Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease

L. Djoussé, B. Knowlton, M. Hayden, E. W. Almqvist, R. Brinkman, Christopher A Ross, Russell Louis Margolis, A. Rosenblatt, A. Durr, C. Dode, P. J. Morrison, A. Novelletto, M. Frontali, R. J A Trent, E. McCusker, E. Gómez-Tortosa, D. Mayo, R. Jones, A. Zanko, M. NanceR. Abramson, O. Suchowersky, J. Paulsen, M. Harrison, Q. Yang, L. A. Cupples, J. F. Gusella, M. E. MacDonald, Richard H. Myers

Research output: Contribution to journalArticle

Abstract

Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. Past studies have shown that the size of expanded CAG repeat is inversely associated with age at onset (AO) of HD. It is not known whether the normal Huntington allele size influences the relation between the expanded repeat and AO of HD. Data collected from two independent cohorts were used to test the hypothesis that the unexpanded CAG repeat interacts with the expanded CAG repeat to influence AO of HD. In the New England Huntington Disease Center Without Walls (NEHD) cohort of 221 HD affected persons and in the HD-MAPS cohort of 533 HD affected persons, we found evidence supporting an interaction between the expanded and unexpanded CAG repeat sizes which influences AO of HD (P = 0.08 and 0.07, respectively). The association was statistically significant when both cohorts were combined (P=0.012). The estimated heritability of the AO residual was 0.56 after adjustment for normal and expanded repeats and their interaction. An analysis of tertiles of repeats sizes revealed that the effect of the normal allele is seen among persons with large HD repeat sizes (47-83). These findings suggest that an increase in the size of the normal repeat may mitigate the expression of the disease among HD affected persons with large expanded CAG repeats.

Original languageEnglish (US)
Pages (from-to)279-282
Number of pages4
JournalAmerican Journal of Medical Genetics
Volume119 A
Issue number3
StatePublished - Jun 15 2003

Fingerprint

Huntington Disease
Age of Onset
Alleles
New England
Neurodegenerative Diseases
Chromosomes

Keywords

  • Genetics
  • Huntington disease
  • Modifier
  • Onset age
  • Trinucleotide repeat

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Djoussé, L., Knowlton, B., Hayden, M., Almqvist, E. W., Brinkman, R., Ross, C. A., ... Myers, R. H. (2003). Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease. American Journal of Medical Genetics, 119 A(3), 279-282.

Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease. / Djoussé, L.; Knowlton, B.; Hayden, M.; Almqvist, E. W.; Brinkman, R.; Ross, Christopher A; Margolis, Russell Louis; Rosenblatt, A.; Durr, A.; Dode, C.; Morrison, P. J.; Novelletto, A.; Frontali, M.; Trent, R. J A; McCusker, E.; Gómez-Tortosa, E.; Mayo, D.; Jones, R.; Zanko, A.; Nance, M.; Abramson, R.; Suchowersky, O.; Paulsen, J.; Harrison, M.; Yang, Q.; Cupples, L. A.; Gusella, J. F.; MacDonald, M. E.; Myers, Richard H.

In: American Journal of Medical Genetics, Vol. 119 A, No. 3, 15.06.2003, p. 279-282.

Research output: Contribution to journalArticle

Djoussé, L, Knowlton, B, Hayden, M, Almqvist, EW, Brinkman, R, Ross, CA, Margolis, RL, Rosenblatt, A, Durr, A, Dode, C, Morrison, PJ, Novelletto, A, Frontali, M, Trent, RJA, McCusker, E, Gómez-Tortosa, E, Mayo, D, Jones, R, Zanko, A, Nance, M, Abramson, R, Suchowersky, O, Paulsen, J, Harrison, M, Yang, Q, Cupples, LA, Gusella, JF, MacDonald, ME & Myers, RH 2003, 'Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease', American Journal of Medical Genetics, vol. 119 A, no. 3, pp. 279-282.
Djoussé L, Knowlton B, Hayden M, Almqvist EW, Brinkman R, Ross CA et al. Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease. American Journal of Medical Genetics. 2003 Jun 15;119 A(3):279-282.
Djoussé, L. ; Knowlton, B. ; Hayden, M. ; Almqvist, E. W. ; Brinkman, R. ; Ross, Christopher A ; Margolis, Russell Louis ; Rosenblatt, A. ; Durr, A. ; Dode, C. ; Morrison, P. J. ; Novelletto, A. ; Frontali, M. ; Trent, R. J A ; McCusker, E. ; Gómez-Tortosa, E. ; Mayo, D. ; Jones, R. ; Zanko, A. ; Nance, M. ; Abramson, R. ; Suchowersky, O. ; Paulsen, J. ; Harrison, M. ; Yang, Q. ; Cupples, L. A. ; Gusella, J. F. ; MacDonald, M. E. ; Myers, Richard H. / Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease. In: American Journal of Medical Genetics. 2003 ; Vol. 119 A, No. 3. pp. 279-282.
@article{4b9ea70586d44d4eac5bcc09755072ea,
title = "Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease",
abstract = "Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. Past studies have shown that the size of expanded CAG repeat is inversely associated with age at onset (AO) of HD. It is not known whether the normal Huntington allele size influences the relation between the expanded repeat and AO of HD. Data collected from two independent cohorts were used to test the hypothesis that the unexpanded CAG repeat interacts with the expanded CAG repeat to influence AO of HD. In the New England Huntington Disease Center Without Walls (NEHD) cohort of 221 HD affected persons and in the HD-MAPS cohort of 533 HD affected persons, we found evidence supporting an interaction between the expanded and unexpanded CAG repeat sizes which influences AO of HD (P = 0.08 and 0.07, respectively). The association was statistically significant when both cohorts were combined (P=0.012). The estimated heritability of the AO residual was 0.56 after adjustment for normal and expanded repeats and their interaction. An analysis of tertiles of repeats sizes revealed that the effect of the normal allele is seen among persons with large HD repeat sizes (47-83). These findings suggest that an increase in the size of the normal repeat may mitigate the expression of the disease among HD affected persons with large expanded CAG repeats.",
keywords = "Genetics, Huntington disease, Modifier, Onset age, Trinucleotide repeat",
author = "L. Djouss{\'e} and B. Knowlton and M. Hayden and Almqvist, {E. W.} and R. Brinkman and Ross, {Christopher A} and Margolis, {Russell Louis} and A. Rosenblatt and A. Durr and C. Dode and Morrison, {P. J.} and A. Novelletto and M. Frontali and Trent, {R. J A} and E. McCusker and E. G{\'o}mez-Tortosa and D. Mayo and R. Jones and A. Zanko and M. Nance and R. Abramson and O. Suchowersky and J. Paulsen and M. Harrison and Q. Yang and Cupples, {L. A.} and Gusella, {J. F.} and MacDonald, {M. E.} and Myers, {Richard H.}",
year = "2003",
month = "6",
day = "15",
language = "English (US)",
volume = "119 A",
pages = "279--282",
journal = "American Journal of Medical Genetics, Part A",
issn = "1552-4825",
publisher = "Wiley-Liss Inc.",
number = "3",

}

TY - JOUR

T1 - Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease

AU - Djoussé, L.

AU - Knowlton, B.

AU - Hayden, M.

AU - Almqvist, E. W.

AU - Brinkman, R.

AU - Ross, Christopher A

AU - Margolis, Russell Louis

AU - Rosenblatt, A.

AU - Durr, A.

AU - Dode, C.

AU - Morrison, P. J.

AU - Novelletto, A.

AU - Frontali, M.

AU - Trent, R. J A

AU - McCusker, E.

AU - Gómez-Tortosa, E.

AU - Mayo, D.

AU - Jones, R.

AU - Zanko, A.

AU - Nance, M.

AU - Abramson, R.

AU - Suchowersky, O.

AU - Paulsen, J.

AU - Harrison, M.

AU - Yang, Q.

AU - Cupples, L. A.

AU - Gusella, J. F.

AU - MacDonald, M. E.

AU - Myers, Richard H.

PY - 2003/6/15

Y1 - 2003/6/15

N2 - Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. Past studies have shown that the size of expanded CAG repeat is inversely associated with age at onset (AO) of HD. It is not known whether the normal Huntington allele size influences the relation between the expanded repeat and AO of HD. Data collected from two independent cohorts were used to test the hypothesis that the unexpanded CAG repeat interacts with the expanded CAG repeat to influence AO of HD. In the New England Huntington Disease Center Without Walls (NEHD) cohort of 221 HD affected persons and in the HD-MAPS cohort of 533 HD affected persons, we found evidence supporting an interaction between the expanded and unexpanded CAG repeat sizes which influences AO of HD (P = 0.08 and 0.07, respectively). The association was statistically significant when both cohorts were combined (P=0.012). The estimated heritability of the AO residual was 0.56 after adjustment for normal and expanded repeats and their interaction. An analysis of tertiles of repeats sizes revealed that the effect of the normal allele is seen among persons with large HD repeat sizes (47-83). These findings suggest that an increase in the size of the normal repeat may mitigate the expression of the disease among HD affected persons with large expanded CAG repeats.

AB - Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. Past studies have shown that the size of expanded CAG repeat is inversely associated with age at onset (AO) of HD. It is not known whether the normal Huntington allele size influences the relation between the expanded repeat and AO of HD. Data collected from two independent cohorts were used to test the hypothesis that the unexpanded CAG repeat interacts with the expanded CAG repeat to influence AO of HD. In the New England Huntington Disease Center Without Walls (NEHD) cohort of 221 HD affected persons and in the HD-MAPS cohort of 533 HD affected persons, we found evidence supporting an interaction between the expanded and unexpanded CAG repeat sizes which influences AO of HD (P = 0.08 and 0.07, respectively). The association was statistically significant when both cohorts were combined (P=0.012). The estimated heritability of the AO residual was 0.56 after adjustment for normal and expanded repeats and their interaction. An analysis of tertiles of repeats sizes revealed that the effect of the normal allele is seen among persons with large HD repeat sizes (47-83). These findings suggest that an increase in the size of the normal repeat may mitigate the expression of the disease among HD affected persons with large expanded CAG repeats.

KW - Genetics

KW - Huntington disease

KW - Modifier

KW - Onset age

KW - Trinucleotide repeat

UR - http://www.scopus.com/inward/record.url?scp=10744225124&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=10744225124&partnerID=8YFLogxK

M3 - Article

C2 - 12784292

AN - SCOPUS:10744225124

VL - 119 A

SP - 279

EP - 282

JO - American Journal of Medical Genetics, Part A

JF - American Journal of Medical Genetics, Part A

SN - 1552-4825

IS - 3

ER -