•The heritability for bipolar disorder was 60% using a novel statistical approach taking into account available time of follow-up, and controlling for sex and year of birth.•The heritability was ...similar to previous family studies performed on the Swedish register data, using traditional twin-modeling methods, indicating that previous methodology have been sufficient.•We detected no influence from common environmental factors in our heritability analysis, due to lack of power. Future studies using transnational twin cohorts to expand the sample-size are needed.•The prevalence for bipolar disorder was higher in females, but genetic factors did not contribute to those sex-differences.
Twin- and family studies have shown variations in the heritability estimates of bipolar disorder (BPD). The current study uses an updated statistical methodology for heritability estimation in BPD by taking available time of follow-up into account while controlling for co-variates. We identified monozygotic and dizygotic same and different sex twins with BPD (n = 804) or unaffected from BPD (n = 91,604) from the Swedish Twin Register and the National Patient Register. We applied structural equational modeling with inversed probability weighting to estimate the heritability, taking into account censoring and truncation of data. Sex-limitation models were constructed to analyze qualitative or quantitative sex-differences in BPD. Heritability for BPD was 60.4% (95% Confidence Interval: 50.3–70.5) after age, sex, left-hand truncation and censoring of the data was taken into account. A larger proportion of females were affected from BPD (females 62.2%; males 37.8%, p < 0.001), but no sex-difference in BPD heritability was found, nor any sex-specific genetic effects. We demonstrated a robust 60% heritability for BPD with no evidence of sex-specific genetic effects on disease liability.
Although development of microbiota in childhood has been linked to chronic immune-related conditions, early childhood determinants of microbiota development have not been fully elucidated. We used ...16S rRNA sequencing to analyse faecal and saliva samples from 83 children at four time-points during their first 2 years of life and from their mothers. Our findings confirm that gut microbiota in infants have low diversity and highlight that some properties are shared with the oral microbiota, although inter-individual differences are present. A considerable convergence in gut microbiota composition was noted across the first 2 years of life, towards a more diverse adult-like microbiota. Mode of delivery accounted for some of the inter-individual variation in early childhood, but with a pronounced attenuation over time. Our study extends previous research with further characterization of the major shift in gut microbiota composition during the first 2 years of life.
Aging is classically conceptualized as an ever-increasing trajectory of damage accumulation and loss of function, leading to increases in morbidity and mortality. However, recent in vitro studies ...have raised the possibility of age reversal. Here, we report that biological age is fluid and exhibits rapid changes in both directions. At epigenetic, transcriptomic, and metabolomic levels, we find that the biological age of young mice is increased by heterochronic parabiosis and restored following surgical detachment. We also identify transient changes in biological age during major surgery, pregnancy, and severe COVID-19 in humans and/or mice. Together, these data show that biological age undergoes a rapid increase in response to diverse forms of stress, which is reversed following recovery from stress. Our study uncovers a new layer of aging dynamics that should be considered in future studies. The elevation of biological age by stress may be a quantifiable and actionable target for future interventions.
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•Biological age undergoes rapid fluctuations in mice and humans•Severe stress induces increases in biological age that are reversed upon recovery•Parabiosis, surgery, pregnancy, and COVID-19 transiently elevate biological age•Biological age recovery rate may predict gerotherapeutics
Poganik et al. analyzed various models of severe stress in mice and humans and found that stress transiently elevates biological age as readout by multiple advanced biomarkers of aging. They demonstrate that biological age is not static, but dynamic.
Genome-wide association studies (GWAS) have contributed to our understanding of glioma susceptibility. To date, 25 risk loci for development of any of the glioma subtypes are known. However, GWAS ...studies reveal little about the molecular processes that lead to increased risk, especially for non-coding single nucleotide polymorphisms (SNP). A particular SNP in intron 2 of LRIG1, rs11706832, has been shown to increase the susceptibility for IDH1 mutated low-grade gliomas (LGG). Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) is important in cancer development as it negatively regulates the epidermal growth factor receptor (EGFR); however, the mechanism responsible for this particular risk SNP and its potential effect on LRIG1 are not known. Using CRISPR-CAS9, we edited rs11706832 in HEK293T cells. Four HEK293T clones with the risk allele were compared to four clones with the non-risk allele for LRIG1 and SLC25A26 gene expression using RT-qPCR, for global gene expression using RNA-seq, and for metabolites using gas chromatography-mass spectrometry (GC-MS). The experiment did not reveal any significant effect of the SNP on the expression levels or splicing patterns of LRIG1 or SLC25A26. The global gene expression analysis revealed that the risk allele C was associated with upregulation of several mitochondrial genes. Gene enrichment analysis of 74 differentially expressed genes in the genome revealed a significant enrichment of type I interferon response genes, where many genes were downregulated for the risk allele C. Gene expression data of IDH1 mutated LGGs from the cancer genome atlas (TCGA) revealed a similar under expression of type I interferon genes associated with the risk allele. This study found the expression levels and splicing patterns of LRIG1 and SLC25A26 were not affected by the SNP in HEK293T cells. However, the risk allele was associated with a downregulation of genes involved in the innate immune response both in the HEK293T cells and in the LGG data from TCGA.
The maternal immune system is going through considerable changes during pregnancy. However, little is known about the determinants of the inflammatory proteome and its relation to pregnancy stages. ...Our aim was to investigate the plasma inflammatory proteome before, during and after pregnancy. In addition we wanted to test whether maternal and child outcomes were associated with the proteome. A cohort of 94 healthy women, enrolled in a longitudinal study with assessments at up to five time points around pregnancy, ninety-two inflammatory proteins were analysed in plasma with a multiplex Proximity Extension Assay. First, principal components analysis were applied and thereafter regression modelling while correcting for multiple testing. We found profound shifts in the overall inflammatory proteome associated with pregnancy stage after multiple testing (p < .001). Moreover, maternal body mass index (BMI) was associated with inflammatory proteome primarily driven by VEGFA, CCL3 and CSF-1 (p < .05). The levels of most inflammatory proteins changed substantially during pregnancy and some of these were related to biological processes such as regulation of immune response. Maternal BMI was significantly associated with higher levels of three inflammation proteins calling for more research in the interplay between pregnancy, inflammation and BMI.
Background
Immunoglobulin E (IgE) sensitization is associated with asthma and allergic diseases. Gestational age influences early immune system development, thereby potentially affecting the process ...of tolerance induction to allergens.
Objective
To study IgE sensitization to common allergens by gestational age from childhood up to early adulthood.
Methods
Population‐based birth cohort, data from the Swedish BAMSE study were used. Allergen‐specific IgE antibodies to a mix of common food (fx5) and inhalant (Phadiatop) allergens were analysed at 4, 8, 16 and 24 years. Sensitization was defined as allergen‐specific IgE ≥0.35 kUA/L to fx5 and/or Phadiatop at each time point. Using logistic regression and generalized estimated equations, adjusted odds ratios (aORs) for sensitization in relation to gestational age were calculated. Replication was sought within the Swedish twin study STOPPA.
Results
In BAMSE, 3522 participants were screened for IgE antibodies during follow‐up; of these, 197 (5.6%) were born preterm (<37 gestational weeks) and 330 (9.4%) post‐term (≥42 weeks). Preterm birth reduced the risk of sensitization to common food and/or inhalant allergens up to early adulthood by 29% (overall aOR = 0.71; 95% CI: 0.52–0.98), and to food allergens specifically by 40% (overall aOR = 0.60; 95% CI: 0.38–0.93). No relation was found between post‐term birth and IgE sensitization at any time point. Replication analyses in STOPPA (N = 675) showed similar risk estimates for sensitization to food and/or inhalant allergens (aOR = 0.72; 95% CI: 0.42–1.21), which resulted in a combined meta‐analysis aOR = 0.71 (95% CI: 0.54–0.94).
Conclusions
Our study suggests an inverse association between preterm birth and long‐term IgE sensitization.
This population‐based Swedish birth cohort study of 3522 infants followed prospectively up to early adulthood assessed the impact of gestational age on IgE sensitization. Preterm birth (<37 weeks) was inversely associated with sensitization to common food and/or inhalant allergens and to food allergens separately. No clear association was found between post‐term birth and IgE sensitization up to the age 24 years.Abbreviations: BAMSE, Barn/Children, Allergy, Milieu, Stockholm, Epidemiology; STOPPA, Swedish Twin study On Prediction and Prevention of Asthma.
Many guidance receptors are proteolytically cleaved by membrane-associated metalloproteases of the ADAM family, leading to the shedding of their ectodomains. Ectodomain shedding is crucial for ...receptor signaling and function, but how this process is controlled in neurons remains poorly understood. Here, we show that the transmembrane protein Lrig2 negatively regulates ADAM-mediated guidance receptor proteolysis in neurons. Lrig2 binds Neogenin, a receptor for repulsive guidance molecules (RGMs), and prevents premature Neogenin shedding by ADAM17 (TACE). RGMa reduces Lrig2-Neogenin interactions, providing ADAM17 access to Neogenin and allowing this protease to induce ectodomain shedding. Regulation of ADAM17-mediated Neogenin cleavage by Lrig2 is required for neurite growth inhibition by RGMa in vitro and for cortical neuron migration in vivo. Furthermore, knockdown of Lrig2 significantly improves CNS axon regeneration. Together, our data identify a unique ligand-gated mechanism to control receptor shedding by ADAMs and reveal functions for Lrigs in neuron migration and regenerative failure.
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•Lrig2 negatively regulates ectodomain shedding of Neogenin by ADAM17•RGMa inhibits Lrig2-Neogenin binding, allowing ADAM17-mediated cleavage of Neogenin•Lrig2 controls neuron migration, and Lrig2 knockdown improves axon regeneration•Lrig2 inhibits ectodomain shedding of multiple, distinct ADAM17 substrates
How proteolytic cleavage of cell-surface proteins is controlled in neurons is incompletely understood. Van Erp and van den Heuvel et al. show that Lrig2 negatively regulates ADAM17-mediated ectodomain shedding of the guidance receptor Neogenin. This process is required for proper neuron migration during embryonic development and during axon regeneration.
Abstract Monozygotic (MZ) twins are often thought to have identical genomes, but recent work has shown that early post-zygotic events can result in a spectrum of DNA variants that are different ...between MZ twins. Such variants may explain phenotypic discordance and contribute to disease etiology. Here we performed whole genome sequencing in 17 pairs of MZ twins discordant for a psychotic disorder (schizophrenia, schizoaffective disorder or bipolar disorder). We examined various classes of rare variants that are discordant within a twin pair. We identified four genes harboring rare, predicted deleterious missense variants that were private to an affected individual in the cohort. Variants in FOXN1 and FLOT2 would have been categorized as damaging from recent schizophrenia and bipolar exome sequencing studies. Additionally, we identified four rare genic copy number variants (CNVs) private to an affected sample, two of which overlapped genes that have shown evidence for association with schizophrenia or bipolar disorder. One such CNV was a 3q29 duplication previously implicated in autism and developmental delay. We have performed the largest MZ twin study for discordant psychotic phenotypes to date. These findings warrant further investigation using other analytical approaches.
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