Identifying plausible genetic models based on association and linkage results: application to type 2 diabetes.

When planning resequencing studies for complex diseases, previous association and linkage studies can constrain the range of plausible genetic models for a given locus. Here, we explore the combinations of causal risk allele frequency (RAFC ) and genotype relative risk (GRRC ) consistent with no or limited evidence for affected sibling pair (ASP) linkage and strong evidence for case-control association. We find that significant evidence for case-control association combined with no or moderate evidence for ASP linkage can define a lower bound for the plausible RAFC . Using data from large type 2 diabetes (T2D) linkage and genome-wide association study meta-analyses, we find that under reasonable model assumptions, 23 of 36 autosomal T2D risk loci are unlikely to be due to causal variants with combined RAFC < 0.005, and four of the 23 are unlikely to be due to causal variants with combined RAFC < 0.05.