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Article: Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset

TitleVenezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset
Authors
Issue Date2004
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings Of The National Academy Of Sciences Of The United States Of America, 2004, v. 101 n. 10, p. 3498-3503 How to Cite?
AbstractHuntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a triplet (CAG) expansion mutation. The length of the triplet repeat is the most important factor in determining age of onset of HD, although substantial variability remains after controlling for repeat length. The Venezuelan HD kindreds encompass 18,149 individuals spanning 10 generations, 15,409 of whom are living. Of the 4,384 immortalized lymphocyte lines collected, 3,989 DNAs were genotyped for their HD alleles, representing a subset of the population at greatest genetic risk. There are 938 heterozygotes, 80 people with variably penetrant alleles, and 18 homozygotes. Analysis of the 83 kindreds that comprise the Venezuelan HD kindreds demonstrates that residual variability in age of onset has both genetic and environmental components. We created a residual age of onset phenotype from a regression analysis of the log of age of onset on repeat length. Familial correlations (correlation ± SE) were estimated for sibling (0.40 ± 0.09), parent-offspring (0.10 ± 0.11), avuncular (0.07 ± 0.11), and cousin (0.15 ± 0.10) pairs, suggesting a familial origin for the residual variance in onset. By using a variance-components approach with all available familial relationships, the additive genetic heritability of this residual age of onset trait is 38%. A model, including shared sibling environmental effects, estimated the components of additive genetic (0.37), shared environment (0.22), and nonshared environment (0.41) variances, confirming that ≈40% of the variance remaining in onset age is attributable to genes other than the HD gene and 60% is environmental.
Persistent Identifierhttp://hdl.handle.net/10722/143706
ISSN
2015 Impact Factor: 9.423
2015 SCImago Journal Rankings: 6.883
PubMed Central ID
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorWexler, NSen_HK
dc.contributor.authorLorimer, Jen_HK
dc.contributor.authorPorter, Jen_HK
dc.contributor.authorGomez, Fen_HK
dc.contributor.authorMoskowitz, Cen_HK
dc.contributor.authorShackell, Een_HK
dc.contributor.authorMarder, Ken_HK
dc.contributor.authorPenchaszadeh, Gen_HK
dc.contributor.authorRoberts, SAen_HK
dc.contributor.authorGayán, Jen_HK
dc.contributor.authorBrocklebank, Den_HK
dc.contributor.authorCherny, SSen_HK
dc.contributor.authorCardon, LRen_HK
dc.contributor.authorGray, Jen_HK
dc.contributor.authorDlouhy, SRen_HK
dc.contributor.authorWiktorski, Sen_HK
dc.contributor.authorHodes, MEen_HK
dc.contributor.authorConneally, PMen_HK
dc.contributor.authorPenney, JBen_HK
dc.contributor.authorGusella, Jen_HK
dc.contributor.authorCha, JHen_HK
dc.contributor.authorIrizarry, Men_HK
dc.contributor.authorRosas, Den_HK
dc.contributor.authorHersch, Sen_HK
dc.contributor.authorHollingsworth, Zen_HK
dc.contributor.authorMacDonald, Men_HK
dc.contributor.authorYoung, ABen_HK
dc.contributor.authorAndresen, JMen_HK
dc.contributor.authorHousman, DEen_HK
dc.contributor.authorMieja De Young, Men_HK
dc.contributor.authorBonilla, Een_HK
dc.contributor.authorStillings, Ten_HK
dc.contributor.authorNegrette, Aen_HK
dc.contributor.authorSnodgrass, SRen_HK
dc.contributor.authorMartinezJaurrieta, MDen_HK
dc.contributor.authorRamosArroyo, MAen_HK
dc.contributor.authorBickham, Jen_HK
dc.contributor.authorRamos, JSen_HK
dc.contributor.authorMarshall, Fen_HK
dc.contributor.authorShoulson, Ien_HK
dc.contributor.authorRey, GJen_HK
dc.contributor.authorFeigin, Aen_HK
dc.contributor.authorArnheim, Nen_HK
dc.contributor.authorAcevedoCruz, Aen_HK
dc.contributor.authorAcosta, Len_HK
dc.contributor.authorAlvir, Jen_HK
dc.contributor.authorFischbeck, Ken_HK
dc.contributor.authorThompson, LMen_HK
dc.contributor.authorYoung, Aen_HK
dc.contributor.authorDure, Len_HK
dc.contributor.authorO'Brien, CJen_HK
dc.contributor.authorPaulsen, Jen_HK
dc.contributor.authorBrickman, Aen_HK
dc.contributor.authorKrch, Den_HK
dc.contributor.authorPeery, Sen_HK
dc.contributor.authorHogarth, Pen_HK
dc.contributor.authorHiggins Jr, DSen_HK
dc.contributor.authorLandwehrmeyeri, Ben_HK
dc.date.accessioned2011-12-16T08:09:51Z-
dc.date.available2011-12-16T08:09:51Z-
dc.date.issued2004en_HK
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2004, v. 101 n. 10, p. 3498-3503en_HK
dc.identifier.issn0027-8424en_HK
dc.identifier.urihttp://hdl.handle.net/10722/143706-
dc.description.abstractHuntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a triplet (CAG) expansion mutation. The length of the triplet repeat is the most important factor in determining age of onset of HD, although substantial variability remains after controlling for repeat length. The Venezuelan HD kindreds encompass 18,149 individuals spanning 10 generations, 15,409 of whom are living. Of the 4,384 immortalized lymphocyte lines collected, 3,989 DNAs were genotyped for their HD alleles, representing a subset of the population at greatest genetic risk. There are 938 heterozygotes, 80 people with variably penetrant alleles, and 18 homozygotes. Analysis of the 83 kindreds that comprise the Venezuelan HD kindreds demonstrates that residual variability in age of onset has both genetic and environmental components. We created a residual age of onset phenotype from a regression analysis of the log of age of onset on repeat length. Familial correlations (correlation ± SE) were estimated for sibling (0.40 ± 0.09), parent-offspring (0.10 ± 0.11), avuncular (0.07 ± 0.11), and cousin (0.15 ± 0.10) pairs, suggesting a familial origin for the residual variance in onset. By using a variance-components approach with all available familial relationships, the additive genetic heritability of this residual age of onset trait is 38%. A model, including shared sibling environmental effects, estimated the components of additive genetic (0.37), shared environment (0.22), and nonshared environment (0.41) variances, confirming that ≈40% of the variance remaining in onset age is attributable to genes other than the HD gene and 60% is environmental.en_HK
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.orgen_HK
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americaen_HK
dc.subject.meshAdolescenten_HK
dc.subject.meshAdulten_HK
dc.subject.meshAge of Onseten_HK
dc.subject.meshAgeden_HK
dc.subject.meshChilden_HK
dc.subject.meshChild, Preschoolen_HK
dc.subject.meshEnvironmenten_HK
dc.subject.meshFemaleen_HK
dc.subject.meshHumansen_HK
dc.subject.meshHuntington Disease - epidemiology - etiology - geneticsen_HK
dc.subject.meshMaleen_HK
dc.subject.meshMiddle Ageden_HK
dc.subject.meshModels, Geneticen_HK
dc.subject.meshPhenotypeen_HK
dc.subject.meshTrinucleotide Repeat Expansionen_HK
dc.subject.meshVenezuela - epidemiologyen_HK
dc.titleVenezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onseten_HK
dc.typeArticleen_HK
dc.identifier.emailCherny, SS: cherny@hku.hken_HK
dc.identifier.authorityCherny, SS=rp00232en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1073/pnas.0308679101en_HK
dc.identifier.pmid14993615-
dc.identifier.pmcidPMC395921-
dc.identifier.scopuseid_2-s2.0-12144288251en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-12144288251&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume101en_HK
dc.identifier.issue10en_HK
dc.identifier.spage3498en_HK
dc.identifier.epage3503en_HK
dc.identifier.isiWOS:000220978000068-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridWexler, NS=7003831887en_HK
dc.identifier.scopusauthoridLorimer, J=8129820700en_HK
dc.identifier.scopusauthoridPorter, J=8129820800en_HK
dc.identifier.scopusauthoridGomez, F=8129820900en_HK
dc.identifier.scopusauthoridMoskowitz, C=7007073910en_HK
dc.identifier.scopusauthoridShackell, E=8129821100en_HK
dc.identifier.scopusauthoridMarder, K=7101692176en_HK
dc.identifier.scopusauthoridPenchaszadeh, G=6603786561en_HK
dc.identifier.scopusauthoridRoberts, SA=7403450675en_HK
dc.identifier.scopusauthoridGayán, J=6603558565en_HK
dc.identifier.scopusauthoridBrocklebank, D=6603151750en_HK
dc.identifier.scopusauthoridCherny, SS=7004670001en_HK
dc.identifier.scopusauthoridCardon, LR=7005082964en_HK
dc.identifier.scopusauthoridGray, J=7404300244en_HK
dc.identifier.scopusauthoridDlouhy, SR=7005318731en_HK
dc.identifier.scopusauthoridWiktorski, S=8129822100en_HK
dc.identifier.scopusauthoridHodes, ME=35377957200en_HK
dc.identifier.scopusauthoridConneally, PM=7007139990en_HK
dc.identifier.scopusauthoridPenney, JB=35377273700en_HK
dc.identifier.scopusauthoridGusella, J=36065462700en_HK
dc.identifier.scopusauthoridCha, JH=34567813000en_HK
dc.identifier.scopusauthoridIrizarry, M=35394287000en_HK
dc.identifier.scopusauthoridRosas, D=6507951712en_HK
dc.identifier.scopusauthoridHersch, S=7005608225en_HK
dc.identifier.scopusauthoridHollingsworth, Z=6701563377en_HK
dc.identifier.scopusauthoridMacDonald, M=7401502160en_HK
dc.identifier.scopusauthoridYoung, AB=7403881833en_HK
dc.identifier.scopusauthoridAndresen, JM=7103027653en_HK
dc.identifier.scopusauthoridHousman, DE=7102570207en_HK
dc.identifier.scopusauthoridMieja De Young, M=8129823500en_HK
dc.identifier.scopusauthoridBonilla, E=7101762204en_HK
dc.identifier.scopusauthoridStillings, T=8129823900en_HK
dc.identifier.scopusauthoridNegrette, A=6701648829en_HK
dc.identifier.scopusauthoridSnodgrass, SR=7006226985en_HK
dc.identifier.scopusauthoridMartinezJaurrieta, MD=8129824200en_HK
dc.identifier.scopusauthoridRamosArroyo, MA=6603828065en_HK
dc.identifier.scopusauthoridBickham, J=8129824800en_HK
dc.identifier.scopusauthoridRamos, JS=8129824900en_HK
dc.identifier.scopusauthoridMarshall, F=35353093200en_HK
dc.identifier.scopusauthoridShoulson, I=7006209481en_HK
dc.identifier.scopusauthoridRey, GJ=7005452001en_HK
dc.identifier.scopusauthoridFeigin, A=7006373790en_HK
dc.identifier.scopusauthoridArnheim, N=7004575713en_HK
dc.identifier.scopusauthoridAcevedoCruz, A=8985083700en_HK
dc.identifier.scopusauthoridAcosta, L=8129825800en_HK
dc.identifier.scopusauthoridAlvir, J=16142123500en_HK
dc.identifier.scopusauthoridFischbeck, K=7004500500en_HK
dc.identifier.scopusauthoridThompson, LM=7403730398en_HK
dc.identifier.scopusauthoridYoung, A=55254704300en_HK
dc.identifier.scopusauthoridDure, L=35373350000en_HK
dc.identifier.scopusauthoridO'Brien, CJ=36757331000en_HK
dc.identifier.scopusauthoridPaulsen, J=7102109661en_HK
dc.identifier.scopusauthoridBrickman, A=7005379435en_HK
dc.identifier.scopusauthoridKrch, D=8129826800en_HK
dc.identifier.scopusauthoridPeery, S=6602241675en_HK
dc.identifier.scopusauthoridHogarth, P=7006249548en_HK
dc.identifier.scopusauthoridHiggins Jr, DS=7202960442en_HK
dc.identifier.scopusauthoridLandwehrmeyeri, B=8129827200en_HK

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