Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis

Meta-analysis identifies seven susceptibility loci involved in the atopic March

Eczema often precedes the development of asthma in a disease course called the a 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10 a'8) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10 a'9). Additional susceptibility loci identified

TDT analysis stratified by maternal specific sensitization.

<p>TDT analysis stratified by maternal specific sensitization.</p

Parent-of-origin analysis of the combined <i>FLG</i> mutations.

<p>Parent-of-origin analysis of the combined <i>FLG</i> mutations.</p

Results of the transmission disequilibrium test.

<p>Results of the transmission disequilibrium test.</p

Frequency of FLG mutations in fathers, mothers, individuals with atopic dermatitis and controls.

<p>Allele and genotype frequencies of the combined <i>FLG</i>-mutations in fathers and mothers were calculated using all available parents. AD refers to the frequency in the AD-affected children including the families and the unrelated AD-cases (available only in the Central European study). Frequency in controls corresponds to population-based individuals with unknown disease status. Results of the Central and Northern European populations are shown in panels A and B, respectively.</p

Parent-of-origin-analysis analysis stratified by maternal specific sensitization.

<p>Parent-of-origin-analysis analysis stratified by maternal specific sensitization.</p

Study populations.

<p>Study populations.</p

Comparison of the MCG and Imprinting models with the full model.

<p>Comparison of the MCG and Imprinting models with the full model.</p

Maternal Filaggrin Mutations Increase the Risk of Atopic Dermatitis in Children: An Effect Independent of Mutation Inheritance

<div><p>Epidemiological studies suggest that allergy risk is preferentially transmitted through mothers. This can be due to genomic imprinting, where the phenotype effect of an allele depends on its parental origin, or due to maternal effects reflecting the maternal genome's influence on the child during prenatal development. Loss-of-function mutations in the filaggrin gene (<i>FLG</i>) cause skin barrier deficiency and strongly predispose to atopic dermatitis (AD). We investigated the 4 most prevalent European <i>FLG</i> mutations (c.2282del4, p.R501X, p.R2447X, and p.S3247X) in two samples including 759 and 450 AD families. We used the multinomial and maximum-likelihood approach implemented in the PREMIM/EMIM tool to model parent-of-origin effects. Beyond the known role of FLG inheritance in AD (R1_{meta-analysis} = 2.4, P = 1.0 x 10⁻³⁶), we observed a strong maternal <i>FLG</i> genotype effect that was consistent in both independent family sets and for all 4 mutations analysed. Overall, children of <i>FLG</i>-carrier mothers had a 1.5-fold increased AD risk (S1 = 1.50, P_{meta-analysis} = 8.4 x 10⁻⁸). Our data point to two independent and additive effects of <i>FLG</i> mutations: i) carrying a mutation and ii) having a mutation carrier mother. The maternal genotype effect was independent of mutation inheritance and can be seen as a non-genetic transmission of a genetic effect. The <i>FLG</i> maternal effect was observed only when mothers had allergic sensitization (elevated allergen-specific IgE antibody plasma levels), suggesting that <i>FLG</i> mutation-induced systemic immune responses in the mother may influence AD risk in the child. Notably, the maternal effect reported here was stronger than most common genetic risk factors for AD recently identified through genome-wide association studies (GWAS). Our study highlights the power of family-based studies in the identification of new etiological mechanisms and reveals, for the first time, a direct influence of the maternal genotype on the offspring’s susceptibility to a common human disease.</p></div