Diagnostic definitions shape genome-wide association findings in atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by heterogeneous pathophysiology and considerable interindividual variability in clinical manifestations. Due to this diversity, multiple diagnostic criteria have been established for AD. Variability in these criteria can substantially affect diagnostic accuracy and, consequently, the outcomes of genome-wide association studies (GWAS), whose reliance on this diagnosis variability has not been thoroughly examined. In this study, we conducted GWAS of AD using two diagnostic definitions within the same cohort: self-reported physicians' diagnoses and dermatologists-confirmed diagnoses. GWAS based on self-reported physicians' diagnoses identified previously reported AD-associated loci, whereas single-variant findings from the smaller dermatologist-confirmed GWAS were interpreted primarily as exploratory. Pathway-specific polygenic risk score analysis suggested enrichment of inflammation-related pathways in the self-reported diagnosis GWAS, whereas central nervous system-related pathways, including hippocampal neuronal apoptosis and microglial inflammation, in the dermatologist-confirmed diagnosis GWAS. Furthermore, Mendelian randomization analysis revealed that AD contributes to right hippocampal shrinkage. These findings imply that diagnostic definitions can influence AD GWAS results and generate a hypothesis that genetic liability to AD is linked to hippocampal pathology.