Abstract
Atopic dermatitis (AD) is a common chronic inflammatory skin disease with high heritability. Previous genome-wide association studies have identified several loci predisposing to AD. These findings explain approximately 30% of the variance in AD susceptibility, suggesting that further work is required to fully understand the genetic underpinnings. We sought to gain additional understanding of the genetic contribution to AD risk by using biobank resources. We completed a genome-wide meta-analysis of AD in 796,661 individuals (Ncases= 22,474) from the FinnGen study, the Estonian Biobank, and the UK Biobank. We further performed downstream in silico analyses to characterize the risk variants at the novel loci. We report 30 loci associating with AD (P< 5×10-8), 5 of which are novel. In 2 of the novel loci, we identified missense mutations with deleterious predictions in desmocollin 1 and serpin family B member 7, genes encoding proteins crucial to epidermal strength and integrity. These findings elucidate novel genetic pathways involved in AD pathophysiology. The likely involvement of desmocollin 1 and serpin family B member 7 in AD pathogenesis may offer opportunities for the development of novel treatment strategies for AD in the future.
Highlights
Approximately 15% to 20% of children and 5% to 10% of adults are affected by atopic dermatitis (AD).[1]
To complement the understanding of the genetic pathways, we completed a genome-wide meta-analysis of association results obtained in FinnGen (8,383 cases, 236,161 controls), Estonian Biobank (11,187 cases, 125,537 controls), and UK Biobank (2,904 cases, 412,489 controls), adding up to 22,474 Atopic dermatitis (AD) cases and 774,187 controls in the study
To test the validity of using International Classification of Diseases, Tenth Revision code L20 as case definition, we compared in FinnGen the effect estimates of the lead variants at the 30 loci obtained with the original case definition against 2 more rigorous definitions
Summary
15% to 20% of children and 5% to 10% of adults are affected by atopic dermatitis (AD).[1]. The key genetic risk factors include mutations in filaggrin, giving rise to epidermal barrier deficiency, or in immune-regulating genes, such as IL-6 receptor, which contribute to immune dysregulation.[3] To complement the understanding of the genetic pathways, we completed a genome-wide meta-analysis of association results obtained in FinnGen (8,383 cases, 236,161 controls), Estonian Biobank (11,187 cases, 125,537 controls), and UK Biobank (2,904 cases, 412,489 controls), adding up to 22,474 AD cases and 774,187 controls in the study. Previous genome-wide association studies have identified several loci predisposing to AD. These findings explain approximately 30% of the variance in AD susceptibility, suggesting that further work is required to fully understand the genetic underpinnings. The likely involvement of desmocollin 1 and serpin family B member 7 in AD pathogenesis may offer opportunities for the development of novel treatment strategies for AD in the future. (J Allergy Clin Immunol 2021;nnn:nnn-nnn.)
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