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Article: Genomewide linkage scan reveals novel loci modifying age of onset of Huntington's disease in the Venezuelan HD kindreds

TitleGenomewide linkage scan reveals novel loci modifying age of onset of Huntington's disease in the Venezuelan HD kindreds
Authors
KeywordsAge of onset
Genomewide
Huntington's disease
Large pedigrees
Linkage
Modifier genes
Issue Date2008
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/35841
Citation
Genetic Epidemiology, 2008, v. 32 n. 5, p. 445-453 How to Cite?
AbstractThe age of onset of Huntington's disease (HD) is inversely correlated with the CAG length in the HD gene. The CAG repeat length accounts for 70% of the variability in HD age of onset. However, 90% of individuals worldwide with expanded alleles possess between 40 and 50 CAG repeat lengths in their HD gene. For these people, the size of their repeat only determines 44% of the variability in their age of onset. Once the effect of the CAG repeat has been accounted for, the residual variance in age of onset is a heritable trait. Targeted candidate gene studies and a genome scan have suggested some loci as potential modifiers of the age of onset of HD. We analyzed the large Venezuelan kindreds in which the HD gene was originally identified. These kindreds offer greater analytic power than standard sib-pair designs. We developed novel pedigree-member selection procedures to maximize power. Using a 5,858-single-nucleotide-polymorphism marker panel, we performed a genomewide linkage analysis. We discovered two novel loci on chromosome 2. Chromosome 2p25 (logarithm of the odds ratio (LOD) = 4.29) and 2q35 (LOD = 3.39) may contain genes that modify age of onset. A third linkage peak on chromosome 6q22 (LOD = 2.48) may confirm the most promising locus from a previous genome scan. Two other candidate loci are suggestive on chromosome 5 (LOD = 3.31 at 5p14 and LOD = 3.14 at 5q32). All these regions harbor candidate genes that are potential HD modifier genes. Finding these modifier genes can reveal accessible and promising new therapeutic pathways and targets to ameliorate and cure HD. © 2008 Wiley-Liss, Inc.
Persistent Identifierhttp://hdl.handle.net/10722/81498
ISSN
2015 Impact Factor: 2.553
2015 SCImago Journal Rankings: 2.101
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorGayán, Jen_HK
dc.contributor.authorBrocklebank, Den_HK
dc.contributor.authorAndresen, JMen_HK
dc.contributor.authorAlkortaAranburu, Gen_HK
dc.contributor.authorCader, MZen_HK
dc.contributor.authorRoberts, SAen_HK
dc.contributor.authorCherny, SSen_HK
dc.contributor.authorWexler, NSen_HK
dc.contributor.authorCardon, LRen_HK
dc.contributor.authorHousman, DEen_HK
dc.date.accessioned2010-09-06T08:18:29Z-
dc.date.available2010-09-06T08:18:29Z-
dc.date.issued2008en_HK
dc.identifier.citationGenetic Epidemiology, 2008, v. 32 n. 5, p. 445-453en_HK
dc.identifier.issn0741-0395en_HK
dc.identifier.urihttp://hdl.handle.net/10722/81498-
dc.description.abstractThe age of onset of Huntington's disease (HD) is inversely correlated with the CAG length in the HD gene. The CAG repeat length accounts for 70% of the variability in HD age of onset. However, 90% of individuals worldwide with expanded alleles possess between 40 and 50 CAG repeat lengths in their HD gene. For these people, the size of their repeat only determines 44% of the variability in their age of onset. Once the effect of the CAG repeat has been accounted for, the residual variance in age of onset is a heritable trait. Targeted candidate gene studies and a genome scan have suggested some loci as potential modifiers of the age of onset of HD. We analyzed the large Venezuelan kindreds in which the HD gene was originally identified. These kindreds offer greater analytic power than standard sib-pair designs. We developed novel pedigree-member selection procedures to maximize power. Using a 5,858-single-nucleotide-polymorphism marker panel, we performed a genomewide linkage analysis. We discovered two novel loci on chromosome 2. Chromosome 2p25 (logarithm of the odds ratio (LOD) = 4.29) and 2q35 (LOD = 3.39) may contain genes that modify age of onset. A third linkage peak on chromosome 6q22 (LOD = 2.48) may confirm the most promising locus from a previous genome scan. Two other candidate loci are suggestive on chromosome 5 (LOD = 3.31 at 5p14 and LOD = 3.14 at 5q32). All these regions harbor candidate genes that are potential HD modifier genes. Finding these modifier genes can reveal accessible and promising new therapeutic pathways and targets to ameliorate and cure HD. © 2008 Wiley-Liss, Inc.en_HK
dc.languageengen_HK
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/35841en_HK
dc.relation.ispartofGenetic Epidemiologyen_HK
dc.rightsGenetic Epidemiology. Copyright © John Wiley & Sons, Inc.en_HK
dc.subjectAge of onseten_HK
dc.subjectGenomewideen_HK
dc.subjectHuntington's diseaseen_HK
dc.subjectLarge pedigreesen_HK
dc.subjectLinkageen_HK
dc.subjectModifier genesen_HK
dc.titleGenomewide linkage scan reveals novel loci modifying age of onset of Huntington's disease in the Venezuelan HD kindredsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0741-0395&volume=32&spage=445&epage=453&date=2008&atitle=Genomewide+Linkage+Scan+Reveals+Novel+Loci+Modifying+Age+of+Onset+of+Huntington%27s+Disease+in+the+Venezuelan+HD+Kindredsen_HK
dc.identifier.emailCherny, SS: cherny@hku.hken_HK
dc.identifier.authorityCherny, SS=rp00232en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/gepi.20317en_HK
dc.identifier.pmid18481795-
dc.identifier.scopuseid_2-s2.0-48949118889en_HK
dc.identifier.hkuros143246en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-48949118889&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume32en_HK
dc.identifier.issue5en_HK
dc.identifier.spage445en_HK
dc.identifier.epage453en_HK
dc.identifier.isiWOS:000257548000006-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridGayán, J=6603558565en_HK
dc.identifier.scopusauthoridBrocklebank, D=6603151750en_HK
dc.identifier.scopusauthoridAndresen, JM=7103027653en_HK
dc.identifier.scopusauthoridAlkortaAranburu, G=24480835200en_HK
dc.identifier.scopusauthoridCader, MZ=6603208037en_HK
dc.identifier.scopusauthoridRoberts, SA=7403450675en_HK
dc.identifier.scopusauthoridCherny, SS=7004670001en_HK
dc.identifier.scopusauthoridWexler, NS=7003831887en_HK
dc.identifier.scopusauthoridCardon, LR=7005082964en_HK
dc.identifier.scopusauthoridHousman, DE=7102570207en_HK

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