Common SNP-based haplotype analysis of the 4p16.3 Huntington disease gene region

Jong Min Lee, Tammy Gillis, Jayalakshmi Srinidhi Mysore, Eliana Marisa Ramos, Richard H. Myers, Michael R. Hayden, Patrick J. Morrison, Martha Nance, Christopher A. Ross, Russell L. Margolis, Ferdinando Squitieri, Annamaria Griguoli, Stefano Di Donato, Estrella Gomez-Tortosa, Carmen Ayuso, Oksana Suchowersky, Ronald J. Trent, Elizabeth McCusker, Andrea Novelletto, Marina FrontaliRandi Jones, Tetsuo Ashizawa, Samuel Frank, Marie Helene Saint-Hilaire, Steven M. Hersch, Herminia D. Rosas, Diane Lucente, Madaline B. Harrison, Andrea Zanko, Ruth K. Abramson, Karen Marder, Jorge Sequeiros, Marcy E. MacDonald, James F. Gusella

Research output: Contribution to journalArticle

Abstract

Age at the onset of motor symptoms in Huntington disease (HD) is determined largely by the length of a CAG repeat expansion in HTT but is also influenced by other genetic factors. We tested whether common genetic variation near the mutation site is associated with differences in the distribution of expanded CAG alleles or age at the onset of motor symptoms. To define disease-associated single-nucleotide polymorphisms (SNPs), we compared 4p16.3 SNPs in HD subjects with population controls in a case:control strategy, which revealed that the strongest signals occurred at a great distance from the HD mutation as a result of "synthetic association" with SNP alleles that are of low frequency in population controls. Detailed analysis delineated a prominent ancestral haplotype that accounted for ∼50% of HD chromosomes and extended to at least 938 kb on about half of these. Together, the seven most abundant haplotypes accounted for ∼83% of HD chromosomes. Neither the extended shared haplotype nor the individual local HTT haplotypes were associated with altered CAG-repeat length distribution or residual age at the onset of motor symptoms, arguing against modification of these disease features by common cis-regulatory elements. Similarly, the 11 most frequent control haplotypes showed no trans-modifier effect on age at the onset of motor symptoms. Our results argue against common local regulatory variation as a factor influencing HD pathogenesis, suggesting that genetic modifiers be sought elsewhere in the genome. They also indicate that genome-wide association analysis with a small number of cases can be effective for regional localization of genetic defects, even when a founder effect accounts for only a fraction of the disorder.

Original languageEnglish
Pages (from-to)434-444
Number of pages11
JournalAmerican Journal of Human Genetics
Volume90
Issue number3
DOIs
Publication statusPublished - Mar 9 2012

Fingerprint

Huntington Disease
Haplotypes
Single Nucleotide Polymorphism
Age of Onset
Genes
Population Control
Chromosomes
Founder Effect
Mutation
Genome-Wide Association Study
Gene Frequency
Alleles
Genome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Lee, J. M., Gillis, T., Mysore, J. S., Ramos, E. M., Myers, R. H., Hayden, M. R., ... Gusella, J. F. (2012). Common SNP-based haplotype analysis of the 4p16.3 Huntington disease gene region. American Journal of Human Genetics, 90(3), 434-444. https://doi.org/10.1016/j.ajhg.2012.01.005

Common SNP-based haplotype analysis of the 4p16.3 Huntington disease gene region. / Lee, Jong Min; Gillis, Tammy; Mysore, Jayalakshmi Srinidhi; Ramos, Eliana Marisa; Myers, Richard H.; Hayden, Michael R.; Morrison, Patrick J.; Nance, Martha; Ross, Christopher A.; Margolis, Russell L.; Squitieri, Ferdinando; Griguoli, Annamaria; Di Donato, Stefano; Gomez-Tortosa, Estrella; Ayuso, Carmen; Suchowersky, Oksana; Trent, Ronald J.; McCusker, Elizabeth; Novelletto, Andrea; Frontali, Marina; Jones, Randi; Ashizawa, Tetsuo; Frank, Samuel; Saint-Hilaire, Marie Helene; Hersch, Steven M.; Rosas, Herminia D.; Lucente, Diane; Harrison, Madaline B.; Zanko, Andrea; Abramson, Ruth K.; Marder, Karen; Sequeiros, Jorge; MacDonald, Marcy E.; Gusella, James F.

In: American Journal of Human Genetics, Vol. 90, No. 3, 09.03.2012, p. 434-444.

Research output: Contribution to journalArticle

Lee, JM, Gillis, T, Mysore, JS, Ramos, EM, Myers, RH, Hayden, MR, Morrison, PJ, Nance, M, Ross, CA, Margolis, RL, Squitieri, F, Griguoli, A, Di Donato, S, Gomez-Tortosa, E, Ayuso, C, Suchowersky, O, Trent, RJ, McCusker, E, Novelletto, A, Frontali, M, Jones, R, Ashizawa, T, Frank, S, Saint-Hilaire, MH, Hersch, SM, Rosas, HD, Lucente, D, Harrison, MB, Zanko, A, Abramson, RK, Marder, K, Sequeiros, J, MacDonald, ME & Gusella, JF 2012, 'Common SNP-based haplotype analysis of the 4p16.3 Huntington disease gene region', American Journal of Human Genetics, vol. 90, no. 3, pp. 434-444. https://doi.org/10.1016/j.ajhg.2012.01.005
Lee, Jong Min ; Gillis, Tammy ; Mysore, Jayalakshmi Srinidhi ; Ramos, Eliana Marisa ; Myers, Richard H. ; Hayden, Michael R. ; Morrison, Patrick J. ; Nance, Martha ; Ross, Christopher A. ; Margolis, Russell L. ; Squitieri, Ferdinando ; Griguoli, Annamaria ; Di Donato, Stefano ; Gomez-Tortosa, Estrella ; Ayuso, Carmen ; Suchowersky, Oksana ; Trent, Ronald J. ; McCusker, Elizabeth ; Novelletto, Andrea ; Frontali, Marina ; Jones, Randi ; Ashizawa, Tetsuo ; Frank, Samuel ; Saint-Hilaire, Marie Helene ; Hersch, Steven M. ; Rosas, Herminia D. ; Lucente, Diane ; Harrison, Madaline B. ; Zanko, Andrea ; Abramson, Ruth K. ; Marder, Karen ; Sequeiros, Jorge ; MacDonald, Marcy E. ; Gusella, James F. / Common SNP-based haplotype analysis of the 4p16.3 Huntington disease gene region. In: American Journal of Human Genetics. 2012 ; Vol. 90, No. 3. pp. 434-444.
@article{bfa6072cf47f464497b55d7e70e88344,
title = "Common SNP-based haplotype analysis of the 4p16.3 Huntington disease gene region",
abstract = "Age at the onset of motor symptoms in Huntington disease (HD) is determined largely by the length of a CAG repeat expansion in HTT but is also influenced by other genetic factors. We tested whether common genetic variation near the mutation site is associated with differences in the distribution of expanded CAG alleles or age at the onset of motor symptoms. To define disease-associated single-nucleotide polymorphisms (SNPs), we compared 4p16.3 SNPs in HD subjects with population controls in a case:control strategy, which revealed that the strongest signals occurred at a great distance from the HD mutation as a result of {"}synthetic association{"} with SNP alleles that are of low frequency in population controls. Detailed analysis delineated a prominent ancestral haplotype that accounted for ∼50{\%} of HD chromosomes and extended to at least 938 kb on about half of these. Together, the seven most abundant haplotypes accounted for ∼83{\%} of HD chromosomes. Neither the extended shared haplotype nor the individual local HTT haplotypes were associated with altered CAG-repeat length distribution or residual age at the onset of motor symptoms, arguing against modification of these disease features by common cis-regulatory elements. Similarly, the 11 most frequent control haplotypes showed no trans-modifier effect on age at the onset of motor symptoms. Our results argue against common local regulatory variation as a factor influencing HD pathogenesis, suggesting that genetic modifiers be sought elsewhere in the genome. They also indicate that genome-wide association analysis with a small number of cases can be effective for regional localization of genetic defects, even when a founder effect accounts for only a fraction of the disorder.",
author = "Lee, {Jong Min} and Tammy Gillis and Mysore, {Jayalakshmi Srinidhi} and Ramos, {Eliana Marisa} and Myers, {Richard H.} and Hayden, {Michael R.} and Morrison, {Patrick J.} and Martha Nance and Ross, {Christopher A.} and Margolis, {Russell L.} and Ferdinando Squitieri and Annamaria Griguoli and {Di Donato}, Stefano and Estrella Gomez-Tortosa and Carmen Ayuso and Oksana Suchowersky and Trent, {Ronald J.} and Elizabeth McCusker and Andrea Novelletto and Marina Frontali and Randi Jones and Tetsuo Ashizawa and Samuel Frank and Saint-Hilaire, {Marie Helene} and Hersch, {Steven M.} and Rosas, {Herminia D.} and Diane Lucente and Harrison, {Madaline B.} and Andrea Zanko and Abramson, {Ruth K.} and Karen Marder and Jorge Sequeiros and MacDonald, {Marcy E.} and Gusella, {James F.}",
year = "2012",
month = "3",
day = "9",
doi = "10.1016/j.ajhg.2012.01.005",
language = "English",
volume = "90",
pages = "434--444",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "3",

}

TY - JOUR

T1 - Common SNP-based haplotype analysis of the 4p16.3 Huntington disease gene region

AU - Lee, Jong Min

AU - Gillis, Tammy

AU - Mysore, Jayalakshmi Srinidhi

AU - Ramos, Eliana Marisa

AU - Myers, Richard H.

AU - Hayden, Michael R.

AU - Morrison, Patrick J.

AU - Nance, Martha

AU - Ross, Christopher A.

AU - Margolis, Russell L.

AU - Squitieri, Ferdinando

AU - Griguoli, Annamaria

AU - Di Donato, Stefano

AU - Gomez-Tortosa, Estrella

AU - Ayuso, Carmen

AU - Suchowersky, Oksana

AU - Trent, Ronald J.

AU - McCusker, Elizabeth

AU - Novelletto, Andrea

AU - Frontali, Marina

AU - Jones, Randi

AU - Ashizawa, Tetsuo

AU - Frank, Samuel

AU - Saint-Hilaire, Marie Helene

AU - Hersch, Steven M.

AU - Rosas, Herminia D.

AU - Lucente, Diane

AU - Harrison, Madaline B.

AU - Zanko, Andrea

AU - Abramson, Ruth K.

AU - Marder, Karen

AU - Sequeiros, Jorge

AU - MacDonald, Marcy E.

AU - Gusella, James F.

PY - 2012/3/9

Y1 - 2012/3/9

N2 - Age at the onset of motor symptoms in Huntington disease (HD) is determined largely by the length of a CAG repeat expansion in HTT but is also influenced by other genetic factors. We tested whether common genetic variation near the mutation site is associated with differences in the distribution of expanded CAG alleles or age at the onset of motor symptoms. To define disease-associated single-nucleotide polymorphisms (SNPs), we compared 4p16.3 SNPs in HD subjects with population controls in a case:control strategy, which revealed that the strongest signals occurred at a great distance from the HD mutation as a result of "synthetic association" with SNP alleles that are of low frequency in population controls. Detailed analysis delineated a prominent ancestral haplotype that accounted for ∼50% of HD chromosomes and extended to at least 938 kb on about half of these. Together, the seven most abundant haplotypes accounted for ∼83% of HD chromosomes. Neither the extended shared haplotype nor the individual local HTT haplotypes were associated with altered CAG-repeat length distribution or residual age at the onset of motor symptoms, arguing against modification of these disease features by common cis-regulatory elements. Similarly, the 11 most frequent control haplotypes showed no trans-modifier effect on age at the onset of motor symptoms. Our results argue against common local regulatory variation as a factor influencing HD pathogenesis, suggesting that genetic modifiers be sought elsewhere in the genome. They also indicate that genome-wide association analysis with a small number of cases can be effective for regional localization of genetic defects, even when a founder effect accounts for only a fraction of the disorder.

AB - Age at the onset of motor symptoms in Huntington disease (HD) is determined largely by the length of a CAG repeat expansion in HTT but is also influenced by other genetic factors. We tested whether common genetic variation near the mutation site is associated with differences in the distribution of expanded CAG alleles or age at the onset of motor symptoms. To define disease-associated single-nucleotide polymorphisms (SNPs), we compared 4p16.3 SNPs in HD subjects with population controls in a case:control strategy, which revealed that the strongest signals occurred at a great distance from the HD mutation as a result of "synthetic association" with SNP alleles that are of low frequency in population controls. Detailed analysis delineated a prominent ancestral haplotype that accounted for ∼50% of HD chromosomes and extended to at least 938 kb on about half of these. Together, the seven most abundant haplotypes accounted for ∼83% of HD chromosomes. Neither the extended shared haplotype nor the individual local HTT haplotypes were associated with altered CAG-repeat length distribution or residual age at the onset of motor symptoms, arguing against modification of these disease features by common cis-regulatory elements. Similarly, the 11 most frequent control haplotypes showed no trans-modifier effect on age at the onset of motor symptoms. Our results argue against common local regulatory variation as a factor influencing HD pathogenesis, suggesting that genetic modifiers be sought elsewhere in the genome. They also indicate that genome-wide association analysis with a small number of cases can be effective for regional localization of genetic defects, even when a founder effect accounts for only a fraction of the disorder.

UR - http://www.scopus.com/inward/record.url?scp=84862831145&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84862831145&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2012.01.005

DO - 10.1016/j.ajhg.2012.01.005

M3 - Article

C2 - 22387017

AN - SCOPUS:84862831145

VL - 90

SP - 434

EP - 444

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 3

ER -