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Large GWAS Meta-Analysis Notches Up Tally of Eczema Risk Variants

NEW YORK (GenomeWeb) – An international team has tracked down 10 new loci with apparent ties to the inflammatory skin condition atopic dermatitis, also known as eczema — work it reported in Nature Genetics today.

Through a multi-ancestry genome-wide association study meta-analysis involving almost 21,400 eczema cases and more than 95,400 controls from 26 past studies, the researchers uncovered more than two dozen new and known eczema-associated sites in the genome.

Validation testing in tens of thousands more cases and nearly 230,000 unaffected controls verified associations for 10 of the new risk loci in Europeans. These included SNPs in and around innate immune genes, T immune cell-related genes, and genes implicated in other inflammatory conditions.

In a statement, the study's co-first author Lavinia Paternoster, an integrative epidemiology and community medicine researcher at the University of Bristol, noted that the findings "give new insights into important disease mechanisms" of eczema.

Paternoster cautioned that each of the newly identified variants contribute only a small proportion to overall heritability of the condition. Nevertheless, she noted that additional scrutiny of these and other variants involved in eczema risk may point to pathways to ping for improved treatment.

Atopic dermatitis is typically marked by inflammation events mediated by T cell pathways and skin barrier changes, the researchers explained. Perhaps not surprisingly, then, mutations that jumble the epidermal barrier-related gene FLG have been linked to strong eczema risk.

Variants with more subtle roles in the disease are still being untangled. Prior GWAS have identified 20 eczema-linked loci in European, Japanese, and Chinese populations, the team noted, though much of the heritability behind eczema remains unexplained.

For the latest look at genetic contributors to the condition, the researchers brought together genotyping data for 21,399 eczema cases and 95,464 unaffected controls.

The majority of these participants were of European descent, though data from studies of individuals with Japanese, African-American, or Latino ancestry were also included.

Based on directly genotyped and imputed variant patterns at more than 15 million sites in the genome, the team narrowed in on 21 loci with genome-wide significant ties to atopic dermatitis in the European individuals and half a dozen more sites with apparent associations in a broader analysis of individuals from all of the ancestry groups.

The suspicious SNP set included variants found at several loci previously linked to conditions such as asthma, allergic sensitization, and self-reported allergy, the study's authors noted.

All told, the team found that 21 of the 27 loci falling out of the meta-analysis turned up in studies of immune-related conditions such as inflammatory bowel disease and psoriasis.

With that in mind, the researchers specifically scrutinized signals at more than 150 variants that have been implicated in IBD, psoriasis, type 1 diabetes, and other autoimmune conditions, uncovering hints of additional overlap between such conditions and genetic risk of eczema.

The team's gene set enrichment analysis suggested that eczema-associated variants were over-represented in genes involved in T cell polarization and innate immune signaling.

Finally, through targeted testing of 11 candidate loci in 21,059 more cases and 228,628 controls, the researchers verified associations at 10 of these sites in individuals of European descent. Six of those showed genome-wide significant associations with eczema in the multi-ancestry analysis.

"All newly identified susceptibility loci are related to (auto)immune regulation," the study's authors concluded. "Although not detracting from the importance of maintaining the skin barrier in the prevention and treatment of atopic dermatitis," they added, "our findings lend support to new approaches targeted at immune modulation."