A genome scan for modifiers of age at onset in Huntington disease: The HD MAPS study

Jian Liang Li, Michael R. Hayden, Elisabeth W. Almqvist, Ryan R. Brinkman, Alexandra Durr, Catherine Dodé, Patrick J. Morrison, Oksana Suchowersky, Christopher A Ross, Russell Louis Margolis, Adam Rosenblatt, Estrella Gómez-Tortosa, David Mayo Cabrero, Andrea Novelletto, Marina Frontali, Martha Nance, Ronald J A Trent, Elizabeth McCusker, Randi Jones, Jane S. PaulsenMadeline Harrison, Andrea Zanko, Ruth K. Abramson, Ana L. Russ, Beth Knowlton, Luc Djoussé, Jayalakshmi S. Mysore, Suzanne Tariot, Michael F. Gusella, Vanessa C. Wheeler, Larry D. Atwood, L. Adrienne Cupples, Marie Saint-Hilaire, Jang Ho J Cha, Steven M. Hersch, Walter J. Koroshetz, James F. Gusella, Marcy E. MacDonald, Richard H. Myers

Research output: Contribution to journalArticle

Abstract

Huntington disease (HD) is caused by the expansion of a CAG repeat within the coding region of a novel gene on 4p16.3. Although the variation in age at onset is partly explained by the size of the expanded repeat, the unexplained variation in age at onset is strongly heritable (h2 = 0.56), which suggests that other genes modify the age at onset of HD. To identify these modifier loci, we performed a 10-cM density genomewide scan in 629 affected sibling pairs (295 pedigrees and 695 individuals), using ages at onset adjusted for the expanded and normal CAG repeat sizes. Because all those studied were HD affected, estimates of allele sharing identical by descent at and around the HD locus were adjusted by a positionally weighted method to correct for the increased allele sharing at 4p. Suggestive evidence for linkage was found at 4p16 (LOD = 1.93), 6p21-23 (LOD = 2.29), and 6q24-26 (LOD = 2.28), which may be useful for investigation of genes that modify age at onset of HD.

Original languageEnglish (US)
Pages (from-to)682-687
Number of pages6
JournalAmerican Journal of Human Genetics
Volume73
Issue number3
DOIs
StatePublished - Sep 1 2003

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Huntington Disease
Age of Onset
Genome
Alleles
Genes
Pedigree

ASJC Scopus subject areas

  • Genetics

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Li, J. L., Hayden, M. R., Almqvist, E. W., Brinkman, R. R., Durr, A., Dodé, C., ... Myers, R. H. (2003). A genome scan for modifiers of age at onset in Huntington disease: The HD MAPS study. American Journal of Human Genetics, 73(3), 682-687. https://doi.org/10.1086/378133

A genome scan for modifiers of age at onset in Huntington disease : The HD MAPS study. / Li, Jian Liang; Hayden, Michael R.; Almqvist, Elisabeth W.; Brinkman, Ryan R.; Durr, Alexandra; Dodé, Catherine; Morrison, Patrick J.; Suchowersky, Oksana; Ross, Christopher A; Margolis, Russell Louis; Rosenblatt, Adam; Gómez-Tortosa, Estrella; Cabrero, David Mayo; Novelletto, Andrea; Frontali, Marina; Nance, Martha; Trent, Ronald J A; McCusker, Elizabeth; Jones, Randi; Paulsen, Jane S.; Harrison, Madeline; Zanko, Andrea; Abramson, Ruth K.; Russ, Ana L.; Knowlton, Beth; Djoussé, Luc; Mysore, Jayalakshmi S.; Tariot, Suzanne; Gusella, Michael F.; Wheeler, Vanessa C.; Atwood, Larry D.; Cupples, L. Adrienne; Saint-Hilaire, Marie; Cha, Jang Ho J; Hersch, Steven M.; Koroshetz, Walter J.; Gusella, James F.; MacDonald, Marcy E.; Myers, Richard H.

In: American Journal of Human Genetics, Vol. 73, No. 3, 01.09.2003, p. 682-687.

Research output: Contribution to journalArticle

Li, JL, Hayden, MR, Almqvist, EW, Brinkman, RR, Durr, A, Dodé, C, Morrison, PJ, Suchowersky, O, Ross, CA, Margolis, RL, Rosenblatt, A, Gómez-Tortosa, E, Cabrero, DM, Novelletto, A, Frontali, M, Nance, M, Trent, RJA, McCusker, E, Jones, R, Paulsen, JS, Harrison, M, Zanko, A, Abramson, RK, Russ, AL, Knowlton, B, Djoussé, L, Mysore, JS, Tariot, S, Gusella, MF, Wheeler, VC, Atwood, LD, Cupples, LA, Saint-Hilaire, M, Cha, JHJ, Hersch, SM, Koroshetz, WJ, Gusella, JF, MacDonald, ME & Myers, RH 2003, 'A genome scan for modifiers of age at onset in Huntington disease: The HD MAPS study', American Journal of Human Genetics, vol. 73, no. 3, pp. 682-687. https://doi.org/10.1086/378133
Li, Jian Liang ; Hayden, Michael R. ; Almqvist, Elisabeth W. ; Brinkman, Ryan R. ; Durr, Alexandra ; Dodé, Catherine ; Morrison, Patrick J. ; Suchowersky, Oksana ; Ross, Christopher A ; Margolis, Russell Louis ; Rosenblatt, Adam ; Gómez-Tortosa, Estrella ; Cabrero, David Mayo ; Novelletto, Andrea ; Frontali, Marina ; Nance, Martha ; Trent, Ronald J A ; McCusker, Elizabeth ; Jones, Randi ; Paulsen, Jane S. ; Harrison, Madeline ; Zanko, Andrea ; Abramson, Ruth K. ; Russ, Ana L. ; Knowlton, Beth ; Djoussé, Luc ; Mysore, Jayalakshmi S. ; Tariot, Suzanne ; Gusella, Michael F. ; Wheeler, Vanessa C. ; Atwood, Larry D. ; Cupples, L. Adrienne ; Saint-Hilaire, Marie ; Cha, Jang Ho J ; Hersch, Steven M. ; Koroshetz, Walter J. ; Gusella, James F. ; MacDonald, Marcy E. ; Myers, Richard H. / A genome scan for modifiers of age at onset in Huntington disease : The HD MAPS study. In: American Journal of Human Genetics. 2003 ; Vol. 73, No. 3. pp. 682-687.
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abstract = "Huntington disease (HD) is caused by the expansion of a CAG repeat within the coding region of a novel gene on 4p16.3. Although the variation in age at onset is partly explained by the size of the expanded repeat, the unexplained variation in age at onset is strongly heritable (h2 = 0.56), which suggests that other genes modify the age at onset of HD. To identify these modifier loci, we performed a 10-cM density genomewide scan in 629 affected sibling pairs (295 pedigrees and 695 individuals), using ages at onset adjusted for the expanded and normal CAG repeat sizes. Because all those studied were HD affected, estimates of allele sharing identical by descent at and around the HD locus were adjusted by a positionally weighted method to correct for the increased allele sharing at 4p. Suggestive evidence for linkage was found at 4p16 (LOD = 1.93), 6p21-23 (LOD = 2.29), and 6q24-26 (LOD = 2.28), which may be useful for investigation of genes that modify age at onset of HD.",
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T1 - A genome scan for modifiers of age at onset in Huntington disease

T2 - The HD MAPS study

AU - Li, Jian Liang

AU - Hayden, Michael R.

AU - Almqvist, Elisabeth W.

AU - Brinkman, Ryan R.

AU - Durr, Alexandra

AU - Dodé, Catherine

AU - Morrison, Patrick J.

AU - Suchowersky, Oksana

AU - Ross, Christopher A

AU - Margolis, Russell Louis

AU - Rosenblatt, Adam

AU - Gómez-Tortosa, Estrella

AU - Cabrero, David Mayo

AU - Novelletto, Andrea

AU - Frontali, Marina

AU - Nance, Martha

AU - Trent, Ronald J A

AU - McCusker, Elizabeth

AU - Jones, Randi

AU - Paulsen, Jane S.

AU - Harrison, Madeline

AU - Zanko, Andrea

AU - Abramson, Ruth K.

AU - Russ, Ana L.

AU - Knowlton, Beth

AU - Djoussé, Luc

AU - Mysore, Jayalakshmi S.

AU - Tariot, Suzanne

AU - Gusella, Michael F.

AU - Wheeler, Vanessa C.

AU - Atwood, Larry D.

AU - Cupples, L. Adrienne

AU - Saint-Hilaire, Marie

AU - Cha, Jang Ho J

AU - Hersch, Steven M.

AU - Koroshetz, Walter J.

AU - Gusella, James F.

AU - MacDonald, Marcy E.

AU - Myers, Richard H.

PY - 2003/9/1

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N2 - Huntington disease (HD) is caused by the expansion of a CAG repeat within the coding region of a novel gene on 4p16.3. Although the variation in age at onset is partly explained by the size of the expanded repeat, the unexplained variation in age at onset is strongly heritable (h2 = 0.56), which suggests that other genes modify the age at onset of HD. To identify these modifier loci, we performed a 10-cM density genomewide scan in 629 affected sibling pairs (295 pedigrees and 695 individuals), using ages at onset adjusted for the expanded and normal CAG repeat sizes. Because all those studied were HD affected, estimates of allele sharing identical by descent at and around the HD locus were adjusted by a positionally weighted method to correct for the increased allele sharing at 4p. Suggestive evidence for linkage was found at 4p16 (LOD = 1.93), 6p21-23 (LOD = 2.29), and 6q24-26 (LOD = 2.28), which may be useful for investigation of genes that modify age at onset of HD.

AB - Huntington disease (HD) is caused by the expansion of a CAG repeat within the coding region of a novel gene on 4p16.3. Although the variation in age at onset is partly explained by the size of the expanded repeat, the unexplained variation in age at onset is strongly heritable (h2 = 0.56), which suggests that other genes modify the age at onset of HD. To identify these modifier loci, we performed a 10-cM density genomewide scan in 629 affected sibling pairs (295 pedigrees and 695 individuals), using ages at onset adjusted for the expanded and normal CAG repeat sizes. Because all those studied were HD affected, estimates of allele sharing identical by descent at and around the HD locus were adjusted by a positionally weighted method to correct for the increased allele sharing at 4p. Suggestive evidence for linkage was found at 4p16 (LOD = 1.93), 6p21-23 (LOD = 2.29), and 6q24-26 (LOD = 2.28), which may be useful for investigation of genes that modify age at onset of HD.

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