Approaches to Understanding the Genetic Basis of Complex Diseases: Overview—What Is the Rationale for the Genome-Wide Approach to Understand Complex Diseases, Its Application and Limitations

Abstract

Pulmonary diseases are complex disorders caused by a number of environmental and genetic factors. Recent advances in technologies and study designs have revealed the genetic components of common diseases. Genetic mapping is an unbiased method to comprehensively identify genes and biological pathways involved in diseases or traits. Genome-wide association studies (GWASs) have convincingly identified disease-associated loci. Most of the associated variants identified by GWASs are located in noncoding regions, and the functional link between those disease-associated variants and clinical phenotypes remains unclear. Recent progress in next-generation sequencing (NGS) technologies has improved the functional annotation of the human genome and highlighted the importance of noncoding regions. Epigenetic studies, transcriptome analyses, and characterization of cis-regulatory regions have revealed a wide variety of molecular phenotypes: RNA expression and stability, transcription factor binding, DNA methylation, histone modifications, and protein levels in various cell types and tissues. Recent genome editing technology and pluripotent stem cells are also helpful to assess the functional effects of genetic risk variants in disease-relevant cell types. Interdisciplinary research to elucidate the relationships between risk variants and molecular phenotypes in the pathologically relevant cell types is necessary to identify the targets of the risk loci and improve our mechanistic understanding of diseases.