We aimed to explore the effect of multiple pre- and postnatal exposures on optic nerve status in young adults due to this critical period for development.
We analysed peripapillary retinal nerve ...fibre layer (RNFL) status and macular thickness at age 18 years in the Copenhagen Prospective Studies on Asthma in Childhood 2000 (COPSAC
) cohort in relation to several exposures.
Of the 269 participants (median (IQR) age, 17.6 (0.6) years; 124 boys), 60 participants whose mothers had smoked during pregnancy had a thinner RNFL: adjusted mean difference -4.6 μm (95% CI -7.7; -1.5 μm, p = 0.004) compared with participants whose mothers had not smoked during pregnancy. A total of 30 participants who were exposed to tobacco smoke both during foetal life and childhood had thinner RNFL: -9.6 μm (-13.4; -5.8 μm, p < 0.001). Smoking during pregnancy was also associated with a macular thickness deficit: -4.7 μm (-9.0; -0.4 μm, p = 0.03). Higher indoor concentrations of particulate matter 2.5 (PM2.5) was associated with thinner RNFL: -3.6 μm (-5.6; -1.6 μm, p < 0.001) and a macular deficit: -2.7 μm (-5.3; -0.1 μm, p = 0.04) in the crude analyses, but not in the adjusted analyses. No difference was found among participants who smoked at age 18 years compared with non-smokers on RNFL or macular thickness.
We found that exposure to smoking during early life was associated with a thinner RNFL and macula at age 18 years. The absence of an association between active smoking at 18 years suggests that the vulnerability of the optic nerve is highest during prenatal life and early childhood.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
Randomized controlled trials (RCTs) suggest a protective effect of high‐dose vitamin D supplementation in pregnancy on offspring risk of persistent wheeze, but only in some individuals, ...which might be explained by variations in vitamin D pathway genes. This study aimed to investigate the effect of vitamin D supplementation by maternal and offspring vitamin D receptor (VDR) genotype and GC genotype, encoding vitamin D binding protein (VDBP), in two RCTs.
Methods
In the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010) RCT, we analyzed the effect of high‐dose vitamin D during pregnancy on the risk of persistent wheeze age 0‐3 years by variants in single nucleotide polymorphisms (SNPs) in VDR (rs1544410, rs2228570, rs7975128, rs7975232) and GC (rs4588, rs7041). Replication was sought in the Vitamin D Antenatal Asthma Reduction Trial (VDAART).
Results
In COPSAC2010, VDR SNP rs1544410 influenced the effect of high‐dose vitamin D: maternal Pinteraction = .049 and child Pinteraction = .001, with the largest effect in offspring from mothers with TT genotype: hazard ratio (95% CI), 0.26 (0.10‐0.68), P = .006, and no effect among CT or CC genotypes: 0.85 (0.48‐1.51), P = .58 and 0.94 (0.47‐1.89), P = .87, respectively. However, these findings were not replicated in VDAART. There was no significant effect modification from maternal or offspring GC genotype in either COPSAC2010 or VDAART: all Pinteraction ≥ .17.
Conclusions
We found that the effect of high‐dose vitamin D supplementation during pregnancy on offspring risk of persistent wheeze was significantly influenced by VDR genotype in the COPSAC2010 RCT, but not VDAART, which may be due to population differences.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Childhood allergic diseases, including asthma, rhinitis and eczema, are prevalent conditions that share strong genetic and environmental components. Diagnosis relies on clinical history and ...measurements of allergen-specific IgE. We hypothesize that a multi-omics model could accurately diagnose childhood allergic disease. We show that nasal DNA methylation has the strongest predictive power to diagnose childhood allergy, surpassing blood DNA methylation, genetic risk scores, and environmental factors. DNA methylation at only three nasal CpG sites classifies allergic disease in Dutch children aged 16 years well, with an area under the curve (AUC) of 0.86. This is replicated in Puerto Rican children aged 9-20 years (AUC 0.82). DNA methylation at these CpGs additionally detects allergic multimorbidity and symptomatic IgE sensitization. Using nasal single-cell RNA-sequencing data, these three CpGs associate with influx of T cells and macrophages that contribute to allergic inflammation. Our study suggests the potential of methylation-based allergy diagnosis.
Abstract
Background
Genome-wide association studies have identified several risk alleles for early childhood asthma, particularly in the 17q21 locus and in the cadherin-related family member 3 ...(CDHR3) gene. Contribution of these alleles to the risk of acute respiratory tract infections (ARI) in early childhood is unclear.
Methods
We analyzed data from the STEPS birth-cohort study of unselected children and the VINKU and VINKU2 studies on children with severe wheezing illness. Genome-wide genotyping was performed on 1011 children. We analyzed the association between 11 preselected asthma risk alleles and the risk of ARIs and wheezing illnesses of various viral etiologies.
Results
The asthma risk alleles in CDHR3, GSDMA, and GSDMB were associated with an increased rate of ARIs (for CDHR3, incidence rate ratio IRR, 1.06; 95% confidence interval CI, 1.01–1.12; P = .02), and risk allele in CDHR3 gene with rhinovirus infections (IRR, 1.10; 95% CI, 1.01–1.20, P = .03). Asthma risk alleles in GSDMA, GSDMB, IKZF3, ZPBP2, and ORMDL3 genes were associated with wheezing illnesses in early childhood, especially rhinovirus-positive wheezing illnesses.
Conclusions
Asthma risk alleles were associated with an increased rate of ARIs and an increased risk of viral wheezing illnesses. Nonwheezing and wheezing ARIs and asthma may have shared genetic risk factors.
Clinical Trials Registration. NCT00494624 and NCT00731575.
Previously identified asthma risk alleles were associated with an increased rate of acute respiratory infections in early childhood. Risk allele CDHR3, coding for rhinovirus species C receptor, was associated with an increased rate of rhinovirus infections.
The genetic consequences of population bottlenecks on patterns of deleterious genetic variation in human populations are of tremendous interest. Based on exome sequencing of 18 Greenlandic Inuit we ...show that the Inuit have undergone a severe ∼20,000-year-long bottleneck. This has led to a markedly more extreme distribution of allele frequencies than seen for any other human population tested to date, making the Inuit the perfect population for investigating the effect of a bottleneck on patterns of deleterious variation. When comparing proxies for genetic load that assume an additive effect of deleterious alleles, the Inuit show, at most, a slight increase in load compared to European, East Asian, and African populations. Specifically, we observe <4% increase in the number of derived deleterious alleles in the Inuit. In contrast, proxies for genetic load under a recessive model suggest that the Inuit have a significantly higher load (20% increase or more) compared to other less bottlenecked human populations. Forward simulations under realistic models of demography support our empirical findings, showing up to a 6% increase in the genetic load for the Inuit population across all models of dominance. Further, the Inuit population carries fewer deleterious variants than other human populations, but those that are present tend to be at higher frequency than in other populations. Overall, our results show how recent demographic history has affected patterns of deleterious variants in human populations.
The upper airways present a barrier to inhaled allergens and microbes, which alter immune responses and subsequent risk for diseases, such as allergic rhinitis (AR).
We tested the hypothesis that ...early-life microbial exposures leave a lasting signature in DNA methylation that ultimately influences the development of AR in children.
We studied upper airway microbiota at 1 week, 1 month, and 3 months of life, and measured DNA methylation and gene expression profiles in upper airway mucosal cells and assessed AR at age 6 years in children in the Copenhagen Prospective Studies on Asthma in Childhood birth cohort.
We identified 956 AR-associated differentially methylated CpGs in upper airway mucosal cells at age 6 years, 792 of which formed 3 modules of correlated differentially methylated CpGs. The eigenvector of 1 module was correlated with the expression of genes enriched for lysosome and bacterial invasion of epithelial cell pathways. Early-life microbial diversity was lower at 1 week (richness P = .0079) in children with AR at age 6 years, and reduced diversity at 1 week was also correlated with the same module’s eigenvector (ρ = −0.25; P = 3.3 × 10−5). We show that the effect of microbiota richness at 1 week on risk for AR at age 6 years was mediated in part by the epigenetic signature of this module.
Our results suggest that upper airway microbial composition in infancy contributes to the development of AR during childhood, and this trajectory is mediated, at least in part, through altered DNA methylation patterns in upper airway mucosal cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A link among sphingolipids, 17q21 genetic variants, and childhood asthma has been suggested, but the underlying mechanisms and characteristics of such an asthma endotype remain to be elucidated.
To ...study the sphingolipid-associated childhood asthma endotype using multiomic data.
We used untargeted liquid chromatography-mass spectrometry plasma metabolomic profiles at the ages of 6 months and 6 years from more than 500 children in the COPSAC
(Copenhagen Prospective Studies on Asthma in Childhood) birth cohort focusing on sphingolipids, and we integrated the 17q21 genotype and nasal gene expression of SPT (serine palmitoyl-CoA transferase) (i.e., the rate-limiting enzyme in
sphingolipid synthesis) in relation to asthma development and lung function traits from infancy until the age 6 years. Replication was sought in the independent VDAART (Vitamin D Antenatal Asthma Reduction Trial) cohort.
Lower concentrations of ceramides and sphingomyelins at the age of 6 months were associated with an increased risk of developing asthma before age 3, which was also observed in VDAART. At the age of 6 years, lower concentrations of key phosphosphingolipids (e.g., sphinganine-1-phosphate) were associated with increased airway resistance. This relationship was dependent on the 17q21 genotype and nasal SPT gene expression, with significant interactions occurring between the genotype and the phosphosphingolipid concentrations and between the genotype and SPT expression, in which lower phosphosphingolipid concentrations and reduced SPT expression were associated with increasing numbers of at-risk alleles. However, the findings did not pass the false discovery rate threshold of <0.05.
This exploratory study suggests the existence of a childhood asthma endotype with early onset and increased airway resistance that is characterized by reduced sphingolipid concentrations, which are associated with 17q21 genetic variants and expression of the SPT enzyme.
Asthma with severe exacerbation is the most common cause of hospitalization among young children. We aim to increase the understanding of this clinically important disease entity through a ...genome-wide association study. The discovery analysis comprises 2866 children experiencing severe asthma exacerbation between ages 2 and 6 years, and 65,415 non-asthmatic controls, and we replicate findings in 918 children from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) birth cohorts. We identify rs281379 near FUT2/MAMSTR on chromosome 19 as a novel risk locus (OR = 1.18 (95% CI = 1.11-1.25), P
= 2.6 × 10
) as well as a biologically plausible interaction between functional variants in FUT2 and ABO. We further discover and replicate a potential causal mechanism behind this interaction related to S. pneumoniae respiratory illnesses. These results suggest a novel mechanism of early childhood asthma and demonstrates the importance of phenotype-specificity for discovery of asthma genes and epistasis.
Prenatal vitamin D
supplementation has been linked to reduced risk of early life asthma/recurrent wheeze. This protective effect appears to be influenced by variations in the 17q21 functional SNP ...rs12936231 of the child, which regulates the expression of
and for which the high-risk CC-genotype is associated with early-onset asthma. However, this does not fully explain the differential effects of supplementation. We investigated the influence of maternal rs12936231 genotype variation on the protective effect of prenatal vitamin D
supplementation against offspring asthma/recurrent wheeze.
We determined the rs12936231 genotype of mother-child pairs from two randomised-controlled trials: the Vitamin D Antenatal Asthma Reduction Trial (VDAART, n=613) and the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC
, n=563) to examine the effect of maternal genotype variation on offspring asthma/recurrent wheeze at age 0-3 years between groups who received high-dose prenatal vitamin D
supplementation
placebo.
Offspring of mothers with low-risk GG-genotype or GC-genotype who received high-dose vitamin D
supplementation had a significantly reduced risk of asthma/recurrent wheeze when compared to the placebo group (hazard ratio HR, 0.54; 95% confidence interval CI, 0.37-0.77; p<0.001 for VDAART and HR, 0.56; 95% CI, 0.35-0.92; p=0.021 for COPSAC
), whereas no difference was observed among the offspring of mothers with high-risk CC-genotype (HR, 1.05; 95% CI, 0.61-1.84; p=0.853 for VDAART and HR, 1.11; 95% CI, 0.54-2.28; p=0.785 for COPSAC
).
Maternal 17q21 genotype has an important influence on the protective effects of prenatal vitamin D
supplementation against offspring asthma/recurrent wheeze.
•Pre-post COVID-19 lockdown comparison on neuropsychiatric outcomes in children.•We explored the role of genetic risk to ADHD on pre-post difference.•There was a significant increase of ...neuropsychiatric outcomes post-lockdown.•We found an interaction of lockdown X genetic risk to ADHD.•Mainly children with high genetic risk to ADHD showed worsening of symptoms.
Previous studies report that the COVID-19 lockdown had an impact on the mental health of the pediatric population. In this study, we harness the deep neuropsychiatric phenotyping of the population-based COPSAC2010 (n = 700) cohort at age 10 to study the impact of the COVID-19 lockdown on mental health outcomes with focus on the role of the genetic vulnerability to attention-deficit/hyperactivity disorder (ADHD), in the form of polygenic risk scores (PRS). A total of 593 children were examined between 2019 and 2021, resulting in two groups of different children, those evaluated before the lockdown (n = 230) and those evaluated after (n = 363). Children assessed after the lockdown presented higher odds of being diagnosed with ADHD and had significantly higher scores in most neuropsychiatric scales, particularly in subscales pertaining to behavior and attention problems. We observed a significant interaction between the lockdown and ADHD PRS on several neuropsychiatric dimensions, with a large post-lockdown increase in children with a high PRS, while there was little to no pre-post difference in children with low PRS. These results indicate mental health consequences of the lockdown in children and suggest that genetically susceptible individuals are more affected by such stressors in childhood.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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