Weighted pairwise correlation and transmission disequilibrium in a common oligogenic disease

Weighted pairwise correlation (WPC) linkage analysis and the transmission disequilibrium test (TDT) for allelic association were applied to simulated family data for a common oligogenic disorder in order to localize genes that increase levels of Q1. Preliminary linear models indicated that Q1 increases with age, Q2, Q3, and the occurrence of D5G28 allele 3 (D5G28(3). WPC provided evidence for linkage of Q1 to Major Gene 1, D5G28 (p < 0.0001), and to other loci when ranks based on age and affection status (Q1 < or > 87.5) were used to define the phenotype. D5G28 was the only locus linked to Q1 (p = 0.01) when the phenotype was defined as Q1 adjusted for age, Q2, Q3, and D5G28(3). The TDT indicated linkage disequilibrium between a gene for elevated Q1 (> 87.5) and alleles at loci adjacent to D5G28: D5G29(2) was apparently protective (p = 0.008) while allele 8 was associated with risk (p = 0.007); D5G30(7) was also apparently protective (p = 0.02). However, significant disequilibrium was not found for D5G28(3), possibly due to lack of adjustment of Q1 and small sample size. These results imply that the combined use of WPC and the TDT may be an effective strategy for genomic screens in complex disorders defined by quantitative traits, especially when the trait can be adjusted for age and other relevant factors.