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| PMID |
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| TITLE |
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| False disease region identification from identity-by-descent haplotype sharing in the presence of phenocopies. |
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| ABSTRACT |
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| Linkage analysis (either parametric or nonparametric) is commonly applied to identify chromosomal regions using related individuals affected by disease. In complex disease the incomplete relationship between phenotype and genotype can be modeled using a phenocopy parameter, the probability that an individual is affected given they do not carry the disease mutation of interest, and a nonpenetrance parameter, the probability that an individual is not affected given they do carry the disease mutation of interest. If the linkage phase between multiple markers and a putative disease locus is known, then haplotypes carrying the mutation can, in principle, be identified by comparing the chromosome segments that are shared identical-by-descent (IBD) across affected individuals. We consider here the effect of a nonzero phenocopy rate on the linkage peak and hence upon the identification of disease haplotypes that are shared IBD between affected individuals. We show, by theory and computer simulation, that in diseases for which there is a nonzero phenocopy rate, the chromosomal regions identified may not include the true disease locus. We utilize a LOD-1 confidence interval for a widely used nonparametric linkage statistic. We find that in small/moderate samples this confidence interval may be inappropriate. We give specific examples where the phenocopy rates are nonnegligible in some complex diseases. The success of further work to identify the causal mutations underlying the linkage peaks in these diseases will depend on researchers allowing for the presence of phenocopies by examining appropriately wide regions around the initial positive linkage finding. |
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| DATE PUBLISHED |
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| HISTORY |
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| PUBSTATUS |
PUBSTATUSDATE |
| pubmed |
2006/04/14 09:00 |
| medline |
2006/05/12 09:00 |
| entrez |
2006/04/14 09:00 |
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| AUTHORS |
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| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Macgregor S |
|
Macgregor |
Stuart |
S |
|
Institute of Evolutionary Biology, University of Edinburgh, West Mains Road, Edinburgh, United Kingdom. stuart.macgregor@qimr.edu.au |
| Knott SA |
|
Knott |
Sara A |
SA |
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| Visscher PM |
|
Visscher |
Peter M |
PM |
|
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| INVESTIGATORS |
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| JOURNAL |
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| VOLUME: 9 |
| ISSUE: 1 |
| TITLE: Twin research and human genetics : the official journal of the International Society for Twin Studies |
| ISOABBREVIATION: Twin Res Hum Genet |
| YEAR: 2006 |
| MONTH: Feb |
| DAY: |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Print |
| ISSN: 1832-4274 |
| ISSNTYPE: Print |
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| MEDLINE JOURNAL |
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| MEDLINETA: Twin Res Hum Genet |
| COUNTRY: England |
| ISSNLINKING: 1832-4274 |
| NLMUNIQUEID: 101244624 |
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| PUBLICATION TYPE |
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| PUBLICATIONTYPE TEXT |
| Journal Article |
| Research Support, Non-U.S. Gov't |
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| COMMENTS AND CORRECTIONS |
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| GRANTS |
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| GENERAL NOTE |
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| KEYWORDS |
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| MESH HEADINGS |
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| DESCRIPTORNAME |
QUALIFIERNAME |
| Alleles |
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| Computer Simulation |
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| Genetic Linkage |
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| Genetic Markers |
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| Genotype |
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| Haplotypes |
genetics |
| Humans |
genetics |
| Inheritance Patterns |
genetics |
| Lod Score |
genetics |
| Models, Genetic |
genetics |
| Mutation |
genetics |
| Phenotype |
genetics |
| Statistics, Nonparametric |
genetics |
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| SUPPLEMENTARY MESH |
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| GENE SYMBOLS |
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| CHEMICALS |
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| REGISTRYNUMBER |
NAMEOFSUBSTANCE |
| 0 |
Genetic Markers |
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| OTHER ID's |
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