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This large-scale genome-wide association analysis of subjects with asthma, hay fever or eczema provides insights into the shared genetic basis of these allergic diseases. The findings suggest that these diseases partly co-occur because they share many genetic risk variants that dysregulate the expression of immune-related genes. Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals 1 , partly because of a shared genetic origin 2 , 3 , 4 . To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants ( P < 3 × 10 −8 ), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes.

Genome-wide association studies have identified many loci associated with hair and skin disease, but identification of causal variants requires deciphering of gene-regulatory networks in relevant cell types. We generated matched single-cell chromatin profiles and transcriptomes from scalp tissue from healthy controls and patients with alopecia areata, identifying diverse cell types of the hair follicle niche. By interrogating these datasets at multiple levels of cellular resolution, we infer 50–100% more enhancer–gene links than previous approaches and show that aggregate enhancer accessibility for highly regulated genes predicts expression. We use these gene-regulatory maps to prioritize cell types, genes and causal variants implicated in the pathobiology of androgenetic alopecia (AGA), eczema and other complex traits. AGA genome-wide association studies signals are enriched in dermal papilla regulatory regions, supporting the role of these cells as drivers of AGA pathogenesis. Finally, we train machine learning models to nominate single-nucleotide polymorphisms that affect gene expression through disruption of transcription factor binding, predicting candidate functional single-nucleotide polymorphism for AGA and eczema. Single-cell RNA- and ATAC-seq analysis of human scalp biopsies characterizes the regulatory programs of heterogeneous cell types. Integration with genome-wide association studies of hair and skin diseases implicates critical cell types, transcription factors and candidate causal variants.

Growth hormone (GH) insensitivity syndrome (GHIS) is a rare clinical condition in which production of insulin-like growth factor 1 is blunted and, consequently, postnatal growth impaired. Autosomal-recessive mutations in signal transducer and activator of transcription (STAT5B), the key signal transducer for GH, cause severe GHIS with additional characteristics of immune and, often fatal, pulmonary complications. Here we report dominant-negative, inactivating STAT5B germline mutations in patients with growth failure, eczema, and elevated IgE but without severe immune and pulmonary problems. These STAT5B missense mutants are robustly tyrosine phosphorylated upon stimulation, but are unable to nuclear localize, or fail to bind canonical STAT5B DNA response elements. Importantly, each variant retains the ability to dimerize with wild-type STAT5B, disrupting the normal transcriptional functions of wild-type STAT5B. We conclude that these STAT5B variants exert dominant-negative effects through distinct pathomechanisms, manifesting in milder clinical GHIS with general sparing of the immune system. Severe growth hormone insensitivity syndrome (GHIS) with immunodeficiency is caused by autosomal recessive mutations in STAT5B. Here the authors report heterozygous STAT5B mutations with dominant-negative effects, causing mild GHIS without immune defects.

Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3x10-8) with age-of-onset. Forty-five variants had comparable effects on the onset of the three individual diseases and 38 were also associated with allergic disease case-control status in an independent study (n = 222,484). We observed a strong negative genetic correlation between age-of-onset and case-control status of allergic disease (rg = -0.63, P = 4.5x10-61), indicating that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. Subsequently, a multivariate GWAS of age-of-onset and case-control status identified a further 26 associations that were missed by the univariate analyses of age-of-onset or case-control status only. Collectively, of the 76 variants identified, 18 represent novel associations for allergic disease. We identified 81 likely target genes of the 76 associated variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, of which we highlight ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7 and UBE2L3. Our results support the notion that early and late onset allergic disease have partly distinct genetic architectures, potentially explaining known differences in pathophysiology between individuals.

Abstract Background Little is known about shared origins between inflammatory bowel disease (IBD) and allergic diseases (asthma, allergic rhinitis, and eczema). We aimed to expand current knowledge on the etiological sources of comorbidities between these disorders using a range of genetically informed methods. Methods Within-individual and familial co-aggregation analysis was applied to 2 873 445 individuals born in Sweden from 1987 to 2014 and their first- and second-degree relatives. Quantitative genetic modeling was applied to 38 723 twin pairs to decompose the genetic and environmental sources for comorbidity. Polygenic risk score analysis between IBD and allergic diseases was conducted in 48 186 genotyped twins, and linkage disequilibrium score regression was applied using publicly available data to explore the genetic overlap. Results IBD was associated with asthma (adjusted odds ratio [aOR], 1.35; 95% confidence interval [CI], 1.30 to 1.40), allergic rhinitis (aOR, 1.27; 95% CI, 1.20 to 1.34), and eczema (aOR, 1.47; 95% CI, 1.38 to 1.56), with similar estimates for ulcerative colitis or Crohn’s disease. The ORs for familial co-aggregation decreased with decreasing genetic relatedness. Quantitative genetic modeling revealed little evidence of common genetic factors between IBD and allergic diseases (eg, IBD and allergic rhinitis; genetic correlation ra = 0.06; 95% CI, −0.03 to 0.15) but did reveal some evidence of unique environmental factors between IBD and eczema (re = 0.16; 95% CI, 0.00 to 0.32). Molecular genetic analyses were similarly null for IBD and allergic diseases, except for a slight association between Crohn’s disease polygenic risk score and eczema (OR, 1.09; 95% CI, 1.06 to 1.12). Conclusions We found little evidence to support a shared origin between IBD and any allergic disease but weak evidence for shared genetic and unique environmental components for IBD and eczema. Lay Summary Comorbidities between inflammatory bowel disease (IBD) with asthma and allergic diseases have been documented, but shared origin remains unknown. Using multiple genetically informed approaches, we found little evidence of a shared origin explaining the comorbidities of IBD with asthma and allergic rhinitis but weak evidence for IBD and eczema.

Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1 , NOTCH4 , and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1 / KCNH8 , TRIB1 / LINC00861 , ZBTB1 , TBX21 / OSBPL7 , and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema. Genetic studies of eczema to date have mostly explored common genetic variation. Here, the authors perform a large meta-analysis for common and rare variants and discover 8 loci associated with eczema. Over 20% of the heritability of the condition is attributable to rare variants.

BackgroundDubowitz syndrome (DS) is an autosomal recessive disorder characterized by the constellation of mild microcephaly, growth and mental retardation, eczema and peculiar facies. Over 140 cases have been reported, but the genetic basis is not understood.MethodsWe enrolled a multiplex consanguineous family from the United Arab Emirates with many of the key clinical features of DS as reported in previous series. The family was analyzed by whole exome sequencing. RNA splicing was evaluated with reverse-transcriptase PCR, immunostaining and western blotting was performed with specific antibodies, and site-specific cytosine-5-methylation was studied with bisulfite sequencing.ResultsWe identified a homozygous splice mutation in the NSUN2 gene, encoding a conserved RNA methyltransferase. The mutation abolished the canonical splice acceptor site of exon 6, leading to use of a cryptic splice donor within an AluY and subsequent mRNA instability. Patient cells lacked NSUN2 protein and there was resultant loss of site-specific 5-cytosine methylation of the tRNA(Asp GTC) at C47 and C48, known NSUN2 targets.ConclusionOur findings establish NSUN2 as the first causal gene with relationship to the DS spectrum phenotype. NSUN2 has been implicated in Myc-induced cell proliferation and mitotic spindle stability, which might help explain the varied clinical presentation in DS that can include chromosomal instability and immunological defects.

Eczema is common in children, and its onset is affected by both genetic and environmental factors. We investigated the effects of genetic and environmental factors on the incidence of eczema in preschool children. 515 preschool children with eczema and 515 children participating in the physical examination were enrolled. The study included the incidence of childhood eczema, the child’s birth and feeding conditions, the history of eczema in the parents, and relevant environmental risk factors, and to comprehensively analyze the genetic and environmental factors influencing childhood eczema. Among 1030 children, 173 parents (8.4%) had eczema, with a heritability of 73.59% for boys’ parents and 58.59% for girls’ parents. Multivariate logistic regression results showed that premature infants, low birth weight, children who had used antibiotics before the age of 1 year the living environment between the first year of mother pregnancy and the first year of the child is humid, a father with a history of eczema, a mother with a history of eczema are risk factors for eczema in children. Actively preventing environmental factors related to eczema may be an effective means to reduce the risk of eczema in children.

Food allergy and eczema are the earliest allergic phenotypes in childhood. These diseases could be related to either IgE-mediated or non-IgE-mediated reactions to the allergen. TNFRSF17 is a key molecule in B cell maturation and is important in both types of responses.We conducted a study comparing the relative expression and the methylation status at the TNFRSF17 in regard to the child’s early atopic sensitisation and allergic phenotypes.In the recruited population of 200 women and 174 children with available clinical data (physical examination by allergist and antigen-specific IgE measurements), 78 cord blood samples were included in the gene expression analysis (relative gene expression with GAPDH as reference by RT-PCR) and 96 samples with microarray DNA methylation data (whole genome methylation profile Infinium MethylationEPIC).The altered TNFRSF17 methylation pattern in the cord blood at both single cg04453550 and mean methylation at upstream of TNFRSF17 was observed in children who developed food allergy and/or eczema in early childhood. The change in methylation profile was mirrored by the relative expression. The profile of IgE sensitisation to food and/or inhalant allergens was not significantly associated with either methylation or expression of TNFRSF17.In conclusion, methylation at the upstream sites at TNFRSF17 in the cord blood at birth is associated with food allergy and eczema early in childhood.

High endotoxin exposure may reduce the risk of allergic sensitization. To determine the relationship between a promoter polymorphism in the CD14 gene (CD14/-159 C to T) and endotoxin exposure in relation to the development of allergic sensitization, eczema, and wheeze within the setting of a birth cohort. We genotyped 442 children (CD14/-159 C to T; rs2569190). We assessed children for allergic sensitization (IgE > 0.2 kU/L to at least one of seven allergens), eczema (physical examination), and parentally reported wheeze. Endotoxin was measured in house dust. Genotype frequencies were consistent with other populations (TT, 25%; CT, 47%; CC, 28%). Sensitization (present in 33% of children) was not associated with genotype. For children with TT and CT genotypes, there was no association between endotoxin and sensitization (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.71-1.23; p = 0.7; and OR, 0.90; 95% CI, 0.77-1.04; p = 0.16, respectively) or endotoxin and eczema (OR, 0.99; 95% CI, 0.81-1.20; p = 0.89; and OR, 1.38; 95% CI, 0.83-2.30; p = 0.22, respectively). In children with the genotype CC, increasing endotoxin load was associated with a marked and significant reduction in the risk of sensitization (OR, 0.70; 95% CI, 0.55-0.89; p = 0.004) and eczema (OR, 0.73; 95% CI, 0.56-0.95; p = 0.02). However, we observed an increased risk of nonatopic wheeze with increasing endotoxin exposure in children with the CC genotype (OR, 1.42; 95% CI, 1.01-1.99; p = 0.04) but not other genotypes. No effect was seen for atopic wheeze. Increasing endotoxin exposure is associated with reduced risk of allergic sensitization and eczema but with increased risk of nonatopic wheeze in children with the CC genotype at -159 of the CD14 gene. The impact of environmental endotoxin may be enhanced in individuals with this genotype.