Admixture effects in the traditional linkage analysis of admixed families

Introduction: Families of admixed ancestry are routinely excluded from traditional linkage analysis (LOD score) or are analyzed as deriving from a homogeneous population of the proband's ethnicity. Using traditional linkage analysis methods to analyze these families is complicated due to the admixture of different disease rates and allele frequencies that occurs. The presence of admixture violates the key assumptions of Hardy-Weinberg equilibrium (HWE) and linkage equilibrium (LE) invoked in the current methods of linkage analysis. If one or both of these assumptions are violated, incorrect inference for linkage could result. Design and Methods: We propose a pooling procedure to correct for inflated estimates of the recombination fraction that can result from admixture when performing traditional linkage analysis. Data were simulated with 30 families per each of 200 replications for a dominant, highly selective, linked disease locus model in order to conduct further testing for allelic LE and HWE, while using an allele pooling procedure to account for allele frequency differences between the 2 populations. The differences in allele frequencies between the populations for the polymorphic loci were 0.05, 0.10 and 0.14. Results and Conclusions: Our pooling procedure does not eradicate all disequilibrium, because those replicates in which the disequilibrium exists are no longer affected by the dis-equilibrium in terms of maximization for linkage. Furthermore, our pooling procedure was able to exclude uninformative families or families far removed from HWE and/or LE that their LOD scores were unreliable.