title: Family-based tests of association and linkage that use unaffected sibs, covariates, and interactions.
abstract: We extend the methodology for family-based tests of association and linkage to allow for both variation in the phenotypes of subjects and incorporation of covariates into general-score tests of association. We use standard association models for a phenotype and any number of predictors. We then construct a score statistic, using likelihoods for the distribution of phenotype, given genotype. The distribution of the score is computed as a function of offspring genotypes, conditional on parental genotypes and trait values for offspring and parents. This approach provides a natural extension of the transmission/disequilibrium test to any phenotype and to multiple genes or environmental factors and allows the study of gene-gene and gene-environment interaction. When the trait varies among subjects or when covariates are included in the association model, the score statistic depends on one or more nuisance parameters. We suggest two approaches for obtaining parameter estimates: (1) choosing the estimate that minimizes the variance of the test statistic and (2) maximizing the statistic over a nuisance parameter and using a corrected P value. We apply our methods to a sample of families with attention-deficit/hyperactivity disorder and provide examples of how covariates and gene-environment and gene-gene interactions can be incorporated.
authors.affiliation: Department of Biostatistical Science, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. lunetta@jimmy.harvard.edu
authors.forename: K L
authors.initials: KL
authors.lastname: Lunetta
authors.forename: S V
authors.initials: SV
authors.lastname: Faraone
authors.forename: J
authors.initials: J
authors.lastname: Biederman
authors.forename: N M
authors.initials: NM
authors.lastname: Laird
mesh_terms: D000483:Alleles; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics; D002874:Chromosome Mapping / Q000379:methods* / Q000706:statistics & numerical data*; D050483:Dopamine Plasma Membrane Transport Proteins; D004777:Environment; D005260:Female; D008040:Genetic Linkage / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008957:Models, Genetic; D009419:Nerve Tissue Proteins; D009679:Nuclear Family; D010641:Phenotype; D017448:Receptors, Dopamine D2 / Q000235:genetics; D050638:Receptors, Dopamine D4; D012737:Sex Factors
chemical_list: D002352:Carrier Proteins; C493599:DRD4 protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4