Additive effects of gene regulatory variants in multifactorial disease

Lois M. Mulligan


The human genome contains extensive sequence variation, the vast majority of which lies in non-coding regions and is not known to be associated with any phenotype. However, as our understanding of the regulatory roles of sequences traditionally thought of as “non-coding” increases, it is clear that this pool of genomic variation may have mechanistic contributions to an array of complex genetic diseases. Multifactorial inheritance patterns underlie the vast majority of clinically relevant diseases of genetic origin. These conditions generally arise from the accumulated effects of multiple disease-associated variants. While familial risks in these diseases are clear, their genetics can be complex, and the significance of individual variants, and any overall pattern or clustering of mutations that give rise to the disease phenotype, difficult to interpret. As a result, it is not easy to predict risk or prognosis with any degree of certainty for the majority of the population.