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Article: A genome-wide scan of 1842 DNA markers for allelic associations with general cognitive ability: A five-stage design using DNA pooling and extreme selected groups

TitleA genome-wide scan of 1842 DNA markers for allelic associations with general cognitive ability: A five-stage design using DNA pooling and extreme selected groups
Authors
Issue Date2001
PublisherSpringer New York LLC. The Journal's web site is located at http://springerlink.metapress.com/openurl.asp?genre=journal&issn=0001-8244
Citation
Behavior Genetics, 2001, v. 31 n. 6, p. 497-509 How to Cite?
AbstractAll measures of cognitive processes correlate moderately at the phenotypic level and correlate substantially at the genetic level. General cognitive ability (g) refers to what diverse cognitive processes have in common. Our goal is to identify quantitative trait loci (QTLs) associated with high g compared with average g. In order to detect QTLs of small effect size, we used extreme selected samples and a five-stage design with nominal alpha levels that permit false positive results in early stages but remove false positives in later stages. As a first step toward a systematic genome scan for allelic association, we used DNA pooling to screen 1842 simple sequence repeat (SSR) markers approximately evenly spaced at 2 cM throughout the genome in a five-stage design: (1) casecontrol DNA pooling (101 cases with mean IQ of 136 and 101 controls with mean IQ of 100), (2) case-control DNA pooling (96 cases with IQ <160 and 100 controls with mean IQ of 102), (3) individual genotyping of Stage 1 sample, (4) individual genotyping of Stage 2 sample, (5) transmission disequilibrium test (TDT; 196 parent-child trios for offspring with IQ <160). The overall Type I error rate is 0.000125, which robustly protects against false positive results. The numbers of markers surviving each stage using a conservative allele-specific directional test were 108, 6, 4, 2, and 0, respectively, for the five stages. A genomic control test using DNA pooling suggested that the failure to replicate the positive case-control results in the TDT analysis was not due to ethnic stratification. Several markers that were close to significance at all stages are being investigated further. Relying on indirect association based on linkage disequilibrium between markers and QTLs means that 100,000 markers may be needed to exclude QTL associations. Because power drops off precipitously for indirect association approaches when a marker is not close to the QTL, we are not planning to genotype additional SSR markers. Instead we are using the same design to screen markers such as cSNPs and SNPs in regulatory regions that are likely to include functional polymorphisms in which the marker can be presumed to be the QTL.
Persistent Identifierhttp://hdl.handle.net/10722/175924
ISSN
2015 Impact Factor: 3.268
2015 SCImago Journal Rankings: 1.457
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorPlomin, Ren_US
dc.contributor.authorHill, Len_US
dc.contributor.authorCraig, IWen_US
dc.contributor.authorMcguffin, Pen_US
dc.contributor.authorPurcell, Sen_US
dc.contributor.authorSham, Pen_US
dc.contributor.authorLubinski, Den_US
dc.contributor.authorThompson, LAen_US
dc.contributor.authorFisher, PJen_US
dc.contributor.authorTuric, Den_US
dc.contributor.authorOwen, MJen_US
dc.date.accessioned2012-11-26T09:02:33Z-
dc.date.available2012-11-26T09:02:33Z-
dc.date.issued2001en_US
dc.identifier.citationBehavior Genetics, 2001, v. 31 n. 6, p. 497-509en_US
dc.identifier.issn0001-8244en_US
dc.identifier.urihttp://hdl.handle.net/10722/175924-
dc.description.abstractAll measures of cognitive processes correlate moderately at the phenotypic level and correlate substantially at the genetic level. General cognitive ability (g) refers to what diverse cognitive processes have in common. Our goal is to identify quantitative trait loci (QTLs) associated with high g compared with average g. In order to detect QTLs of small effect size, we used extreme selected samples and a five-stage design with nominal alpha levels that permit false positive results in early stages but remove false positives in later stages. As a first step toward a systematic genome scan for allelic association, we used DNA pooling to screen 1842 simple sequence repeat (SSR) markers approximately evenly spaced at 2 cM throughout the genome in a five-stage design: (1) casecontrol DNA pooling (101 cases with mean IQ of 136 and 101 controls with mean IQ of 100), (2) case-control DNA pooling (96 cases with IQ <160 and 100 controls with mean IQ of 102), (3) individual genotyping of Stage 1 sample, (4) individual genotyping of Stage 2 sample, (5) transmission disequilibrium test (TDT; 196 parent-child trios for offspring with IQ <160). The overall Type I error rate is 0.000125, which robustly protects against false positive results. The numbers of markers surviving each stage using a conservative allele-specific directional test were 108, 6, 4, 2, and 0, respectively, for the five stages. A genomic control test using DNA pooling suggested that the failure to replicate the positive case-control results in the TDT analysis was not due to ethnic stratification. Several markers that were close to significance at all stages are being investigated further. Relying on indirect association based on linkage disequilibrium between markers and QTLs means that 100,000 markers may be needed to exclude QTL associations. Because power drops off precipitously for indirect association approaches when a marker is not close to the QTL, we are not planning to genotype additional SSR markers. Instead we are using the same design to screen markers such as cSNPs and SNPs in regulatory regions that are likely to include functional polymorphisms in which the marker can be presumed to be the QTL.en_US
dc.languageengen_US
dc.publisherSpringer New York LLC. The Journal's web site is located at http://springerlink.metapress.com/openurl.asp?genre=journal&issn=0001-8244en_US
dc.relation.ispartofBehavior Geneticsen_US
dc.subject.meshAdolescenten_US
dc.subject.meshAllelesen_US
dc.subject.meshCase-Control Studiesen_US
dc.subject.meshChilden_US
dc.subject.meshFemaleen_US
dc.subject.meshGene Poolen_US
dc.subject.meshGenetic Markers - Geneticsen_US
dc.subject.meshGenetic Testingen_US
dc.subject.meshGenome, Humanen_US
dc.subject.meshHumansen_US
dc.subject.meshIntelligence - Geneticsen_US
dc.subject.meshMaleen_US
dc.subject.meshOhioen_US
dc.subject.meshPhenotypeen_US
dc.subject.meshQuantitative Trait, Heritableen_US
dc.titleA genome-wide scan of 1842 DNA markers for allelic associations with general cognitive ability: A five-stage design using DNA pooling and extreme selected groupsen_US
dc.typeArticleen_US
dc.identifier.emailSham, P: pcsham@hku.hken_US
dc.identifier.authoritySham, P=rp00459en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1023/A:1013385125887en_US
dc.identifier.pmid11838529-
dc.identifier.scopuseid_2-s2.0-18244402218en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-18244402218&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume31en_US
dc.identifier.issue6en_US
dc.identifier.spage497en_US
dc.identifier.epage509en_US
dc.identifier.isiWOS:000173695100002-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridPlomin, R=36050187200en_US
dc.identifier.scopusauthoridHill, L=7202617092en_US
dc.identifier.scopusauthoridCraig, IW=7102548208en_US
dc.identifier.scopusauthoridMcguffin, P=22954119700en_US
dc.identifier.scopusauthoridPurcell, S=7005489464en_US
dc.identifier.scopusauthoridSham, P=34573429300en_US
dc.identifier.scopusauthoridLubinski, D=7004686165en_US
dc.identifier.scopusauthoridThompson, LA=7403729523en_US
dc.identifier.scopusauthoridFisher, PJ=7402666944en_US
dc.identifier.scopusauthoridTuric, D=6603622360en_US
dc.identifier.scopusauthoridOwen, MJ=36044041500en_US
dc.identifier.citeulike3929607-

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