Standard linkage and association methods identify the mechanism of four susceptibility genes for a simulated complex disease

The simulated dataset of the Genetic Analysis Workshop 14 provided affection status and the presence or absence of 12 traits. It was determined that all affected individuals must have traits E, F and H (EFH phenotype) and they must also have either trait B (B subtype) or traits C, D, and G (CDG subtype). A genome screen was performed, and linkage peaks were identified on chromosomes 1, 3, 5, and 9 using microsatellite markers. Dense panels of single-nucleotide polymorphism (SNP) markers were ordered for each of the four linkage peaks. In each case, association analyses identified a single SNP that accounted for the linkage evidence. The SNP on chromosome 1 appeared to primarily influence the B subtype, while the SNPs on chromosomes 5 and 9 primarily influenced the CDG subtype. The chromosome 3 SNP had the strongest effect and influenced both subtypes, as well as the requisite EFH phenotype. Recognizing the two subtypes prior to linkage analysis was key to identifying these loci using only a single replicate. This highlights the need in real life situations for careful examination of the phenotypic data prior to genetic analysis.