

AU - Myers, Richard H.

AU - Housman, David E.

AU - Wexler, Nancy S.

AU - Lorimer, Judith

AU - Porter, Julie

AU - Gomez, Fidela

AU - Moskowitz, Carol

AU - Gerstenhaber, Kelly Posner

AU - Shackell, Edith

AU - Marder, Karen

AU - Penchaszadeh, Graciela

AU - Roberts, Simone A.

AU - Brickman, Adam

AU - Brocklebank, Denise

AU - Gray, Jacqueline

AU - Dlouhy, Stephen R.

AU - Wiktorski, Sandra

AU - Hodes, Marion E.

AU - Conneally, P. Michael

AU - Penney, John B.

AU - Cha, Jang Ho

AU - Irizarry, Micheal

AU - Rosas, Diana

AU - Hersch, Steven

AU - Hollingsworth, Zane

AU - Young, Anne B.

AU - Housman, David E.

AU - de Young, Margot Mieja

AU - Bonilla, Ernesto

AU - Stillings, Theresa

AU - Negrette, Americo

AU - Snodgrass, S. Robert

AU - Martinez-Jaurrieta, Maria Dolores

AU - Ramos-Arroyoh, 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 - Moran, Shelley Peery

AU - Krch, Denise

AU - Hogarth, Penelope

AU - Higgins, Donald S.

AU - Landwehrmeyer, Bernhard

AU - Hayden, Michael R.

AU - Almqvist, Elisabeth W.

AU - Brinkman, Ryan R.

AU - Suchowersky, Oksana

AU - Durr, Alexandra

AU - Dodé, C.

AU - Squitieri, Ferdinando

AU - Morrison, Patrick J.

AU - Nance, Martha

AU - Ross, Christopher A.

AU - Margolis, Russell L.

AU - Rosenblatt, Adam

AU - Estrella, Gómez Tortosai

AU - Cabrero, David Mayo

AU - Trent, Ronald J.A.

AU - McCusker, Elizabeth

AU - Novelletto, Andrea

AU - Frontali, Marina

AU - Jones, Randi

AU - Zanko, Andrea

AU - Ashizawa, Tetsuo

AU - Lazzarini, Alice

AU - Li, Jian Liang

AU - Wheeler, Vanessa C.

AU - Russ, Ana L.

AU - Xu, Gang

AU - Mysore, Jayalakshmi S.

AU - Gillis, Tammy

AU - Hakky, Michael

AU - Cupples, L. Adrienne

AU - Saint-Hilaire, Marie

AU - Hersch, Steven M.

PY - 2007/5/1

Y1 - 2007/5/1

N2 - Age of onset for Huntington's disease (HD) varies inversely with the length of the disease-causing CAG repeat expansion in the HD gene. A simple exponential regression model yielded adjusted R-squared values of 0.728 in a large set of Venezuelan kindreds and 0.642 in a North American, European, and Australian sample (the HD MAPS cohort). We present evidence that a two-segment exponential regression curve provides a significantly better fit than the simple exponential regression. A plot of natural log-transformed age of onset against CAG repeat length reveals this segmental relationship. This two-segment exponential regression on age of onset data increases the adjusted R-squared values by 0.012 in the Venezuelan kindreds and by 0.035 in the HD MAPS cohort. Although the amount of additional variance explained by the segmental regression approach is modest, the two slopes of the two-segment regression are significantly different from each other in both the Venezuelan kindreds [F(2, 439) =11.13, P =2 × 10-5] and in the HD MAPS cohort [F(2, 688) =38.27, P = 2 × 10-16]. In both populations, the influence of each CAG repeat on age of onset appears to be stronger in the adult-onset range of CAG repeats than in the juvenile-onset range.

AB - Age of onset for Huntington's disease (HD) varies inversely with the length of the disease-causing CAG repeat expansion in the HD gene. A simple exponential regression model yielded adjusted R-squared values of 0.728 in a large set of Venezuelan kindreds and 0.642 in a North American, European, and Australian sample (the HD MAPS cohort). We present evidence that a two-segment exponential regression curve provides a significantly better fit than the simple exponential regression. A plot of natural log-transformed age of onset against CAG repeat length reveals this segmental relationship. This two-segment exponential regression on age of onset data increases the adjusted R-squared values by 0.012 in the Venezuelan kindreds and by 0.035 in the HD MAPS cohort. Although the amount of additional variance explained by the segmental regression approach is modest, the two slopes of the two-segment regression are significantly different from each other in both the Venezuelan kindreds [F(2, 439) =11.13, P =2 × 10-5] and in the HD MAPS cohort [F(2, 688) =38.27, P = 2 × 10-16]. In both populations, the influence of each CAG repeat on age of onset appears to be stronger in the adult-onset range of CAG repeats than in the juvenile-onset range.

KW - Huntington's disease

KW - Multiple linear regression

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AN - SCOPUS:34247120606

SN - 0003-4800

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EP - 301

JO - Annals of Human Genetics

JF - Annals of Human Genetics

IS - 3

ER -

The relationship between CAG repeat length and age of onset differs for Huntington's disease patients with juvenile onset or adult onset

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