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Filaggrin (FLG) loss-of-function skin barrier gene mutations are associated with atopic dermatitis (AD) and transepidermal water loss (TEWL). We investigated whether FLG mutation inheritance, skin barrier impairment, and AD also predispose to allergic sensitization to foods. Six hundred and nineteen exclusively breastfed infants were recruited at 3 months of age and examined for AD and disease severity (SCORing Atopic Dermatitis (SCORAD)), and screened for the common FLG mutations. TEWL was measured on unaffected forearm skin. In addition, skin prick testing was performed to six study foods (cow’s milk, egg, cod, wheat, sesame, and peanut). Children with AD were significantly more likely to be sensitized (adjusted odds ratio (OR)=6.18, 95% confidence interval (CI): 2.94–12.98, P<0.001), but this effect was independent of FLG mutation carriage, TEWL, and AD phenotype (flexural vs. non-flexural). There was also a strong association between food sensitization and AD severity (adjusted ORSCORAD<20=3.91, 95% CI: 1.70–9.00, P=0.001 vs. adjusted ORSCORAD⩾20=25.60, 95% CI: 9.03–72.57, P<0.001). Equally, there was a positive association between AD and sensitization with individual foods (adjusted ORegg=9.48, 95% CI: 3.77–23.83, P<0.001; adjusted ORcow’s milk=9.11, 95% CI: 2.27–36.59, P=0.002; adjusted ORpeanut=4.09, 95% CI: 1.00–16.76, P=0.05). AD is the main skin-related risk factor for food sensitization in young infants. In exclusively breastfed children, this suggests that allergic sensitization to foods can be mediated by cutaneous antigen-presenting cells.

Irwin McLean and colleagues show that the flaky tail mouse mutant has a frameshift mutation in the gene encoding filaggrin. Topical application of allergen to flaky tail mice results in skin inflammation and enhanced cutaneous allergen priming, shedding light on the mechanisms underlying filaggrin-related atopic disease. Loss-of-function mutations in the FLG (filaggrin) gene cause the semidominant keratinizing disorder ichthyosis vulgaris 1 and convey major genetic risk for atopic dermatitis (eczema) 2 , 3 , 4 , eczema-associated asthma 2 , 3 and other allergic phenotypes 5 . Several low-frequency FLG null alleles occur in Europeans and Asians, with a cumulative frequency of ∼9% in Europe 4 . Here we report a 1-bp deletion mutation, 5303delA, analogous to common human FLG mutations, within the murine Flg gene in the spontaneous mouse mutant flaky tail (ft). We demonstrate that topical application of allergen to mice homozygous for this mutation results in cutaneous inflammatory infiltrates and enhanced cutaneous allergen priming with development of allergen-specific antibody responses. These data validate flaky tail as a useful model of filaggrin deficiency and provide experimental evidence for the hypothesis that antigen transfer through a defective epidermal barrier is a key mechanism underlying elevated IgE sensitization and initiation of cutaneous inflammation in humans with filaggrin-related atopic disease.

Ichthyosis vulgaris (OMIM 146700) is the most common inherited disorder of keratinization and one of the most frequent single-gene disorders in humans. The most widely cited incidence figure is 1 in 250 based on a survey of 6,051 healthy English schoolchildren 1 . We have identified homozygous or compound heterozygous mutations R501X and 2282del4 in the gene encoding filaggrin ( FLG ) as the cause of moderate or severe ichthyosis vulgaris in 15 kindreds. In addition, these mutations are semidominant; heterozygotes show a very mild phenotype with incomplete penetrance. The mutations show a combined allele frequency of ∼4% in populations of European ancestry, explaining the high incidence of ichthyosis vulgaris. Profilaggrin is the major protein of keratohyalin granules in the epidermis. During terminal differentiation, it is cleaved into multiple filaggrin peptides that aggregate keratin filaments. The resultant matrix is cross-linked to form a major component of the cornified cell envelope. We find that loss or reduction of this major structural protein leads to varying degrees of impaired keratinization.

Background People with psychosis die on average 25 years earlier than those in the general population, with cardiovascular disease (CVD) contributing to much of the excess mortality. This cross-sectional study aimed to identify the relationship between lifestyle risk factors for CVD – poor nutrition, smoking and low physical activity levels – and dyslipidaemia, hypertension and hyperglycaemia while controlling for potential confounders in 1825 people from the Survey of High Impact Psychosis (SHIP) in Australia. We also aimed to identify clustering patterns of lifestyle risk factors and associated demographic variables. Methods Three logistic regressions were used to predict the effect of nutrition, smoking and physical activity on dyslipidaemia, hypertension and hyperglycaemia while controlling for clozapine use, sex and age. Clustering patterns of nutrition, smoking and physical activity were examined using the two-step cluster method which is based on hierarchical cluster analysis. Demographic variables associated with different clusters were identified using measures of association. Results Smoking status had a positive association with dyslipidaemia (adjusted odds ratio = 0.50; 95% confidence interval = 0.32–0.78; p  = 0.002). Other cardiovascular disease lifestyle risk factors did not have a significant relationship with dyslipidaemia, hypertension and hyperglycaemia. Clustering patterns of lifestyle risk factors showed that younger men, with low education levels, and relying on a government pension, were most likely to display the poorest lifestyle risk behaviours. The largest cluster (42%) of participants was characterised by a mixed demographic profile and were most likely to display poor nutrition and low physical activity levels but less likely to smoke. Conclusions Only smoking status had a significant positive association with dyslipidaemia which could indicate that there are additional factors affecting the relationship between other cardiovascular lifestyle risk factors and dyslipidaemia, hypertension and hyperglycaemia in people with psychosis. Unknown confounders and traditional lifestyle risk factors may explain the high rates of CVD in this group. Clustering of lifestyle risk factors and their demographic profiles could help the design of intervention programs in people with psychosis.

Restricted and repetitive behaviours (RRBs) are observed in many children presenting with characteristics of autism and are frequently the targets of psychological interventions. This study used Interpretative Phenomenological Analysis (IPA) to identify positive and negative interpretations from four young adults who received behavioural interventions in their childhood designed to ‘fix’ RRBs. Two superordinate themes were identified: (1) Doubt, stigma and being fixed according to others, and (2) Embracing Authenticity. They highlighted juxtaposed positions from exclusion, rejection, criticism, and self-doubt in childhood, to rejecting societal censure and embracing authentic growth in adult life. As adults, though the participants recognised themselves as neurologically different from others, they redefined themselves through a lens of neurodiversity, and therefore as not needing to be fixed.

Keratin 7 (K7) is a Type II member of the keratin superfamily and despite its widespread expression in different types of simple and transitional epithelia, its functional role in vivo remains elusive, in part due to the lack of any appropriate mouse models or any human diseases that are associated with KRT7 gene mutations. Using conventional gene targeting in mouse embryonic stem cells, we report here the generation and characterisation of the first K7 knockout mouse. Loss of K7 led to increased proliferation of the bladder urothelium although this was not associated with hyperplasia. K18, a presumptive type I assembly partner for K7, showed reduced expression in the bladder whereas K20, a marker of the terminally differentiated superficial urothelial cells was transcriptionally up-regulated. No other epithelia were seen to be adversely affected by the loss of K7 and western blot and immunofluorescence microscopy analysis revealed that the expression of K8, K18, K19 and K20 were not altered in the absence of K7, with the exception of the kidney where there was reduced K18 expression.

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10−6). Novel reciprocal case–control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.

The 22q11.2 deletion (22q11DS) is a common chromosomal microdeletion and a potent risk factor for psychotic illness. Prior studies reported widespread cortical changes in 22q11DS, but were generally underpowered to characterize neuroanatomic abnormalities associated with psychosis in 22q11DS, and/or neuroanatomic effects of variability in deletion size. To address these issues, we developed the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta-Analysis) 22q11.2 Working Group, representing the largest analysis of brain structural alterations in 22q11DS to date. The imaging data were collected from 10 centers worldwide, including 474 subjects with 22q11DS (age = 18.2 ± 8.6; 46.9% female) and 315 typically developing, matched controls (age = 18.0 ± 9.2; 45.9% female). Compared to controls, 22q11DS individuals showed thicker cortical gray matter overall (left/right hemispheres: Cohen’s d = 0.61/0.65), but focal thickness reduction in temporal and cingulate cortex. Cortical surface area (SA), however, showed pervasive reductions in 22q11DS (left/right hemispheres: d = −1.01/−1.02). 22q11DS cases vs. controls were classified with 93.8% accuracy based on these neuroanatomic patterns. Comparison of 22q11DS-psychosis to idiopathic schizophrenia (ENIGMA-Schizophrenia Working Group) revealed significant convergence of affected brain regions, particularly in fronto-temporal cortex. Finally, cortical SA was significantly greater in 22q11DS cases with smaller 1.5 Mb deletions, relative to those with typical 3 Mb deletions. We found a robust neuroanatomic signature of 22q11DS, and the first evidence that deletion size impacts brain structure. Psychotic illness in this highly penetrant deletion was associated with similar neuroanatomic abnormalities to idiopathic schizophrenia. These consistent cross-site findings highlight the homogeneity of this single genetic etiology, and support the suitability of 22q11DS as a biological model of schizophrenia.

Coparenting competence (CC) is a concept that describes the sense of collective efficacy that parents experience in raising children. An advantage of CC is that it bridges a gap between family systems thinking and efficacy theory, where extant research and theory have focused on the self-efficacy of one or both parents. This study aimed to develop a self-reported measure of CC. Methodology: Participants (n = 302), including cohabiting mothers (n = 240) and fathers (n = 62), completed an online survey (112 items) comprising demographic questions, the Coparenting Relationship Scale (CRS), the Parenting Sense of Competence Scale (PSOC), the Strengths and Difficulties Questionnaire (SDQ), and 36 items designed to explore perceptions of CC. Results: Factor analyses on 36-CC items identified 10 items that reliably formed a brief Coparenting Competence Scale (CCS; Alpha = 0.89). Analysis of convergent and divergent validity demonstrated that the CCS measures a unique construct that is linked to parenting self-efficacy, measured by PSOC (r = 0.47), and coparenting quality, assessed by the CRS (r = 0.63). There was a significant association between CCS and SDQ across age groups and an association stronger than that found for the CRS and SDQ in the current cohort. Conclusions and Implications: The study found support for the reliability and validity of the CCS. Coparenting competence, assessed by the CCS, was found to be distinct from factors previously used to represent coparenting quality in multivariate scales. The strength of associations between the CCS and SDQ suggests this new measure may have an important role in coparenting research.