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

Guan W, Boehnke M, Pluzhnikov A, Cox NJ, Scott LJ
Genet Epidemiol. 2012 36 (8): 820-8

PMID: 22865662 · PMCID: PMC3578091 · DOI:10.1002/gepi.21668

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.

© 2012 Wiley Periodicals, Inc.

MeSH Terms (12)

Case-Control Studies Diabetes Mellitus, Type 2 Gene Frequency Genetic Linkage Genetic Predisposition to Disease Genome, Human Genome-Wide Association Study Genotype Humans Linkage Disequilibrium Meta-Analysis as Topic Models, Genetic

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