USE OF PARENTS, SIBS AND UNRELATED CONTROLS FOR DETECTION OF ASSOCIATIONS BETWEEN GENETIC-MARKERS AND DISEASE

Detecting the association between genetic markers and complex diseases can be a critical first step toward identification of the genetic bas is of disease. Misleading associations can be avoided by choosing as c ontrols the parents of diseased cases, but the availability of parents often Limits this design to early-onset: disease. Alternatively, sib controls offer a valid design. A general multivariate score statistic is presented, to detect the association between a multiallelic genetic marker locus and affection status; this general approach is applicabl e to designs that use parents as controls, sibs as controls, or even u nrelated controls whose genotypes do not fit Hardy-Weinberg proportion s or that pool any combination of these different designs, The benefit of this multivariate score statistic is that it will tend to be the m ost powerful method when multiple marker alleles are associated with a ffection status. To plan these types of studies, we present methods to compute sample size and power, allowing for varying sibship sizes, as certainment criteria, and genetic models of risk. The results indicate that sib controls have less power than parental controls and that the power of sib controls can be increased by increasing either the numbe r of affected sibs per sibship or the number of unaffected control sib s, The sample-size results indicate that the use of sib controls to te st for associations, by use of either a single-marker locus or a genom ewide screen, will be feasible for markers that have a dominant effect and for common alleles having a recessive effect. The results present ed will be useful for investigators planning studies using sibs as con trols.