Genetic Basis of Complex Genetic Disease: The Contribution of Disease Heterogeneity to Missing Heritability

Abstract

The genetic basis of complex genetic disease can be quantified by heritability, which is an estimate of the relative importance of genetic and non-genetic factors in contributing to differences between individuals for any given trait. Heritability is estimated from phenotypic records in data sets of families and represents contributions from genetic variants across the frequency spectrum and of any kind and function. Advances in technology allow direct interrogation of some kinds of DNA variants. Specific DNA variants identified in the era of genome-wide association studies explain only a fraction of the heritability estimated from family studies, as do less common variants identified through whole exome sequencing. If true effect sizes of risk variants are small, studies to date may be underpowered to detect individual risk variants; but the studies may be well-powered to detect the total contribution from common risk variants, and this has explained some of the missing heritability. Here we review explanations for the so-called “still-missing heritability” and focus particularly on the issue of genetic heterogeneity.