False-positive rates in two-point parametric linkage analysis

Two-point linkage analyses of whole genome sequence data are a promising approach to identify rare variants that segregate with complex diseases in large pedigrees because, in theory, the causal variants have been genotyped. We used whole genome sequence data and simulated traits provided by Genetic Analysis Workshop 18 to evaluate the proportion of false-positive findings in a binary trait using classic two-point parametric linkage analysis. False-positive genome-wide significant log of odds (LOD) scores were identified in more than 80% of 50 replicates for a binary phenotype generated by dichotomizing a quantitative trait that was simulated with a polygenic component (that was not based on any of the provided whole genome sequence genotypes). In contrast, when the trait was truly nongenetic (created by randomly assigning affected-unaffected status), the number of false-positive results was well controlled. These results suggest that when using two-point linkage analyses on whole genome sequence data, one should carefully examine regions yielding significant two-point LOD scores with multipoint analysis and that a more stringent significance threshold may be needed.