Investigating asthma heterogeneity through shared and distinct genetics: Insights from genome-wide cross-trait analysis

Asthma is a heterogeneous respiratory disease reflecting distinct pathobiologic mechanisms. These mechanisms are based, at least partly, on different genetic factors shared by many other conditions, such as allergic diseases and obesity. Investigating the shared genetic effects enables better understanding of the mechanisms of phenotypic correlations and is less subject to confounding by environmental factors. The increasing availability of large-scale genome-wide association study (GWAS) for asthma has enabled researchers to examine the genetic contributions to the epidemiologic associations between asthma subtypes and those between coexisting diseases and/or traits and asthma. Studies have found not only shared but also distinct genetic components between asthma subtypes, indicating that the heterogeneity is related to distinct genetics. This review summarizes a recently compiled analytic approach—genome-wide cross-trait analysis—to determine shared and distinct genetic architecture. The genome-wide cross-trait analysis features in several analytic aspects: genetic correlation, cross-trait meta-analysis, Mendelian randomization, polygenic risk score, and functional analysis. In this article, we discuss in detail the scientific goals that can be achieved by these analyses, their advantages, and their limitations. We also make recommendations for future directions: (1) ethnicity-specific asthma GWASs and (2) application of cross-trait methods to multiomics data to dissect the heritability found in GWASs. Finally, these analytic approaches are also applicable to complex and heterogeneous traits beyond asthma.