Mapping genes for polygenic disorders: considerations for study design in the complex trait of inflammatory bowel disease

Abstract

While the methodology for the mapping of Mendelian disorders is well established, the practical and theoretical steps required for successful gene identification in a complex trait are still difficult to predict. A number of analytical models and simulations based on repetitive drawings from predefined statistical distributions are available. To supplement these analytical models, we developed an integrated simulation approach by directly simulating entire populations under a disease model based on epidemiological data. Random mating, nonoverlapping populations and the absence of differential fitness were assumed. Samples were drawn from these homogeneous and heterogeneous populations and analyzed with established analysis tools. We investigated the properties of linkage and association studies in inflammatory bowel disease - modeled as a six-locus polygenic disorder - as an example of this approach. In nonparametric linkage studies, lod scores varied widely, with the median required sample size depending on the locus-specific relative sibling risk. A fine mapping resolution <4 cM was found to require nonparametric lod scores >10. Family-based association studies (TDT test) and case-control studies showed a similar sensitivity and can identify risk loci in populations with moderate levels of linkage disequilibrium in sample sizes of 500-800 triplets. Case-control association studies were prone to false-positive results if applied in heterogeneous populations, with the false-positive rate increasing with sample size because population heterogeneity is detected with increasing power.