Mother adversity and co-residence time impact mother-child similarity in genome-wide and gene-specific methylation profiles.

BACKGROUND: The effects of adverse life events on physical and psychological health, with DNA methylation (DNAm) as a critical underlying mechanism, have been extensively studied. However, the epigenetic resemblance between mother and child in the context of neglectful caregiving, and whether it may be shaped by the emotional impact of maternal stressful events and the duration of co-residence (indexed by child age), remains unknown. The present study examined mother-child similarity in methylation profiles, considering the potential effect of mother adversity, mother empathy, neglect-control group, child age (an index of years of mother-child co-residence), and mother age. Using Illumina Epic arrays, we quantified DNAm in 115 mother-child saliva samples. We obtained a methylation similarity index by computing correlation coefficients between methylation profiles within dyads, for the entire epigenome, and five specific genes related to stress and empathy: NR3C1, FKPB5, OXTR, SCL6A4, and BDNF. RESULTS: The methylation profiles of the mother-child familial pairs significantly correlated as compared to mother-child random pairs for the entire epigenome and NR3C1, FKBP5, OXTR and BDNF genes. Next, multiple linear regression models observed associations of mother adversity, child age, and neglect-control group on mother-child methylation similarity, only significant in mother-child familial pairs, after correcting for multiple comparisons. Higher mother adversity was associated with lower mother-child methylation similarity for the epigenome-wide analysis, for the BDNF gene, and in the neglect-control group for the OXTR gene. In turn, being an older child (longer co-residence) was associated with higher mother-child methylation similarity. CONCLUSIONS: Mother adversity and co-residence time are modulating factors in the intergenerational methylation process that offer a window into development-dependent adaptations that can be affected by both hereditary and environmental factors, significantly observed only in biological dyads. A twofold implication for child well-being emerges, one is positive in that children of mothers exposed to life adversity or neglect did not necessarily inherit their methylation patterns. The other is concerning due to the influence of time spent living together, which affects similarity with the mother and potentially increases the risk of inheriting an epigenetic profile associated with future dysfunctional parenting patterns. This underscores the importance of the 'the earlier, the better' recommendation by the Child Protection System, which is not always followed.

Large-Scale Mendelian Randomization Study Reveals Circulating Blood-based Proteomic Biomarkers for Psychopathology and Cognitive Task Performance.

Background: Research on peripheral (e.g., blood-based) biomarkers for psychiatric illness has typically been low-throughput in terms of both the number of subjects and the range of assays performed. Moreover, traditional case-control studies examining blood-based biomarkers are subject to potential confounds of treatment and other exposures common to patients with psychiatric illnesses. Our research addresses these challenges by leveraging large-scale, high-throughput proteomics data and Mendelian Randomization (MR) to examine the causal impact of circulating proteins on psychiatric phenotypes and cognitive task performance. Methods: We utilized plasma proteomics data from the UK Biobank (3,072 proteins assayed in 34,557 European-ancestry individuals) and deCODE Genetics (4,719 proteins measured across 35,559 Icelandic individuals). Significant proteomic quantitative trait loci (both cis-pQTLs and trans-pQTLs) served as MR instruments, with the most recent GWAS for schizophrenia, bipolar disorder, major depressive disorder, and cognitive task performance (all excluding overlapping UK Biobank participants) as phenotypic outcomes. Results: MR revealed 109 Bonferroni-corrected causal associations (44 novel) involving 88 proteins across the four phenotypes. Several immune-related proteins, including interleukins and complement factors, stood out as pleiotropic across multiple outcome phenotypes. Drug target enrichment analysis identified several novel potential pharmacologic repurposing opportunities, including anti-inflammatory agents for schizophrenia and bipolar disorder and duloxetine for cognitive performance. Conclusions: Identification of causal effects for these circulating proteins suggests potential biomarkers for these conditions and offers insights for developing innovative therapeutic strategies. The findings also indicate substantial evidence for the pleiotropic effects of many proteins across different phenotypes, shedding light on the shared etiology among psychiatric conditions and cognitive ability.

Salivary Epigenetic Measures of Body Mass Index and Social Determinants of Health Across Childhood and Adolescence.

Importance: Children who are socioeconomically disadvantaged are at increased risk for high body mass index (BMI) and multiple diseases in adulthood. The developmental origins of health and disease hypothesis proposes that early life conditions affect later-life health in a manner that is only partially modifiable by later-life experiences. Objective: To examine whether epigenetic measures of BMI developed in adults are valid biomarkers of childhood BMI and if they are sensitive to early life social determinants of health. Design, Setting, and Participants: This population-based study of over 3200 children and adolescents aged 8 to 18 years included data from 2 demographically diverse US pediatric cohort studies that combine longitudinal and twin study designs. Analyses were conducted from 2021 to 2022. Exposures: Socioeconomic status, marginalized groups. Main Outcome and Measure: Salivary epigenetic BMI, BMI. Analyses were conducted to validate the use of saliva epigenetic BMI as a potential biomarker of child BMI and to examine associations between epigenetic BMI and social determinants of health. Results: Salivary epigenetic BMI was calculated from 2 cohorts: (1) 1183 individuals aged 8 to 18 years (609 female [51%]; mean age, 13.4 years) from the Texas Twin Project and (2) 2020 children (1011 female [50%]) measured at 9 years of age and 15 years of age from the Future of Families and Child Well-Being Study. Salivary epigenetic BMI was associated with children's BMI (r = 0.36; 95% CI, 0.31-0.40 to r = 0.50; 95% CI, 0.42-0.59). Longitudinal analysis found that epigenetic BMI was highly stable across adolescence but remained both a leading and lagging indicator of BMI change. Twin analyses showed that epigenetic BMI captured differences in BMI between monozygotic twins. Moreover, children from more disadvantaged socioeconomic status (b = -0.13 to -0.15 across samples) and marginalized racial and ethnic groups (b = 0.08-0.34 across samples) had higher epigenetic BMI, even when controlling for concurrent BMI, pubertal development, and tobacco exposure. Socioeconomic status at birth relative to concurrent socioeconomic status best predicted epigenetic BMI in childhood and adolescence (b = -0.15; 95% CI, -0.20 to -0.09). Conclusion and Relevance: This study demonstrated that epigenetic measures of BMI calculated from pediatric saliva samples were valid biomarkers of childhood BMI and may be associated with early-life social inequalities. The findings are in line with the hypothesis that early-life conditions are especially important factors in epigenetic regulation of later-life health. Research showing that health later in life is linked to early-life conditions has important implications for the development of early-life interventions that could significantly extend healthy life span.

Sex-specific DNA methylation in saliva from the multi-ethnic Future of Families and Child Wellbeing Study.

The prevalence and severity of many diseases differs by sex, potentially due to sex-specific patterns in DNA methylation. Autosomal sex-specific differences in DNA methylation have been observed in cord blood and placental tissue but are not well studied in saliva or in diverse populations. We sought to characterize sex-specific DNA methylation on autosomal chromosomes in saliva samples from children in the Future of Families and Child Wellbeing Study, a multi-ethnic prospective birth cohort containing an oversampling of Black, Hispanic and low-income families. DNA methylation from saliva samples was analysed on 796 children (50.6% male) at both ages 9 and 15 with DNA methylation measured using the Illumina HumanMethylation 450k array. An epigenome-wide association analysis of the age 9 samples identified 8,430 sex-differentiated autosomal DNA methylation sites (P < 2.4 × 10-7), of which 76.2% had higher DNA methylation in female children. The strongest sex-difference was in the cg26921482 probe, in the AMDHD2 gene, with 30.6% higher DNA methylation in female compared to male children (P < 1 × 10-300). Treating the age 15 samples as an internal replication set, we observed highly consistent results between the ages 9 and 15 measurements, indicating stable and replicable sex-differentiation. Further, we directly compared our results to previously published DNA methylation sex differences in both cord blood and saliva and again found strong consistency. Our findings support widespread and robust sex-differential DNA methylation across age, human tissues, and populations. These findings help inform our understanding of potential biological processes contributing to sex differences in human physiology and disease.

Association between the timing of childhood adversity and epigenetic patterns across childhood and adolescence: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC) prospective cohort.

BACKGROUND: Childhood adversity is a potent determinant of health across development and is associated with altered DNA methylation signatures, which might be more common in children exposed during sensitive periods in development. However, it remains unclear whether adversity has persistent epigenetic associations across childhood and adolescence. We aimed to examine the relationship between time-varying adversity (defined through sensitive period, accumulation of risk, and recency life course hypotheses) and genome-wide DNA methylation, measured three times from birth to adolescence, using data from a prospective, longitudinal cohort study. METHODS: We first investigated the relationship between the timing of exposure to childhood adversity between birth and 11 years and blood DNA methylation at age 15 years in the Avon Longitudinal Study of Parents and Children (ALSPAC) prospective cohort study. Our analytic sample included ALSPAC participants with DNA methylation data and complete childhood adversity data between birth and 11 years. We analysed seven types of adversity (caregiver physical or emotional abuse, sexual or physical abuse [by anyone], maternal psychopathology, one-adult households, family instability, financial hardship, and neighbourhood disadvantage) reported by mothers five to eight times between birth and 11 years. We used the structured life course modelling approach (SLCMA) to identify time-varying associations between childhood adversity and adolescent DNA methylation. Top loci were identified using an R2 threshold of 0·035 (ie, ≥3·5% of DNA methylation variance explained by adversity). We attempted to replicate these associations using data from the Raine Study and Future of Families and Child Wellbeing Study (FFCWS). We also assessed the persistence of adversity-DNA methylation associations we previously identified from age 7 blood DNA methylation into adolescence and the influence of adversity on DNA methylation trajectories from ages 0-15 years. FINDINGS: Of 13 988 children in the ALSPAC cohort, 609-665 children (311-337 [50-51%] boys and 298-332 [49-50%] girls) had complete data available for at least one of the seven childhood adversities and DNA methylation at 15 years. Exposure to adversity was associated with differences in DNA methylation at 15 years for 41 loci (R2 ≥0·035). Sensitive periods were the most often selected life course hypothesis by the SLCMA. 20 (49%) of 41 loci were associated with adversities occurring between age 3 and 5 years. Exposure to one-adult households was associated with differences in DNA methylation at 20 [49%] of 41 loci, exposure to financial hardship was associated with changes at nine (22%) loci, and physical or sexual abuse was associated with changes at four (10%) loci. We replicated the direction of associations for 18 (90%) of 20 loci associated with exposure to one-adult household using adolescent blood DNA methylation from the Raine Study and 18 (64%) of 28 loci using saliva DNA methylation from the FFCWS. The directions of effects for 11 one-adult household loci were replicated in both cohorts. Differences in DNA methylation at 15 years were not present at 7 years and differences identified at 7 years were no longer apparent by 15 years. We also identified six distinct DNA methylation trajectories from these patterns of stability and persistence. INTERPRETATION: These findings highlight the time-varying effect of childhood adversity on DNA methylation profiles across development, which might link exposure to adversity to potential adverse health outcomes in children and adolescents. If replicated, these epigenetic signatures could ultimately serve as biological indicators or early warning signs of initiated disease processes, helping identify people at greater risk for the adverse health consequences of childhood adversity. FUNDING: Canadian Institutes of Health Research, Cohort and Longitudinal Studies Enhancement Resources, EU's Horizon 2020, US National Institute of Mental Health.

Measuring the long arm of childhood in real-time: Epigenetic predictors of BMI and social determinants of health across childhood and adolescence.

Children who are socioeconomically disadvantaged are at increased risk for high body mass index (BMI) and multiple diseases in adulthood. The developmental origins of health and disease hypothesis proposes that early life conditions affect later-life health in a manner that is only partially modifiable by later-life experiences. Epigenetic mechanisms may regulate the influence of early life conditions on later life health. Recent epigenetic studies of adult blood samples have identified DNA-methylation sites associated with higher BMI and worse health (epigenetic-BMI). Here, we used longitudinal and twin study designs to examine whether epigenetic predictors of BMI developed in adults are valid biomarkers of child BMI and are sensitive to early life social determinants of health. Salivary epigenetic-BMI was calculated from two samples: (1) N=1,183 8-to-19-year-olds (609 female, mean age=13.4) from the Texas Twin Project (TTP), and (2) N=2,020 children (1,011 female) measured at 9 and 15 years from the Future of Families and Child Well-Being Study (FFCWS). We found that salivary epigenetic-BMI is robustly associated with children's BMI (r=0.36 to r=0.50). Longitudinal analysis suggested that epigenetic-BMI is highly stable across adolescence, but remains both a leading and lagging indicator of BMI change. Twin analyses showed that epigenetic-BMI captures differences in BMI between monozygotic twins. Moreover, children from more disadvantaged socioeconomic status (SES) and marginalized race/ethnic groups had higher epigenetic-BMI, even when controlling for concurrent BMI, pubertal development, and tobacco exposure. SES at birth relative to concurrent SES best predicted epigenetic-BMI in childhood and adolescence. We show for the first time that epigenetic predictors of BMI calculated from pediatric saliva samples are valid biomarkers of childhood BMI that are sensitive to social inequalities. Our findings are in line with the hypothesis that early life conditions are especially important factors in epigenetic regulation of later life health. Research showing that health later in life is linked to early life conditions have important implications for the development of early-life interventions that could significantly extend healthy life span.

The shared mother-child epigenetic signature of neglect is related to maternal adverse events.

Studies of DNA methylation have revealed the biological mechanisms by which life adversity confers risk for later physical and mental health problems. What remains unknown is the "biologically embedding" of maternal adverse experiences resulting in maladaptive parenting and whether these epigenetic effects are transmitted to the next generation. This study focuses on neglectful mothering indexed by a severe disregard for the basic and psychological needs of the child. Using the Illumina Human Methylation EPIC BeadChip in saliva samples, we identified genes with differentially methylated regions (DMRs) in those mothers with (n = 51), versus those without (n = 87), neglectful behavior that present similar DMRs patterns in their children being neglected versus non-neglected (n = 40 vs. 75). Mothers reported the emotional intensity of adverse life events. After covariate adjustment and multiple testing corrections, we identified 69 DMRs in the mother epigenome and 42 DMRs in the child epigenome that were simultaneously above the α = 0.01 threshold. The common set of nine DMRs contained genes related to childhood adversity, neonatal and infant diabetes, child neurobehavioral development and other health problems such as obesity, hypertension, cancer, posttraumatic stress, and the Alzheimer's disease; four of the genes were associated with maternal life adversity. Identifying a shared epigenetic signature of neglect linked to maternal life adversity is an essential step in breaking the intergenerational transmission of one of the most common forms of childhood maltreatment.

Polymethylation scores for prenatal maternal smoke exposure persist until age 15 and are detected in saliva in the Fragile Families and Child Wellbeing cohort.

Prenatal maternal smoking is associated with low birthweight, neurological disorders, and asthma in exposed children. DNA methylation signatures can function as biomarkers of prenatal smoke exposure. However, the robustness of DNA methylation signatures across child ages, genetic ancestry groups, or tissues is not clear. Using coefficients from a meta-analysis of prenatal smoke exposure and DNA methylation in newborn cord blood, we created polymethylation scores of saliva DNA methylation from children at ages 9 and 15 in the Fragile Families and Child Wellbeing study. In the full sample at age 9 (n = 753), prenatal smoke exposure was associated with a 0.51 (95%CI: 0.35, 0.66) standard deviation higher polymethylation score. The direction and magnitude of the association was consistent in European and African genetic ancestry samples. In the full sample at age 15 (n = 747), prenatal smoke exposure was associated with a 0.48 (95%CI: 0.32, 0.63) standard deviation higher polymethylation score, and the association was attenuated among the European and Admixed-Latin genetic ancestry samples. The polymethylation score classified prenatal smoke exposure accurately (AUC age 9 = 0.77, age 15 = 0.76). Including the polymethylation score increased the AUC of base model covariates by 5 (95% CI: (2.1, 7.2)) percentage points, while including a single candidate site in the AHRR gene did not (P-value = 0.19). Polymethylation scores for prenatal smoking were portable across genetic ancestries and more accurate than an individual DNA methylation site. Polymethylation scores from saliva samples could serve as robust and practical biomarkers of prenatal smoke exposure.

Saliva cell type DNA methylation reference panel for epidemiological studies in children.

Saliva is a widely used biological sample, especially in pediatric research, containing a heterogenous mixture of immune and epithelial cells. Associations of exposure or disease with saliva DNA methylation can be influenced by cell-type proportions. Here, we developed a saliva cell-type DNA methylation reference panel to estimate interindividual cell-type heterogeneity in whole saliva studies. Saliva was collected from 22 children (7-16 years) and sorted into immune and epithelial cells, using size exclusion filtration and magnetic bead sorting. DNA methylation was measured using the Illumina MethylationEPIC BeadChip. We assessed cell-type differences in DNA methylation profiles and tested for enriched biological pathways. Immune and epithelial cells differed at 181,577 (22.8%) DNA methylation sites (t-test p < 6.28 × 10-8). Immune cell hypomethylated sites are mapped to genes enriched for immune pathways (p < 3.2 × 10-5). Epithelial cell hypomethylated sites were enriched for cornification (p = 5.2 × 10-4), a key process for hard palette formation. Saliva immune and epithelial cells have distinct DNA methylation profiles which can drive whole-saliva DNA methylation measures. A primary saliva DNA methylation reference panel, easily implemented with an R package, will allow estimates of cell proportions from whole saliva samples and improve epigenetic epidemiology studies by accounting for measurement heterogeneity by cell-type proportions.

Reduction in Epigenetic Age Acceleration Is Related to Empathy in Mothers with Neglectful Caregiving.

DNA methylation clocks are used as molecular estimators of epigenetic age, but with little evidence in mothers and none in neglectful mothering. We investigated differences in epigenetic age acceleration (EAA) and the role of empathy using the PhenoAge clock. We collected saliva samples from mothers with extreme disregard for their child's needs (50 in the neglect group, NG) and mothers with non-neglectful caregiving (87 in the control group, CG). Mothers completed an empathy scale, along with questionnaires of their own childhood maltreatment, adverse life events and psychiatric disorders. Sociodemographic variables potentially affecting EAA were also measured. The ANCOVA solution showed a significant increase in EAA in the NG compared to the CG, after adjustment for maternal age, number of pregnancies, financial assistance, adverse events, childhood maltreatment and psychiatric disorder. The group interaction effects showed a reduction in EAA for greater empathic concern and for a higher education level both as positive factors, and an increment in EAA for mothers living in a two-parent family as a risk factor, all in the NG. Our findings open the search for protective factors of EAA associated with caregiver behavior to reduce health vulnerabilities and poor social functioning, especially for mothers at risk of maladaptive caregiving.

Prenatal Particulate Matter Exposure Is Associated with Saliva DNA Methylation at Age 15: Applying Cumulative DNA Methylation Scores as an Exposure Biomarker.

Exposure in utero to particulate matter (PM2.5 and PM10) is associated with maladaptive health outcomes. Although exposure to prenatal PM2.5 and PM10 has cord blood DNA methylation signatures at birth, signature persistence into childhood and saliva cross-tissue applicability has not been tested. In the Fragile Families and Child Wellbeing Study, a United States 20-city birth cohort, average residential PM2.5 and PM10 during the three months prior to birth was estimated using air quality monitors with inverse distance weighting. Saliva DNA methylation at ages 9 (n = 749) and 15 (n = 793) was measured using the Illumina HumanMethylation 450 k BeadArray. Cumulative DNA methylation scores for particulate matter were estimated by weighting participant DNA methylation at each site by independent meta-analysis effect estimates and standardizing the sums. Using a mixed-effects regression analysis, we tested the associations between cumulative DNA methylation scores at ages 9 and 15 and PM exposure during pregnancy, adjusted for child sex, age, race/ethnicity, maternal income-to-needs ratio, nonmartial birth status, and saliva cell-type proportions. Our study sample was 50.5% male, 56.3% non-Hispanic Black, and 19.8% Hispanic, with a median income-to-needs ratio of 1.4. Mean exposure levels for PM2.5 were 27.9 µg/m3/day (standard deviation: 7.0; 23.7% of observations exceeded safety standards) and for PM10 were 15.0 µg/m3/day (standard deviation: 3.1). An interquartile range increase in PM2.5 exposure (10.73 µg/m3/day) was associated with a -0.0287 standard deviation lower cumulative DNA methylation score for PM2.5 (95% CI: -0.0732, 0.0158, p = 0.20) across all participants. An interquartile range increase in PM10 exposure (3.20 µg/m3/day) was associated with a -0.1472 standard deviation lower cumulative DNA methylation score for PM10 (95% CI: -0.3038, 0.0095, p = 0.06) across all participants. The PM10 findings were driven by the age 15 subset where an interquartile range increase in PM10 exposure was associated with a -0.024 standard deviation lower cumulative DNA methylation score for PM10 (95% CI: -0.043, -0.005, p = 0.012). Findings were robust to adjustment for PM exposure at ages 1 and 3. In utero PM10-associated DNA methylation differences were identified at age 15 in saliva. Benchmarking the timing and cell-type generalizability is critical for epigenetic exposure biomarker assessment.

The Effect of Childhood Socioeconomic Position and Social Mobility on Cognitive Function and Change Among Older Adults: A Comparison Between the United States and England.

OBJECTIVES: This study aims to examine the relationship between childhood socioeconomic position (SEP) and cognitive function in later life within nationally representative samples of older adults in the United States and England, investigate whether these effects are mediated by later-life SEP, and determine whether social mobility from childhood to adulthood affects cognitive function and decline. METHOD: Using data from the Health and Retirement Study (HRS) and the English Longitudinal Survey of Ageing (ELSA), we examined the relationships between measures of SEP, cognitive performance and decline using individual growth curve models. RESULTS: High childhood SEP was associated with higher cognitive performance at baseline in both cohorts and did not affect the rate of decline. This benefit dissipated after adjusting for education and adult wealth in the United States. Respondents with low childhood SEP, above median education, and high adult SEP had better cognitive performance at baseline than respondents with a similar childhood background and less upward mobility in both countries. DISCUSSION: These findings emphasize the impact of childhood SEP on cognitive trajectories among older adults. Upward mobility may partially compensate for disadvantage early in life but does not protect against cognitive decline.