Average semivariance yields accurate estimates of the fraction of marker-associated genetic variance and heritability in complex trait analyses.

Abstract

The development of genome-informed methods for identifying quantitative trait loci (QTL) and studying the genetic basis of quantitative variation in natural and experimental populations has been driven by advances in high-throughput genotyping. For many complex traits, the underlying genetic variation is caused by the segregation of one or more ‘large-effect’ loci, in addition to an unknown number of loci with effects below the threshold of statistical detection. The large-effect loci segregating in populations are often necessary but not sufficient for predicting quantitative phenotypes. They are, nevertheless, important enough to warrant deeper study and direct modelling in genomic prediction problems. We explored the accuracy of statistical methods for estimating the fraction of marker-associated genetic variance (p) and heritability () for large-effect loci underlying complex phenotypes. We found that commonly used statistical methods overestimate p and . The source of the upward bias was traced to inequalities between the expected values of variance components in the numerators and denominators of these parameters. Algebraic solutions for bias-correcting estimates of p and were found that only depend on the degrees of freedom and are constant for a given study design. We discovered that average semivariance methods, which have heretofore not been used in complex trait analyses, yielded unbiased estimates of p and , in addition to best linear unbiased predictors of the additive and dominance effects of the underlying loci. The cryptic bias problem described here is unrelated to selection bias, although both cause the overestimation of p and . The solutions we described are predicted to more accurately describe the contributions of large-effect loci to the genetic variation underlying complex traits of medical, biological, and agricultural importance.