Family-based tests of association and linkage that use unaffected sibs, covariates, and interactions

We extend the methodology for family-based tests of association and linkage to allow for both variation in the phenotypes of subjects and incorporatio n of covariates into general-score tests of association. We use standard as sociation models for a phenotype and any number of predictors. Fire then co nstruct a score statistic, using likelihoods for the distribution of phenot ype, given genotype. The distribution of the score is computed as a functio n of offspring genotypes, conditional on parental genotypes and trait value s 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-enviro nment interaction. When the trait varies among subjects or when covariates are included in the association model, the score statistic depends on one o r more nuisance parameters. We suggest two approaches for obtaining paramet er estimates: (1) choosing the estimate that minimizes the variance of the test statistic and (2) maximizing the statistic over a nuisance parameter a nd using a corrected P value. We apply our methods to a sample of families with attention-deficit/hyperactivity disorder and provide examples of how c ovariates and gene-environment and gene-gene interactions can be incorporat ed.