title: Identifying plausible genetic models based on association and linkage results: application to type 2 diabetes.
abstract: 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.
authors.affiliation: Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Weihua
authors.initials: W
authors.lastname: Guan
authors.forename: Michael
authors.initials: M
authors.lastname: Boehnke
authors.forename: Anna
authors.initials: A
authors.lastname: Pluzhnikov
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Scott
mesh_terms: D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005787:Gene Frequency; D008040:Genetic Linkage / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D015894:Genome, Human / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D015201:Meta-Analysis as Topic; D008957:Models, Genetic