Abstract
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 (FLG) cause skin barrier deficiency and strongly predispose to atopic dermatitis (AD). We investigated the 4 most prevalent European FLG 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 (R1meta-analysis = 2.4, P = 1.0 x 10−36), we observed a strong maternal FLG genotype effect that was consistent in both independent family sets and for all 4 mutations analysed. Overall, children of FLG-carrier mothers had a 1.5-fold increased AD risk (S1 = 1.50, Pmeta-analysis = 8.4 x 10−8). Our data point to two independent and additive effects of FLG 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 FLG maternal effect was observed only when mothers had allergic sensitization (elevated allergen-specific IgE antibody plasma levels), suggesting that FLG 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.
Highlights
Atopic dermatitis (AD, eczema) is a chronic inflammatory skin disease with 10–20% prevalence in industrialized countries
We found that filaggrin gene (FLG) mutations in the mother, not the father, increased the atopic dermatitis (AD) risk of the children, even if the child did not inherit the mutation
Our study indicates that maternal FLG mutations act as strong environmental risk factors for the child and highlights the potential of family-based studies in uncovering novel disease mechanisms in medical genetics
Summary
Atopic dermatitis (AD, eczema) is a chronic inflammatory skin disease with 10–20% prevalence in industrialized countries. Genome-wide association studies (GWAS) have successfully identified common genetic variants predisposing to AD, but the effect of these risk loci is small and altogether only account for a fraction of the disease heritability. Loss-of-function mutations in FLG were identified as the cause of ichthyosis vulgaris, a common Mendelian trait characterized by dry, scaly skin and frequent AD [2]. Subsequent studies revealed that FLG mutations strongly predispose to AD [3,4]. This observation has been widely replicated, rendering FLG the strongest and best characterized AD risk locus to date [1]. Evidence from human and animal studies demonstrated that filaggrin deficiency results in altered skin structure, impaired barrier function and enhanced antigen penetration through the skin, leading to the production of allergen-specific IgE antibodies (specific sensitization) and AD [5,6,7]
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