Genetic architecture of a complex trait and its implications for fitness and genome-wide association studies

A model is investigated in which mutations that affect a complex trait (e.g., heart disease) also affect fitness because the trait is a component of fitness or because the mutations have pleiotropic effects onfitness. Themodel predicts that the genetic variance, and hence the heritability, in the trait is contributed bymutations at low frequency in the population, unless the mean strength of selection of mutations that affect the trait is very small or weakly selected mutations tend to contribute disproportionately to the trait compared with strongly selected mutations. Furthermore, it is shown that each rare mutation tends to contribute more to the variance than each common mutation. These results may explain why most genome-wide association studies have failed to find associations that explainmuch of the variance. It is also shown that most of the variance in fitness contributed by newnonsynonymous mutations is caused by mutations at very low frequency in the population. This implies that most low-frequency SNPs, which are observed in current resequencing studies of, for example, 100 chromosomes, probably have little impact on the variance infitness or traits. Finally, it is shown that the variance contributed by a category of mutations (e.g., coding or regulatory) depends largely upon the mean strength of selection; this has implications for understanding which types of mutations are likely to be responsible for the variance in fitness and inherited disease.