Uniting biobank resources reveals novel genetic pathways modulating susceptibility for atopic dermatitis

Abstract

Background: 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. Objective: We sought to gain additional understanding of the genetic contribution to AD risk by using biobank resources. Methods: We completed a genome-wide meta-analysis of AD in 796,661 individuals (N cases 5 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. Results: We report 30 loci associating with AD (P < 5 3 10 28 ), 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. Conclusions: 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. (J Allergy Clin Immunol 2021;nnn:nnn-nnn.)

Integrated single-cell chromatin and transcriptomic analyses of human scalp reveal etiological insights into genetic risk for hair and skin disease

“…For eczema, we identified a total of 137 genes linked to fine-mapped SNPs (fmGWAS-linked genes), the majority of which were expressed in T-cell or keratinocyte clusters (Figure 5D). These genes included important modulators of immune signaling such as TNF, CTLA4 and FASLG, and previously nominated GWAS gene targets including IL6R, PUS10 and IL2RA 8, 84 . For androgenetic alopecia, we identified 130 fmGWAS-linked genes, the majority of which were accessible in keratinocyte or fibroblast clusters (Figure 5E).…”

“…Furthermore, this SNP had been previously identified as a highly significant eQTL for IL18RAP expression in blood, with the G allele increasing expression (p-value 4.8 x 10 -54 , Normalized Effect Size (NES) 0.28). While this locus is one of the most strongly associated with eczema 8, 84 , it is also a region with significant linkage disequilibrium and contains multiple potential gene targets, making identification of causal SNPs for this locus challenging and highlighting the utility of our multi-tiered approach (Figure 6E). IL18RAP is an accessory protein that is required for potentiation of IL-18 signaling through the IL18 receptor complex 93 , and IL-18 overexpression in the skin of mice induces a phenotype similar to atopic dermatitis 94 , suggesting a mechanistic pathway for this causal variant.…”

Cross-disorder genetic analysis of immune diseases reveals distinct disease groups and associated genes that converge on common pathogenic pathways

“…We downloaded GWAS summary statistics from published studies on the most common autoimmune disorders: T1D 7 , RA 8 , JIA 38 , SLE 39 , CD 40 , UC 40 , AST 41 , ECZ 42 , PSC 43 (Supplementary Table 1). Where necessary, rsIDs were added to the summary statistics using the reference file provided in the Genomic SEM repository (https://utexas.app.box.com/s/vkd36n197m8klbaio3yzoxsee6sxo11v/file/576598996073).…”

“…We downloaded GWAS summary statistics from published studies on the most common autoimmune disorders: T1D 7 , RA 8 , JIA 38 , SLE 39 , CD 40 , UC 40 , AST 41 , ECZ 42 , PSC 43 (Supplementary Table 1). Where necessary, rsIDs were added to the summary statistics using…”

Break on through: The role of innate immunity and barrier defence in atopic dermatitis and psoriasis

“…In contrast, type 2associated cells, including T H 2 cells, eosinophils, basophils and ILC2 can increase during AD. GWAS analysis (publicly available databases: GWAS database, https://www.ebi.ac.uk/gwas/; GWAS Central, https://www.gwascentral.org/; accessed 15.11.2021; filtered for psoriasis and atopic eczema traits) of the most common SNPs associated with psoriasis (Pso) and atopic dermatitis (AD) are summarised in the Venn diagram rs6913137, rs2853950, rs3130573, rs7756521, rs9263717, rs2233959, rs2524096, rs12199223, rs1265078, rs2249742, rs2853961, and many more [191,192] TNFAIP3 rs582757, rs610604, rs6933987, rs643177 [181,[193][194][195][196] NFKB1A rs8016947 [193,196] IL36RN rs387906914, rs397514629 [75,197,198] LCE3B rs4845454, rs11205044, rs1581803 [64,199,200] LCE3D rs4085613, rs4112788, rs6677595 [193,194,201] AD and psoriasis HLA-A/B AD: rs148203517, rs4713555, rs28752924, rs28383323, rs200291258, rs9405068, rs4713555, rs2251396; Pso: rs4406273, rs2523619, rs17728338, rs75851973, rs76956521, rs1960278, rs12212594, rs4959062, rs4349859, rs10484554 [64,80,172,173,181,191,193,196,202] CARD14 AD: rs535171797; Pso: rs11652075 [193,203] IL12B AD: rs3212227, rs393548, rs436857; Pso: rs2082412, rs3212227, rs3213094, rs2546890, rs12188300, rs12188300, rs6887695 [78,[193][194][195][204][205][206] IL13 AD: rs848, rs1295686, rs847, rs1295685, rs20541, rs12188917; Pso: rs20541, rs1295685, rs847…”