Genetics of Atopic Dermatitis: From DNA Sequence to Clinical Relevance

Abstract

Atopic dermatitis (AD) is a complex disease that is thought to be triggered by environmental factors in genetically susceptible individuals. Twin studies have estimated the heritability of AD to be approximately 75%, with the null (loss-of-function) mutations of the gene encoding filaggrin (FLG) (chromosome 1q21.3) as the strongest known genetic risk factor. The discovery of the filaggrin gene was important in the emerging model for AD pathogenesis, combining skin barrier function with adaptive and innate immunity. Assisted by the recent development of large-scale high-throughput genomics, more than 30 genetic loci have been linked to AD across different populations. Identification of these loci, together with functional studies, has already provided new insights into disease biology and identified novel drug targets. Further, these susceptibility loci are laying the groundwork for phenome-wide association studies to test their multiple phenotype relationships and application of Mendelian randomization to investigate causal relationships. Despite many known genes, a majority of the genetic risk for AD is yet unexplored. Therefore, studies investigating refined phenotype groups, low-frequency and rare genetic variation, gene-gene and/or gene-environment interactions, epigenetic mechanisms and data from multi-omics technologies are warranted. In this review, we describe genetic discoveries for AD, including results from candidate gene studies, studies of AD-like genetic diseases, genome-wide association studies and genetic sequencing studies. We explain how some of these genetic discoveries have unraveled new mechanistic insights into the pathogenesis of AD and exemplify how personal genetic data could be used for preventive strategies and a tailored treatment regimen (i.e., precision medicine).