Biology subjects

Saffery, R.

Publications and source records attributed to Saffery, R..

11 recordsLinked to original sources

bioRxiv2026

Genetic, intrinsic, and environmental determinants of innate immune cytokine responses in healthy four-year-old children

Abstract/SummaryInnate immune responses are crucial for host defence but vary markedly between individuals. Although determinants of this variation are well characterised in adults, data from healthy children remain scarce. We therefore profiled whole-blood cytokine responses to innate immune stimulation in 286 children aged approximately four years and examined genetic, host-intrinsic, and environmental correlates of response. Cytokine responses showed marked inter-individual heterogeneity and stimulus-specific patterns. The top 50 genetic variants explained a substantial proportion ([~]20-45%) of this variance across many stimulus conditions, including a biologically coherent association of the STING locus with cGAMP-induced cytokine production. In contrast, sex, age, adiposity, and perinatal variables showed limited or modest associations. Systemic inflammatory biomarkers of systemic inflammation (hsCRP, glycoprotein acetyls, granulocyte-to-lymphocyte ratio) were strongly positively associated with cytokine responses. Finally, seasonal population-level viral infection burden was positively associated with antiviral and inflammatory cytokine responses. Collectively, these findings advance our understanding of variation in early-life whole-blood cytokine responses, underscoring this developmental period as a critical window for understanding immune development trajectories relevant to long-term health.

immunology↗

bioRxiv2025

Skin microbiome composition and function in the development of atopic diseases during infancy

BackgroundAtopic dermatitis (AD), food sensitization (FS), and food allergy (FA) frequently co-occur in infancy, but the factors driving distinct atopic phenotypes remain unclear. While FLG null mutations are major genetic risk factors for AD, they explain only a fraction of disease heritability, suggesting a potential role for the skin microbiome. ObjectiveTo determine how early-life skin microbiome composition and its interaction with host genetics contribute to distinct atopic phenotypes in infancy. MethodsWe analyzed >1,000 skin swabs from 429 infants in the VITALITY cohort using deep shotgun metagenomic sequencing at 2-3 months (pre-diagnosis) and 12 months (post-diagnosis). Differential abundance, strain-level, and microbial genome-wide association analyses were performed to identify taxonomic and functional features associated with AD, FS, FA, and their co-occurrence, as well as with FLG mutation status. ResultsWithin AD, microbial signatures differed by co-occurring FA or FS. At 12 months, Staphylococcus epidermidis was enriched in infants with AD alone, whereas infants with AD and FA exhibited decreased Staphylococcus hominis and Lactococcus species, along with increased Dermacoccus nishinomiyaensis and Malassezia slooffiae. At 2-3 months, early skin dysbiosis characterized by enrichment of Staphylococcus species was associated with subsequent development of AD with FS or FA, but not AD alone. Among infants with AD, FLG mutation carriers exhibited additional microbial shifts, including reduced Streptococcus species and increased Malassezia slooffiae. Strain-level analyses revealed mother-infant sharing of skin microbial taxa associated with AD, and microbial genome-wide association analyses identified species-specific genes linked to AD severity. ConclusionsInfant atopic phenotypes are associated with distinct, phenotype-specific features of the skin microbiome that emerge both before and after clinical disease onset. By resolving microbial differences within AD according to allergic co-occurrence, host genetics, and early-life timing, this study highlights the infant skin microbiome as a potential target for early risk stratification.

microbiology↗

bioRxiv2025

Prenatal Environmental Determinants of Aromatase Brain-Promoter Methylation in Cord Blood: Chemical, Airborne, Pharmacological, and Nutritional Factors

Aromatase, an enzyme encoded by the gene CYP19A1, plays central roles in neurodevelopment. In the brain, its function is to convert androgens into neuroestrogens, ensuring balanced hormonal signalling. Both animal experiments and human studies have shown that, in males, disruption of aromatase, either genetically or epigenetically, can increase symptoms of autism. Prenatal exposure to bisphenol A (BPA), a common plastic chemical, can increase levels of DNA methylation--a key epigenetic modification--at the brain-specific CYP19A1 promoter, P1.f, reducing CYP19A1 expression. However, the extent to which other neurodevelopmentally relevant environmental exposures influence P1.f methylation remains unclear. Here, in the Barwon Infant Study (BIS) birth cohort (N = 906), we analysed the association between 25 prenatal exposures (from five classes previously linked to neurodevelopmental outcomes: manufactured chemicals, air pollution, and pharmacological, nutrition and sunlight-related factors) and methylation of the CYP19A1 P1.f promoter using Weighted Quantile Sum (WQS) regression. We found that the WQS mixture index, a weighted combination of the prenatal exposures, was positively associated with higher P1.f methylation (Adjusted Mean Difference (AMD) = 0.712 (95% CI 0.11, 1.315), p = 0.021), indicating reduced brain aromatase activity. Prenatal exposures with the strongest contribution to the mixture effect included bisphenols (including BPA), reduced sunlight, household mould, phthalates, low folate intake, and air pollution. These findings highlight epigenetic modification of the aromatase gene as a biologically plausible, convergent mechanism through which multiple environmental risk factors for autism may exert effects.

genomics↗

bioRxiv2025

Prenatal DEHP plastic chemical exposure increases the likelihood of child autism and ADHD symptoms through epigenetic programming

Increasing evidence implicates prenatal exposure to di-(2-ethylhexyl) phthalate (DEHP), a common endocrine-disrupting plastic chemical, in autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). However, the underlying mechanisms are poorly understood. Here we examined whether cord blood DNA methylation, a key epigenetic marker, mediates the association between prenatal DEHP exposure and ASD/ADHD symptoms in 847 children enrolled in the Barwon Infant Study. ASD and ADHD are complex phenotypes characterised by differences at the gene regulatory network and neuronal circuit level, where heterogeneous genetic and environmental risk factors converge. Accordingly, we employed a data-driven computational strategy that helped elucidate broader functional epigenetic signatures of ASD and ADHD elicited by DEHP exposure. This included (1) a methylation profile score for DEHP exposure (MPSDEHP), and (2) an analysis of co-methylated gene networks. Causal mediation analysis demonstrated that both MPSDEHP and a DEHP-associated network of co-methylated genes mediated the effect of DEHP exposure on increased ASD and ADHD symptoms at ages 2 and 4 years (proportion of effect mediated ranged from 0.21 to 0.80). The co-methylation network was enriched for neural cell-type markers, ASD risk genes (including FOXP1, SHANK2, and PLXNB1), and targets of endocrine receptors previously linked to DEHP (including targets of the estrogen receptor ER and the glucocorticoid receptor GR), providing biological plausibility. We validated key results in independent blood (n=66) and postmortem brain (n=40) DNA methylation datasets. These findings provide mechanistic evidence linking DEHP to ASD and ADHD symptoms and reinforce growing concerns regarding the risks of prenatal exposure.\n\nSignificanceExposure to endocrine-disrupting plastic chemicals has been linked to adverse neurodevelopment, but the underlying biological mechanisms remain unclear. We demonstrate that prenatal exposure to di-(2-ethylhexyl) phthalate (DEHP), a common plasticizer, increases autism and ADHD symptoms through alterations in DNA methylation, a key epigenetic regulator of gene activity. Using birth cohort data, we identify epigenetic signatures of prenatal DEHP exposure, including alterations in an endocrine-related co-methylation network enriched for neural cell-type markers and known autism-associated genes. These signatures mediate the effects of DEHP on autism and ADHD symptoms and are also associated with autism in external blood and postmortem-brain datasets, providing independent validation. This causal evidence further underscores concerns regarding the consequences of prenatal plastic-chemical exposure on the developing brain.

neuroscience↗

bioRxiv2023

A genome catalog of the early-life human skin microbiome

Metagenome-assembled genomes have greatly expanded the reference genomes for skin microbiome. However, the current reference genomes are largely based on samples from adults in North America and lack representation from infants and individuals from other continents. Here we used ultra-deep shotgun metagenomic sequencing to profile the skin microbiota of 215 infants at age 2-3 months and 12 months who were part of the VITALITY trial in Australia as well as 67 maternally-matched samples. Based on the infant samples, we present the Early-Life Skin Genomes (ELSG) catalog, comprising 9,194 bacterial genomes from 1,029 species, 206 fungal genomes from 13 species, and 39 eukaryotic viral sequences. This genome catalog substantially expands the diversity of species previously known to comprise human skin microbiome and improves the classification rate of sequenced data by 25%. The protein catalog derived from these genomes provides insights into the functional elements such as defense mechanisms that distinguish early-life skin microbiome. We also found evidence for vertical transmission at the microbial community, individual skin bacterial species and strain levels between mothers and infants. Overall, the ELSG catalog uncovers the skin microbiome of a previously underrepresented age group and population and provides a comprehensive view of human skin microbiome diversity, function, and transmission in early life.

genomics↗

bioRxiv2022

The X-factor in ART: does the use of Assisted Reproductive Technologies influence DNA methylation on the X chromosome?

BackgroundAssisted reproductive technologies (ART) may perturb DNA methylation (DNAm) in early embryonic development. Although a handful of epigenome-wide association studies of ART have been published, none have investigated CpGs on the X chromosome. To bridge this knowledge gap, we leveraged one of the largest collections of mother-father-newborn trios of ART and non-ART (natural) conceptions to date to investigate DNAm differences on the X chromosome. Materials and MethodsThe discovery cohort consisted of 982 ART and 963 non-ART trios from the Norwegian Mother, Father, and Child Cohort Study (MoBa). The replication cohort consisted of 149 ART and 58 non-ART neonates from the Australian "Clinical review of the Health of adults conceived following Assisted Reproductive Technologies" (CHART) study. The Illumina EPIC array was used to measure DNA methylation (DNAm) in both datasets. In the MoBa cohort, we performed a set of X-chromosome-wide association studies ("XWASs" hereafter) to search for sex-specific DNAm differences between ART and non-ART newborns. We tested several models to investigate the influence of various confounders, including parental DNAm. We also searched for differentially methylated regions (DMRs) and regions of co-methylation flanking the most significant CpGs. For replication purposes, we ran an analogous model to our main model on the CHART dataset. Results and conclusionsIn the MoBa cohort, we found more differentially methylated CpGs and DMRs in girls than boys. Most of the associations persisted even after controlling for parental DNAm and other confounders. Many of the significant CpGs and DMRs were in gene-promoter regions, and several of the genes linked to these CpGs are expressed in tissues relevant for both ART and sex (testis, placenta, and fallopian tube). We found no support for parental infertility as an explanation for the observed associations in the newborns. The most significant CpG in the boys-only analysis was in UBE2DNL, which is expressed in testes but with unknown function. The most significant CpGs in the girls-only analysis were in EIF2S3 and AMOT. These three loci also displayed differential DNAm in the CHART cohort. Overall, genes that co-localized with the significant CpGs and DMRs are implicated in several key biological processes (e.g., neurodevelopment) and disorders (e.g., intellectual disability and autism. These connections are particularly compelling in light of previous findings indicating that neurodevelopmental outcomes differ in ART-conceived children compared to naturally-conceived.

genetics↗

bioRxiv2022

Genomic contributions to infant and toddler vocabulary scores: Implications for association with health-, cognition- and behaviour-related outcomes

BackgroundThe number of words children produce (expressive vocabulary) and understand (receptive vocabulary) changes rapidly during early development, partially due to genetic factors, although mechanisms are not well understood. Here, we performed a meta-genome-wide association study within the EAGLE consortium and investigated polygenic overlap with later-life traits, including Attention-Deficit/Hyperactivity Disorder (ADHD) and cognition. MethodsWe studied 37,913 parent-reported vocabulary size measures (English, Dutch, Danish) for 17,298 children of European descent. Meta-analyses were performed for early-phase expressive (infancy, 15-18 months), late-phase expressive (toddlerhood, 24-38 months) and late-phase receptive (toddlerhood, 24-38 months) vocabulary. Subsequently, we estimated Single-Nucleotide Polymorphism heritability (SNP-h2), genetic correlations (rg) and modelled underlying genetic factor structures with multivariate models. ResultsContributions of common genetic variation to early-life vocabulary were modest (SNP-h2: 0.08(SE=0.01) to 0.24(SE=0.03)) and multi-factorial. Genetic overlap between infant expressive and toddler receptive vocabulary was near zero (rg=0.07(SE=0.10)), although both measures were genetically related to toddler expressive vocabulary (rg=0.69(SE=0.14) and rg=0.67(SE=0.16), respectively). Consistently, polygenic association patterns with later-life traits differed: Genetic links with cognition emerged only in toddlerhood (e.g. toddler receptive vocabulary and intelligence: rg=0.36(SE=0.12)), despite comparable study power for infant measures. Furthermore, increased polygenic ADHD risk was associated with larger infant expressive vocabulary (rg=0.23(SE=0.08)), as confirmed by ADHD-symptom-based follow-up analyses in the Avon Longitudinal Study of Parents and Children (ALSPAC-rg=0.54(SE=0.26)). Genetic relationships with toddler receptive vocabulary were, however, opposite (ALSPAC-rg=-0.74(SE=0.23)), highlighting developmental changes in genetic architectures. ConclusionsMultiple genetic components contribute to early-life vocabulary development, shaping polygenic association patterns with later-life ADHD symptoms and cognition.

genomics↗

bioRxiv2021

Developmental and Intergenerational Landscape of Human Circulatory Lipidome and its Association with Obesity Risk

Lipids play a vital role in human health and development, but changes to their circulatory levels during gestation and in early life are poorly understood. Here we present the first developmental and intergenerational landscape of the human circulatory lipidome, derived by profiling of 480 lipid species representing 25 lipid classes, in mothers and their offspring (n=2491). Levels of 66% of the profiled lipids increased in maternal circulation during gestation, while cord blood had higher concentrations of acylcarnitines and lysophospholipids. The offspring lipidome at age six years revealed striking similarities with postnatal maternal lipidome (adult) in its lipid composition and concentrations. Comparison of lipids associated with child and maternal adiposity identified a 92% overlap, implying intergenerational similarities in the lipid signatures of obesity risk. We also catalogued lipid signatures linked with maternal adiposity during gestation and offspring birthweight, and validated (>70% overlap) the findings in an independent birth-cohort (n=1935).

systems biology↗

bioRxiv2021

Application of high dimensional flow cytometry and unsupervised analysis to define the immune cell landscape of early childhood respiratory and blood compartments

The cellular landscape of the paediatric respiratory system remains largely uncharacterised and as a result, the mechanisms of highly prevalent childhood respiratory diseases remain poorly understood. A major limitation in defining mechanisms of disease has been the availability of tissue samples collected in early life, as well as technologies that permit deep immune analysis from limited sample volumes. In this work, we developed new experimental methods and applied unsupervised analytical tools to profile the local (bronchoalveolar lavage) and systemic (whole blood) immune response in childhood respiratory disease. We quantified and comprehensively phenotyped immune cell populations across blood and lung compartments in young children (under 6 years of age), showed that inflammatory cells in the BAL express higher levels of activation and migration markers relative to their systemic counterparts, and applied new analytical tools to reveal novel tissue-resident macrophage and infiltrating monocyte populations in the paediatric lung. To our knowledge, this is the first description of the use of these methods for paediatric respiratory samples. Combined with matched analysis of the systemic immune cell profile, the application of these pipelines will increase our understanding of childhood lung disease with potential to identify clinically relevant disease biomarkers.

immunology↗

bioRxiv2018

Supragingival plaque microbiome ecology and functional potential in the context of health and disease

To address the question of how microbial diversity and function in the oral cavities of children relates to caries diagnosis, we surveyed the supragingival plaque biofilm microbiome in 44 juvenile twin pairs. Using shotgun sequencing, we constructed a genome encyclopedia describing the core supragingival plaque microbiome. Caries phenotypes contained statistically significant enrichments in specific genome abundances and distinct community composition profiles including strain-level changes. Metabolic pathways that are statistically associated with caries include several sugar-associated phosphotransferase systems, antimicrobial resistance, and metal transport. Numerous closely-related previously-uncharacterized microbes had substantial variation in central metabolism, including the loss of biosynthetic pathways resulting in auxotrophy, changing the ecological role. We also describe the first complete Gracilibacteria genomes from the human microbiome. Caries is a microbial community metabolic disorder that cannot be described by a single etiology and our results provide the information needed for next generation diagnostic tools and therapeutics for caries.

microbiology↗

bioRxiv2017

Inference about causation between body mass index and DNA methylation in blood from a twin family study

BackgroundSeveral studies have reported DNA methylation in blood to be associated with body mass index (BMI), but only a few have investigated causal aspects of the association. We used a twin family design to assess this association at two life points and applied a novel analytical approach to investigate the evidence for causality.\n\nMethodsThe methylation profile of DNA from peripheral blood was measured for 479 Australian women (mean age 56 years) from 130 twin families. Linear regression was used to estimate the associations of methylation at ~410 000 cytosine-guanine dinucleotides (CpG), and of the average methylation at ~20 000 genes, with current BMI, BMI at age 18-21 years, and the change between the two (BMI change). A novel regression-based methodology for twins, Inference about Causation through Examination of Familial Confounding (ICE FALCON), was used to assess causation.\n\nResultsAt 5% false discovery rate, nine, six and 12 CpGs at 24 loci were associated with current BMI, BMI at age 18-21 years and BMI change, respectively. The average methylation of BHLHE40 and SOCS3 loci was associated with current BMI, and of PHGDH locus was associated with BMI change. From the ICE FALCON analyses with BMI as the predictor and methylation as the outcome, a womans methylation level was associated with her co-twins BMI, and the association disappeared conditioning on her own BMI, consistent with BMI causing methylation. To the contrary, using methylation as the predictor and BMI as the outcome, a womans BMI was not associated with her co-twins methylation level, consistent with methylation not causing BMI.\n\nConclusionFor middle-aged women, peripheral blood DNA methylation at several genomic locations is associated with current BMI, BMI at age 18-21 years and BMI change. Our study suggests that BMI has a causal effect on peripheral blood DNA methylation.

epidemiology↗