Statistical Methods For Gene/environment Interaction And Genetic Susceptibility

National Institute Of Environmental Health Sciences

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Abstract

We have studied the application of specimen pooling to DNA from case-parent triads when the genotyping assay counts the number of variant alleles in a pooled specimen. Our procedure partitions a sample of triads into small subsets of, say, two triads each, and, for each subset, constructs three pooled DNA specimens: one each from mothers, from fathers, and from offspring. Treating the individual genotypes that comprise each pool as missing data, our log-linear-modeling approach uses the expectation-maximization algorithm to estimate relative risk parameters for inherited alleles, maternal alleles, or parent-of-origin effects, something other DNA pooling approaches cannot do. We see little loss of power compared to genotyping individuals when genotypes are measured without error, but power declines as genotyping error rates increase. For sufficiently accurate assays, our approach promises to reduce genotyping costs with minimal loss of power. Genome-wide association studies usually focus on variation in autosomal genes; however, less studied genetic mechanisms may also influence risk for complex disease. We have studied three mechanisms that can induce differential risk in maternal versus paternal lineages of affected individuals. These include mitochondrial variants (inherited from the mother), imprinted genes (where the effect of variants depends on the parent of origin), and maternal genes (that influence risk through modulation of the prenatal environment). Asymmetries in risk can be measured by inter-lineage relative risks or relative odds. We define the relative risks of interest; and, under certain simplifying assumptions, we derived algebraic expressions for the inter-lineage relative risks predicated on commonly used risk models. We find that careful analyses of family history data provide clues about whether these mechanisms contribute to risk but dissecting which mechanism may be operating requires genotype data on family members. When using case-parent triads to study the association of single nucleotide polymorphisms with disease, the phenotype of the child is used but the phenotypes of the parents are ignored but all three family members are genotyped. When parental phenotypes for the disease under study are available, including them in the analysis should bring more information to bear on disease-gene associations. We are in the process of developing and evaluating new approaches for using parental phenotypes together with the usual data from case-parents studies to increase power for detecting associations. (see also Z01 ES040007 BB; PI Clare Weinberg.)