A Model of Compound Heterozygous, Loss-of-Function Alleles Is Broadly Consistent with Observations from Complex-Disease GWAS Datasets

The genetic component of complex disease risk in humans remains largely unexplained. A corollary is that the allelic spectrum of genetic variants contributing to complex disease risk is unknown. Theoretical models that relate population genetic processes to the maintenance of genetic variation for quantitative traits may suggest profitable avenues for future experimental design. Here we use forward simulation to model a genomic region evolving under a balance between recurrent deleterious mutation and Gaussian stabilizing selection. We consider multiple genetic and demographic models, and several different methods for identifying genomic regions harboring variants associated with complex disease risk. We demonstrate that the model of gene action, relating genotype to phenotype, has a qualitative effect on several relevant aspects of the population genetic architecture of a complex trait. In particular, the genetic model impacts genetic variance component partitioning across the allele frequency spectrum and the power of statistical tests. Models with partial recessivity closely match the minor allele frequency distribution of significant hits from empirical genome-wide association studies without requiring homozygous effect sizes to be small. We highlight a particular gene-based model of incomplete recessivity that is appealing from first principles. Under that model, deleterious mutations in a genomic region partially fail to complement one another. This model of gene-based recessivity predicts the empirically observed inconsistency between twin and SNP based estimated of dominance heritability. Furthermore, this model predicts considerable levels of unexplained variance associated with intralocus epistasis. Our results suggest a need for improved statistical tools for region based genetic association and heritability estimation.Author Summary: Gene action determines how mutations affect phenotype. When placed in an evolutionary context, the details of the genotype-to-phenotype model can impact the maintenance of genetic variation for complex traits. Likewise, non-equilibrium demographic history may affect patterns of genetic variation. Here, we explore the impact of genetic model and population growth on distribution of genetic variance across the allele frequency spectrum underlying risk for a complex disease. Using forward-in-time population genetic simulations, we show that the genetic model has important impacts on the composition of variation for complex disease risk in a population. We explicitly simulate genome-wide association studies (GWAS) and perform heritability estimation on population samples. A particular model of gene-based partial recessivity, based on allelic non-complementation, aligns well with empirical results. This model is congruent with the dominance variance estimates from both SNPs and twins, and the minor allele frequency distribution of GWAS hits.