Family-based association analysis unconditional on parental genotypes models the effects of observed genotypes. This approach has been shown to have greater power than conditional methods. In this chapter, we review popular association analysis methods accounting for familial correlations: the marginal model using generalized estimating equations (GEE), the mixed model with a polygenic random component, and genome-wide association analyses. The marginal approach does not explicitly model familial correlations but uses the information to improve the efficiency of parameter estimates. This model, using GEE, is useful when the correlation structure is not of interest; the correlations are treated as nuisance parameters. In the mixed model, familial correlations are modeled as random effects, e.g., the polygenic inheritance model accounts for correlations originating from shared genomic components within a family. These unconditional methods provide a flexible modeling framework for general pedigree data to accommodate traits with various distributions and many types of covariate effects. Genome-wide association studies usually test more than 10,000 SNPs and thus traditional statistical methods accounting for the familial correlations often suffer from a computational burden. Multiple approaches that have been recently proposed to avoid this computational issue are reviewed. The single-marker analysis procedures are demonstrated using the R package gee and the ASSOC program in the S.A.G.E. package, including how to prepare input data, conduct the analysis, and interpret the output. ASSOC allows models to include random components of additional familial correlations that may be not sufficiently explained by a polygenic effect and addresses nonnormality of response variables by transformation methods. With its ease of use, ASSOC provides a useful tool for association analysis of large pedigree data.
Keywords: ASSOC; Family-based association test; GEE; GWAS; Generalized estimating equations; Generalized linear mixed model; Genome-wide association studies; Heritability; Linear mixed model; Marginal model; Observed genotype; Polygenic inheritance; R package gee; S.A.G.E.; Unconditional method; Variance components; Working correlation.