Mayumi Tamari

Role of Lung Function Genes in the Development of Asthma

Although our previous GWAS failed to identify SNPs associated with pulmonary function at the level of genomewide significance, it did show that the heritability for FEV1/FVC was 41.6% in a Japanese population, suggesting that the heritability of pulmonary function traits can be explained by the additive effects of multiple common SNPs. In addition, our previous study indicated that pulmonary function genes identified in previous GWASs in non-Japanese populations accounted for 4.3% to 12.0% of the entire estimated heritability of FEV1/FVC in a Japanese population. Therefore, given that many loci with individual weak effects may contribute to asthma risk, in this study, we created a quantitative score of genetic load based on 16 SNPs implicated in lower lung function in both Japanese and non-Japanese populations. This genetic risk score (GRS) for lower FEV1/FVC was consistently associated with the onset of asthma (P = 9.6 × 10−4) in 2 independent Japanese populations as well as with the onset of COPD (P = 0.042). Clustering of asthma patients based on GRS levels indicated that an increased GRS may be responsible for the development of a particular phenotype of asthma characterized by early onset, atopy, and severer airflow obstruction.

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

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.

Genome-Wide Association Study for Atopic Dermatitis in the Japanese Population

Atopic dermatitis (AD) is a chronic inflammatory skin disease in which there are considerable genetic contributions. Genome-wide association studies (GWASs) provide an unbiased method to identify the genetic factors of human diseases and phenotypes comprehensively. Although it is well known that loss-of-function mutations in FLG are the most significant genetic risk factor for AD, recent GWASs, immunochip analyses, and meta-analyses of GWASs have identified a number of loci associated with AD. Candidate genes identified by GWASs of AD are involved in skin barrier functions and innate and adaptive immune responses. Those findings imply a substantial overlap of genetic components with other autoimmune and inflammatory diseases. Genetic variants may influence molecular phenotypes, including RNA expression and stability, transcription factor binding, DNA methylation, histone modifications, and protein levels. Understanding the functional links between susceptibility variants and phenotypic traits is crucial to improve our knowledge of AD. Further interdisciplinary research is necessary for translation of the genetics of AD into clinical practice.