Confounding of indirect genetic and epigenetic effects

Abstract

An individual’s phenotype reflects a complex interplay of the direct effects of their DNA, epigenetic modifications of their DNA induced by their parents, and indirect effects of their parents’ DNA. Here, we present theory that shows there is a greater degree of potential confounding between direct, epigenetic imprinting, maternal and paternal genetic effects than has been previously considered, especially under assortative mating. We show how covariances among these effects contribute substantially to the population-level variance. Assortative mating alters the variance by inducing increased homozygosity and correlations within and across loci, which may lead to covariance of parental genetic effects, a measure of the similarity of the indirect genetic effects among parents on their children. We propose that this assortment for parental characteristics, where biological parents create similar environments for their children, can create shared parental effects across traits and the appearance of cross-trait assortative mating. Our results demonstrate that single-locus, marginal estimates commonly made in genome-wide association studies are impossible to interpret causally, even from within-family studies. Understanding the genetic basis of complex traits requires controlling for the covariances among loci across the genome (both cis- and trans-correlations) when estimating genetic effects, which could be achieved by fitting all variants and all forms of genetic effect (direct, maternal, paternal, parent-of-origin) jointly.