Association mapping of complex diseases in linked regions: estimation of genetic effects and feasibility of testing rare variants

Association mapping in linked regions is a current major approach for the identification of genes for complex diseases. Loci contributing to linkage, even with small values of sibling recurrence risk (lambda(s)), may be equivalent to substantial underlying genetic effects for association studies. For disease alleles with a frequency as low as 1%, highly reliable association studies (80% power for significance level alpha=10(-6)) require only 277, 781, and 1289 families or cases and controls for loci detected with lambda(s) of 1.5, 1.1, and 1.05, respectively, under a multiplicative genetic model. Under alternative models, provided epistatic effects are minor, larger achievable sample sizes will provide sufficient power to map almost any disease gene that may have initially contributed to linkage.