The vast majority of success in defining genetic risk in disease has been a result of traditional gene-hunting efforts to find mutations that underlie monogenic diseases. In this approach, our understanding of disease revolves around the idea of normal and abnormal variation, with the latter greatly increasing the risk of disease. In considering the genetics of complex disease and particularly the role of common variants that affect expression, a more nuanced perspective is useful. The difference in genetic effect between rare high-risk variants and common low-risk variants is quantitative and not qualitative, as illustrated in Parkinson’s disease: point mutations within the α-synuclein gene39 and genomic multiplications containing this gene6 lead to monogenic disease, whereas a common haplotype of the α-synuclein gene moderates the risk of sporadic disease.40
