The genetic architecture of molecular traits

Most diseases have both an environmental and genetic component. Although many diseases are strongly heritable, individual genetic variants typically confer only a small effect on disease, and thus these diseases are strongly polygenic. Paradoxically, molecular traits, such as gene expression, methylation, protein or metabolite levels, typically have a lower heritability, but sometimes individual genetic variants show much higher effect sizes on these traits. In this review, we discuss the genetic architecture of these molecular traits, and contrast this to the genetic architecture of complex diseases, and provide explanations why strong effects of individual genetic variants on molecular traits do not necessarily need to translate into increased risk of disease.