Forward-Time Simulations of Human Populations with Complex Diseases

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Abstract
Due to the increasing power of personal computers, as well as the availability of flexible forward-time simulation programs like simuPOP, it is now possible to simulate the evolution of complex human diseases using a forward-time approach. This approach is potentially more powerful than the coalescent approach since it allows simulations of more than one disease susceptibility locus using almost arbitrary genetic and demographic models. However, the application of such simulations has been deterred by the lack of a suitable simulation framework. For example, it is not clear when and how to introduce disease mutants—especially those under purifying selection—to an evolving population, and how to control the disease allele frequencies at the last generation. In this paper, we introduce a forward-time simulation framework that allows us to generate large multi-generation populations with complex diseases caused by unlinked disease susceptibility loci, according to specified demographic and evolutionary properties. Unrelated individuals, small or large pedigrees can be drawn from the resulting population and provide samples for a wide range of study designs and ascertainment methods. We demonstrate our simulation framework using three examples that map genes associated with affection status, a quantitative trait, and the age of onset of a hypothetical cancer, respectively. Nonadditive fitness models, population structure, and gene–gene interactions are simulated. Case-control, sibpair, and large pedigree samples are drawn from the simulated populations and are examined by a variety of gene-mapping methods. Complex diseases such as hypertension and diabetes are usually caused by multiple disease-susceptibility genes, environment factors, and interactions between them. Simulating populations or samples with complex diseases is an effective approach to study the likely genetic architecture of these diseases and to develop more effective gene-mapping methods. Compared to traditional backward-time (coalescent) methods, population-based, forward-time simulations are more suitable for this task because they can simulate almost arbitrary demographic and genetic features. Forward-time simulations also allow the researcher to perform head-to-head comparisons among gene-mapping methods based on different study designs and ascertainment methods. Unfortunately, evolving a population generation by generation is a random process, so the fates of disease alleles are unpredictable and there is no effective way to control the disease allele frequency at the present generation. In this paper, the authors propose a simulation method that avoids these problems and makes forward-time population simulation a practical solution for the simulation of complex diseases.