Integration of linkage analyses and disease association studies.

The REGD procedure of the S.A.G.E. [1994] system was used to determine the mode of inheritance of the rare disease given in Problem 1. The likelihood ratio test statistic indicated that we should reject the hypotheses of dominant and recessive inheritance at the 0.01 level, so codominant inheritance was assumed. The estimated penetrance values computed from the beta estimates given by the S.A.G.E. output were 1.0, 0.7, and 0.0 for the AA, AB, and BB genotypes respectively. A sample of three markers from each chromosome was used to determine which chromosome(s) gave evidence of having loci linked to the disease locus. The lod minus 0.83 support interval, which has been shown to provide the best approximation to 95% coverage among interval estimates [Nemesure et al., in press], was obtained for each of these markers. The criterion for rejecting the hypothesis of close linkage using the support interval methodology required that the left side of the lod minus 0.83 support interval about the maximum likelihood estimate, theta, includes only values greater than theta = 0.10. This criterion suggested that chromosomes 2, 3, and 6 did not contain the disease genes. Classical lod-score linkage analysis using the usual criteria of 3.0 for linkage and -2.0 for exclusion did not result in any regions being identified. On dropping the required lod score to 1.0, chromosomes 1, 3, and 6 gave results in favor of linkage with lod scores of 1.94 (theta = 0.19), 1.20 (theta = 0.24), and 1.30 (theta = 0.23), respectively. Association studies comparing unrelated cases to unrelated controls were done for all markers on all chromosomes. Two associations were observed which were significant at the 0.05 level after adjusting for the large number of multiple comparisons being made. The strongest association observed was between allele 7 of marker 23 on chromosome 5 and the disease (chi 2(1) = 52.20, OR = 4.7) and the second strongest was between allele 8 of marker 31 on chromosome 1 (chi 2(1) = 20.10, OR = 3.4).