title: Linkage disequilibrium mapping in trisomic populations: analytical approaches and an application to congenital heart defects in Down syndrome.
abstract: Many of the birth defects associated with trisomy exhibit both variable expressivity and incomplete penetrance. This variability suggests that it is allelic variation and not simply the presence of an additional chromosome that leads to the development of certain trisomy-associated birth defects. With the proper tools, one may use trisomic populations to identify genes involved in the development of specific birth defects. A trisomic population may be advantageous over a normal population if the defect is over-represented in the trisomic population. Alternatively, one can view the trisomic populations as a "model system" to offer insight into aspects of both normal and abnormal embryonic development. Standard disomic linkage disequilibrium mapping approaches need to be adjusted to account for the presence of the additional genetic material in the trisomic individuals. We present an approach for linkage disequilibrium mapping of variable phenotypes in a trisomic population that adequately accounts for the additional alleles and the pattern of non-independent inheritance. We establish the laboratory methods and statistical tools necessary to conduct an association study in a trisomic population. As an example, we have applied these tools to a pilot study of Down syndrome-associated congenital heart defects.
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Kimberly F
authors.initials: KF
authors.lastname: Kerstann
authors.forename: Eleanor
authors.initials: E
authors.lastname: Feingold
authors.forename: Sallie B
authors.initials: SB
authors.lastname: Freeman
authors.forename: Lora J H
authors.initials: LJ
authors.lastname: Bean
authors.forename: Robert
authors.initials: R
authors.lastname: Pyatt
authors.forename: Stuart
authors.initials: S
authors.lastname: Tinker
authors.forename: Amy H
authors.initials: AH
authors.lastname: Jewel
authors.forename: George
authors.initials: G
authors.lastname: Capone
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Sherman
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D002874:Chromosome Mapping / Q000379:methods*; D004314:Down Syndrome / Q000235:genetics*; D005838:Genotype; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D008432:Mathematical Computing; D008957:Models, Genetic; D015233:Models, Statistical; D009124:Muscle Proteins / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014314:Trisomy / Q000235:genetics*
chemical_list: D009124:Muscle Proteins; C104671:SH3BGR protein, human