Research question: To explore the causal relationship and molecular mechanism between atopic dermatitis (AD) and cardiovascular- kidney -metabolic syndrome (CKM). Research aims: To explore the potential causal relationships between AD and various components of CKM through observational phenome-wide association study (PheWAS), polygenic risk score (PRS), as well as one-sample mendelian randomization and two-sample mendelian randomization. To investigate the tissue specificity of AD and components of CKM, in order to reveal potential molecular correlations. Scientific Rationale: To address these challenges, we employ several advanced genetic and statistical approaches, each with distinct principles and applications: 1. Observational PheWAS is a method to systematically explore the association between genetic variation and multiple phenotypes. Unlike traditional GWAS, which focuses on a single disease, PheWAS utilizes standardized phenotypic classification systems (such as ICD coding) to detect pleiotropy at genetic loci across a wide range of phenotypes. 2. PRS is a quantitative indicator that predicts an individual’s susceptibility to complex traits or diseases by aggregating the effect sizes of multiple genetic variants. 3. One-sample MR uses genetic variation in the same population as an instrumental variable (IV) to directly estimate the causal relationship between exposure and outcome. 4. Two-sample MR estimates causal effects through two independent sets of GWAS data, and deals with instrumental variable heterogeneity or horizontal pleiotropy by inverse variance weighting (IVW), MR-Egger and other methods. 5. Stratified LD score regression (S-LDSC) is a widely used estimation method for heritability enrichment. It enables quantification of SNP-based heritability of AD and CKM in various cells and tissues by using Z-statistic and corresponding P-values derived from regression coefficients. 6. Multi-marker Analysis of GenoMic Annotation (MAGMA) maps.
