Molecular phenotypes that are causal to complex traits can have low heritability and are expected to have small influence

Work on genetic makeup of complex traits has led to some unexpected findings. Molecular trait heritability estimates have consistently been lower than those of common diseases, even though it is intuitively expected that the genotype signal weakens as it becomes more dissociated from DNA. Further, results from very large studies have not been sufficient to explain most of the heritable signal, and suggest hundreds if not thousands of responsible alleles. Here, I demonstrate how trait heritability depends crucially on the definition of the phenotype, and is influenced by the variability of the assay, measurement strategy, and the quantification approach used. For a phenotype downstream of many molecular traits, it is possible that its heritability is larger than for any of its upstream determinants. I also rearticulate via models and data that if a phenotype has many dependencies, a large number of small effect alleles are expected. However, even if these alleles do drive highly heritable causal intermediates that can be modulated, it does not imply that large changes in phenotype can be obtained.