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Epigenetic processes, such as DNA methylation, show potential as biological markers and mechanisms underlying gene-environment interplay in the prediction of mental health and other brain-based phenotypes. However, little is known about how peripheral epigenetic patterns relate to individual differences in the brain itself. An increasingly popular approach to address this is by combining epigenetic and neuroimaging data; yet, research in this area is almost entirely comprised of cross-sectional studies in adults. To bridge this gap, we established the Methylation, Imaging and NeuroDevelopment (MIND) Consortium, which aims to bring a developmental focus to the emerging field of Neuroimaging Epigenetics by (i) promoting collaborative, adequately powered developmental research via multi-cohort analyses; (ii) increasing scientific rigor through the establishment of shared pipelines and open science practices; and (iii) advancing our understanding of DNA methylation-brain dynamics at different developmental periods (from birth to emerging adulthood), by leveraging data from prospective, longitudinal pediatric studies. MIND currently integrates 15 cohorts worldwide, comprising (repeated) measures of DNA methylation in peripheral tissues (blood, buccal cells, and saliva) and neuroimaging by magnetic resonance imaging across up to five time points over a period of up to 21 years (Npooled DNAm = 11,299; Npooled neuroimaging = 10,133; Npooled combined = 4,914). By triangulating associations across multiple developmental time points and study types, we hope to generate new insights into the dynamic relationships between peripheral DNA methylation and the brain, and how these ultimately relate to neurodevelopmental and psychiatric phenotypes.
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Background: The occurrence of post-traumatic stress disorder (PTSD) following a traumatic event is associated with biological differences that can represent the susceptibility to PTSD, the impact of trauma, or the sequelae of PTSD itself. These effects include differences in DNA methylation (DNAm), an important form of epigenetic gene regulation, at multiple CpG loci across the genome. Moreover, these effects can be shared or specific to both central and peripheral tissues. Here, we aim to identify blood DNAm differences associated with PTSD and characterize the underlying biological mechanisms by examining the extent to which they mirror associations across multiple brain regions. Methods: As the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup, we conducted the largest cross-sectional meta-analysis of epigenome-wide association studies (EWASs) of PTSD to date, involving 5077 participants (2156 PTSD cases and 2921 trauma-exposed controls) from 23 civilian and military studies. PTSD diagnosis assessments were harmonized following the standardized guidelines established by the PGC-PTSD Workgroup. DNAm was assayed from blood using either Illumina HumanMethylation450 or MethylationEPIC (850K) BeadChips. A common QC pipeline was applied. Within each cohort, DNA methylation was regressed on PTSD, sex (if applicable), age, blood cell proportions, and ancestry. An inverse variance-weighted meta-analysis was performed. We conducted replication analyses in tissue from multiple brain regions, neuronal nuclei, and a cellular model of prolonged stress. Results: We identified 11 CpG sites associated with PTSD in the overall meta-analysis (1.44e-09 < p < 5.30e-08), as well as 14 associated in analyses of specific strata (military vs civilian cohort, sex, and ancestry), including CpGs in AHRR and CDC42BPB. Many of these loci exhibit blood-brain correlation in methylation levels and cross-tissue associations with PTSD in multiple brain regions. Methylation at most CpGs correlated with their annotated gene expression levels. Conclusions: This study identifies 11 PTSD-associated CpGs, also leverages data from postmortem brain samples, GWAS, and genome-wide expression data to interpret the biology underlying these associations and prioritize genes whose regulation differs in those with PTSD.
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Background: Incorporating genomic data into risk prediction has become an increasingly useful approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not. Methods: Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts. Results: The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p-0.003), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p < 0.001) predictive power for post-deployment PTSD. Conclusion: Results, especially those from the eMRS, reinforce earlier findings that methylation and trauma are interconnected and can be leveraged to increase the correct classification of those with vs. without PTSD. Moreover, our models can potentially be a valuable tool in predicting the future risk of developing PTSD. As more data become available, including additional molecular, environmental, and psychosocial factors in these scores may enhance their accuracy in predicting the condition and, relatedly, improve their performance in independent cohorts.
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Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings.
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Transtorno Depressivo Maior , Estudo de Associação Genômica Ampla , Humanos , Predisposição Genética para Doença , Transtorno Depressivo Maior/genética , Depressão , Mapeamento Cromossômico , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
INTRODUCTION: Lifestyle factors such as smoking, alcohol use, suboptimal diet, and inadequate physical activity have been associated with increased risk of cardiovascular diseases. There are limited data on these risk factors among patients with psychosis in low- and middle-income countries. OBJECTIVES: This study aimed to establish the prevalence of lifestyle cardiovascular risk factors, and the 10-year cardiovascular risk scores and associated factors in patients with psychosis compared to controls at Moi Teaching and Referral Hospital in Eldoret, Kenya. METHODS: A sample of 297 patients with schizophrenia, schizoaffective disorder, or bipolar mood disorder; and 300 controls matched for age and sex were included in this analysis. A study specific researcher-administered questionnaire was used to collect data on demographics, antipsychotic medication use, smoking, alcohol intake, diet, and physical activity. Weight, height, abdominal circumference, and blood pressure were also collected to calculate the Framingham 10-year Cardiovascular Risk Score (FRS), while blood was drawn for measurement of glucose level and lipid profile. Pearson's chi-squared tests and t-tests were employed to assess differences in cardiovascular risk profiles between patients and controls, and a linear regression model was used to determine predictors of 10-year cardiovascular risk in patients. RESULTS: Compared to controls, patients with psychosis were more likely to have smoked in their lifetimes (9.9% vs. 3.3%, p = 0.006) or to be current smokers (13.8% vs. 7%, p = 0.001). Over 97% of patients with psychosis consumed fewer than five servings of fruits and vegetables per week; 78% engaged in fewer than three days of vigorous exercise per week; and 48% sat for more than three hours daily. The estimated 10-year risk of CVD was relatively low in this study: the FRS in patients was 3.16, compared to 2.93 in controls. The estimated 10-year cardiovascular risk in patients was significantly associated with female sex (p = 0.007), older patients (p < 0.001), current tobacco smoking (p < 0.001), and metabolic syndrome (p < 0.001). CONCLUSION: In the setting of Eldoret, there is suboptimal physical exercise and intake of healthy diet among patients with psychosis and controls. While the estimated risk score among patients is relatively low in our study, these data may be useful for informing future studies geared towards informing interventions to promote healthy lifestyles in this population.
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Doenças Cardiovasculares , Transtornos Psicóticos , Humanos , Adulto , Feminino , Fatores de Risco , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Prevalência , Quênia/epidemiologia , Transtornos Psicóticos/epidemiologia , Estilo de Vida , Fatores de Risco de Doenças Cardíacas , Hospitais , Encaminhamento e ConsultaRESUMO
OBJECTIVE: Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD. METHOD: Meta-analyses were conducted on 18 cohorts of European ancestry (17,339 PPD cases and 53,426 controls), one cohort of East Asian ancestry (975 cases and 3,780 controls), and one cohort of African ancestry (456 cases and 1,255 controls), totaling 18,770 PPD cases and 58,461 controls. Post-GWAS analyses included 1) single-nucleotide polymorphism (SNP)-based heritability ([Formula: see text]), 2) genetic correlations between PPD and other phenotypes, and 3) enrichment of the PPD GWAS findings in 27 human tissues and 265 cell types from the mouse central and peripheral nervous system. RESULTS: No SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. The [Formula: see text] of PPD was 0.14 (SE=0.02). Significant genetic correlations were estimated for PPD with MDD, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. Cell-type enrichment analyses implicate inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern that differs from MDD. CONCLUSIONS: While more samples are needed to reach genome-wide levels of significance, the results presented confirm PPD as a polygenic and heritable phenotype. There is also evidence that despite a high correlation with MDD, PPD may have unique genetic components. Cell enrichment results suggest GABAergic neurons, which converge on a common mechanism with the only medication approved by the U.S. Food and Drug Administration for PPD (brexanolone).
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Transtorno Bipolar , Depressão Pós-Parto , Transtorno Depressivo Maior , Feminino , Humanos , Animais , Camundongos , Transtorno Depressivo Maior/genética , Estudo de Associação Genômica Ampla , Depressão Pós-Parto/genética , Predisposição Genética para Doença , Transtorno Bipolar/genética , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
BACKGROUND: Exposure to indoor air pollution during pregnancy has been linked to neurodevelopmental delay in toddlers. Epigenetic modification, particularly DNA methylation (DNAm), may explain this link. In this study, we employed three high-dimensional mediation analysis methods (HIMA, DACT, and gHMA) followed by causal mediation analysis to identify differentially methylated CpG sites and genes that mediate the association between indoor air pollution and neurodevelopmental delay. Analyses were performed using data from 142 mother to child pairs from a South African birth cohort, the Drakenstein Child Health Study. DNAm from cord blood was measured using the Infinium MethylationEPIC and HumanMethylation450 arrays. Neurodevelopment was assessed at age 2 years using the Bayley Scores of Infant and Toddler Development, 3rd edition across four domains (cognitive development, general adaptive behavior, language, and motor function). Particulate matter with an aerodynamic diameter of 10 µm or less (PM10) was measured inside participants' homes during the second trimester of pregnancy. RESULTS: A total of 29 CpG sites and 4 genes (GOPC, RP11-74K11.1, DYRK1A, RNMT) were identified as significant mediators of the association between PM10 and cognitive neurodevelopment. The estimated proportion mediated (95%-confidence interval) ranged from 0.29 [0.01, 0.86] for cg00694520 to 0.54 [0.11, 1.56] for cg05023582. CONCLUSIONS: Our findings suggest that DNAm may mediate the association between prenatal PM10 exposure and cognitive neurodevelopment. DYRK1A and several genes that our CpG sites mapped to, including CNKSR1, IPO13, IFNGR1, LONP2, and CDH1, are associated with biological pathways implicated in cognitive neurodevelopment and three of our identified CpG sites (cg23560546 [DAPL1], cg22572779 [C6orf218], cg15000966 [NT5C]) have been previously associated with fetal brain development. These findings are novel and add to the limited literature investigating the relationship between indoor air pollution, DNAm, and neurodevelopment, particularly in low- and middle-income country settings and non-white populations.
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Poluição do Ar em Ambientes Fechados , Metilação de DNA , Deficiências do Desenvolvimento , Pré-Escolar , Feminino , Humanos , Lactente , Gravidez , Poluição do Ar em Ambientes Fechados/efeitos adversos , Coorte de Nascimento , África do Sul/epidemiologia , Deficiências do Desenvolvimento/epidemiologiaRESUMO
Prenatal maternal stressful life events are associated with adverse neurodevelopmental outcomes in offspring. Biological mechanisms underlying these associations are largely unknown, but DNA methylation likely plays a role. This meta-analysis included twelve non-overlapping cohorts from ten independent longitudinal studies (N = 5,496) within the international Pregnancy and Childhood Epigenetics consortium to examine maternal stressful life events during pregnancy and DNA methylation in cord blood. Children whose mothers reported higher levels of cumulative maternal stressful life events during pregnancy exhibited differential methylation of cg26579032 in ALKBH3. Stressor-specific domains of conflict with family/friends, abuse (physical, sexual, and emotional), and death of a close friend/relative were also associated with differential methylation of CpGs in APTX, MyD88, and both UHRF1 and SDCCAG8, respectively; these genes are implicated in neurodegeneration, immune and cellular functions, regulation of global methylation levels, metabolism, and schizophrenia risk. Thus, differences in DNA methylation at these loci may provide novel insights into potential mechanisms of neurodevelopment in offspring.
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African populations are vastly underrepresented in genetic studies but have the most genetic variation and face wide-ranging environmental exposures globally. Because systematic evaluations of genetic prediction had not yet been conducted in ancestries that span African diversity, we calculated polygenic risk scores (PRSs) in simulations across Africa and in empirical data from South Africa, Uganda, and the United Kingdom to better understand the generalizability of genetic studies. PRS accuracy improves with ancestry-matched discovery cohorts more than from ancestry-mismatched studies. Within ancestrally and ethnically diverse South African individuals, we find that PRS accuracy is low for all traits but varies across groups. Differences in African ancestries contribute more to variability in PRS accuracy than other large cohort differences considered between individuals in the United Kingdom versus Uganda. We computed PRS in African ancestry populations using existing European-only versus ancestrally diverse genetic studies; the increased diversity produced the largest accuracy gains for hemoglobin concentration and white blood cell count, reflecting large-effect ancestry-enriched variants in genes known to influence sickle cell anemia and the allergic response, respectively. Differences in PRS accuracy across African ancestries originating from diverse regions are as large as across out-of-Africa continental ancestries, requiring commensurate nuance.
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Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Predisposição Genética para Doença/genética , Herança Multifatorial/genética , Uganda/epidemiologia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Recent efforts have focused on developing methylation risk scores (MRS), a weighted sum of the individual's DNA methylation (DNAm) values of pre-selected CpG sites. Most of the current MRS approaches that utilize Epigenome-wide association studies (EWAS) summary statistics only include genome-wide significant CpG sites and do not consider co-methylation. New methods that relax the p-value threshold to include more CpG sites and account for the inter-correlation of DNAm might improve the predictive performance of MRS. We paired informed co-methylation pruning with P-value thresholding to generate pruning and thresholding (P+T) MRS and evaluated its performance among multi-ancestry populations. Through simulation studies and real data analyses, we demonstrated that pruning provides an improvement over simple thresholding methods for prediction of phenotypes. We demonstrated that European-derived summary statistics can be used to develop P+T MRS among other populations such as African populations. However, the prediction accuracy of P+T MRS may differ across multi-ancestry population due to environmental/cultural/social differences.
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Metilação de DNA , Epigenoma , Ilhas de CpG , Fatores de Risco , Fenótipo , Estudo de Associação Genômica AmplaRESUMO
Maternal psychological distress during pregnancy has been linked to adverse outcomes in children with evidence of sex-specific effects on brain development. Here, we investigated whether in utero exposure to intimate partner violence (IPV), a particularly severe maternal stressor, is associated with brain structure in young infants from a South African birth cohort. Exposure to IPV during pregnancy was measured in 143 mothers at 28-32 weeks' gestation and infants underwent structural and diffusion magnetic resonance imaging (mean age 3 weeks). Subcortical volumetric estimates were compared between IPV-exposed (n = 63; 52% female) and unexposed infants (n = 80; 48% female), with white matter microstructure also examined in a subsample (IPV-exposed, n = 28, 54% female; unexposed infants, n = 42, 40% female). In confound adjusted analyses, maternal IPV exposure was associated with sexually dimorphic effects in brain volumes: IPV exposure predicted a larger caudate nucleus among males but not females, and smaller amygdala among females but not males. Diffusivity alterations within white matter tracts of interest were evident in males, but not females exposed to IPV. Results were robust to the removal of mother-infant pairs with pregnancy complications. Further research is required to understand how these early alterations are linked to the sex-bias in neuropsychiatric outcomes later observed in IPV-exposed children.
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Coorte de Nascimento , Violência por Parceiro Íntimo , Masculino , Criança , Lactente , Gravidez , Humanos , Feminino , Recém-Nascido , África do Sul , Violência por Parceiro Íntimo/psicologia , Mães/psicologia , EncéfaloRESUMO
Introduction: Neurocognitive impairment (NCI) is commonly exhibited among patients experiencing their first episode of psychosis. However, there are few resources in many low-income countries, such as Uganda, that allow for the administration of extensive neurocognitive test batteries for the detection of NCI. NeuroScreen is a brief tablet-based neurocognitive assessment battery that can be administered by all levels of healthcare staff. We examined the validity of NeuroScreen to assess neurocognition and detect NCI in first-episode psychosis (FEP) patients in Uganda. Methods: We enrolled 112 participants FEP patients and matched controls at Butabika Mental Referral Hospital. Each participant completed NeuroScreen and a traditionally administered neurocognitive battery: the MATRIC Consensus Cognitive Battery (MCCB). We examined correlations between participant performance on NeuroScreen and the MCCB. A ROC curve determined sensitivity and specificity of NeuroScreen to detect NCI as determined by MCCB criterion. Results: There was a large, statistically significant correlation between overall performance on NeuroScreen and the MCCB [r(112) = 0.64, p < .001]. Small to large correlations were found between tests in the MCCB and NeuroScreen batteries. The ROC curve of NeuroScreen performance to detect MCCB-defined NCI had an area under curve of 0.80 and optimal sensitivity and specificity of 83 % and 60 %, respectively. Conclusion: There was a moderate positive correlation between overall performance on both batteries. NeuroScreen shows promise as a valid assessment battery to assess neurocognition and detect NCI in FEP patients in Uganda. Further studies of NeuroScreen in healthy individuals and in a range of mental disorders are recommended.
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OBJECTIVE: The variety of instruments used to assess posttraumatic stress disorder (PTSD) allows for flexibility, but also creates challenges for data synthesis. The objective of this work was to use a multisite mega analysis to derive quantitative recommendations for equating scores across measures of PTSD severity. METHOD: Empirical Bayes harmonization and linear models were used to describe and mitigate site and covariate effects. Quadratic models for converting scores across PTSD assessments were constructed using bootstrapping and tested on hold out data. RESULTS: We aggregated 17 data sources and compiled an n = 5,634 sample of individuals who were assessed for PTSD symptoms. We confirmed our hypothesis that harmonization and covariate adjustments would significantly improve inference of scores across instruments. Harmonization significantly reduced cross-dataset variance (28%, p < .001), and models for converting scores across instruments were well fit (median R² = 0.985) with an average root mean squared error of 1.46 on sum scores. CONCLUSIONS: These methods allow PTSD symptom severity to be placed on multiple scales and offers interesting empirical perspectives on the role of harmonization in the behavioral sciences. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
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Transtornos de Estresse Pós-Traumáticos , Veteranos , Humanos , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Teorema de Bayes , Índice de Gravidade de DoençaRESUMO
African populations are the most diverse in the world yet are sorely underrepresented in medical genetics research. Here, we examine the structure of African populations using genetic and comprehensive multi-generational ethnolinguistic data from the Neuropsychiatric Genetics of African Populations-Psychosis study (NeuroGAP-Psychosis) consisting of 900 individuals from Ethiopia, Kenya, South Africa, and Uganda. We find that self-reported language classifications meaningfully tag underlying genetic variation that would be missed with consideration of geography alone, highlighting the importance of culture in shaping genetic diversity. Leveraging our uniquely rich multi-generational ethnolinguistic metadata, we track language transmission through the pedigree, observing the disappearance of several languages in our cohort as well as notable shifts in frequency over three generations. We find suggestive evidence for the rate of language transmission in matrilineal groups having been higher than that for patrilineal ones. We highlight both the diversity of variation within Africa as well as how within-Africa variation can be informative for broader variant interpretation; many variants that are rare elsewhere are common in parts of Africa. The work presented here improves the understanding of the spectrum of genetic variation in African populations and highlights the enormous and complex genetic and ethnolinguistic diversity across Africa.
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Variação Genética , Genética Populacional , África Austral , População Negra/genética , Estruturas Genéticas , Variação Genética/genética , HumanosRESUMO
Prenatal tobacco exposure (PTE) and prenatal alcohol exposure (PAE) have been associated with an increased risk of delayed neurodevelopment in children as well as differential newborn DNA methylation (DNAm). However, the biological mechanisms connecting PTE and PAE, DNAm, and neurodevelopment are largely unknown. Here we aim to determine whether differential DNAm mediates the association between PTE and PAE and neurodevelopment at 6 (N = 112) and 24 months (N = 184) in children from the South African Drakenstein Child Health Study. PTE and PAE were assessed antenatally using urine cotinine measurements and the ASSIST questionnaire, respectively. Cord blood DNAm was measured using the EPIC and 450 K BeadChips. Neurodevelopment (cognitive, language, motor, adaptive behavior, socioemotional) was measured using the Bayley Scales of Infant and Toddler Development, Third Edition. We constructed methylation risk scores (MRS) for PTE and PAE and conducted causal mediation analysis (CMA) with these MRS as mediators. Next, we conducted a high-dimensional mediation analysis to identify individual CpG sites as potential mediators, followed by a CMA to estimate the average causal mediation effects (ACME) and total effect (TE). PTE and PAE were associated with neurodevelopment at 6 but not at 24 months. PTE MRS reached a prediction accuracy (R2) of 0.23 but did not significantly mediate the association between PTE and neurodevelopment. PAE MRS was not predictive of PAE (R2 = 0.006). For PTE, 31 CpG sites and eight CpG sites were identified as significant mediators (ACME and TE P < 0.05) for the cognitive and motor domains at 6 months, respectively. For PAE, 16 CpG sites and 1 CpG site were significant mediators for the motor and adaptive behavior domains at 6 months, respectively. Several of the associated genes, including MAD1L1, CAMTA1, and ALDH1A2 have been implicated in neurodevelopmental delay, suggesting that differential DNAm may partly explain the biological mechanisms underlying the relationship between PTE and PAE and child neurodevelopment.
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Nicotiana , Efeitos Tardios da Exposição Pré-Natal , Coorte de Nascimento , Desenvolvimento Infantil , Cotinina , Metilação de DNA , Etanol , Feminino , Humanos , Lactente , Recém-Nascido , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , África do SulRESUMO
BACKGROUND AND AIMS: There is increasing evidence indicating that air pollution exposure is associated with neuronal damage. Since pregnancy is a critical window of vulnerability, air pollution exposure during this period could have adverse effects on neurodevelopment. This study aims 1) to analyze associations of prenatal exposure to indoor air pollution (particulate matter with diameters ≤10 µm, PM10) and tobacco smoke with neurodevelopment and 2) to determine whether these associations are mediated by deviations of epigenetic gestational age from chronological gestational age (ΔGA). METHODS: Data of 734 children from the South African Drakenstein Child Health Study were analyzed. Prenatal PM10 exposure was measured using devices placed in the families' homes. Maternal smoking during pregnancy was determined by maternal urine cotinine measures. The Bayley Scales of Infant and Toddler Development III (BSID-III) was used to measure cognition, language and motor development and adaptive behavior at two years of age. Linear regression models adjusted for maternal age, gestational age, sex of child, ancestry, birth weight/length, and socioeconomic status were used to explore associations between air pollutants and BSID-III scores. A mediation analysis was conducted to analyze if these associations were mediated by ΔGA using DNA methylation measurements from cord blood. RESULTS: An increase of one interquartile range in natural-log transformed PM10 (lnPM10; 1.58 µg/m3) was significantly associated with lower composite scores in cognition, language, and adaptive behavior sub-scores (composite score ß-estimate [95%-confidence interval]: -0.950 [-1.821, -0.120]). Maternal smoking was significantly associated with lower adaptive behavior scores (-3.386 [-5.632, -1.139]). Associations were not significantly mediated by ΔGA (e.g., for PM10 and cognition, proportion mediated [p-value]: 4% [0.52]). CONCLUSION: We found an association of prenatal exposure to indoor air pollution (PM10) and tobacco smoke on neurodevelopment at two years of age, particularly cognition, language, and adaptive behavior. Further research is needed to understand underlying biological mediators.
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Poluentes Atmosféricos , Poluição do Ar em Ambientes Fechados , Poluição do Ar , Efeitos Tardios da Exposição Pré-Natal , Poluição por Fumaça de Tabaco , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Poluição do Ar em Ambientes Fechados/efeitos adversos , Poluição do Ar em Ambientes Fechados/análise , Coorte de Nascimento , Cognição , Estudos de Coortes , Feminino , Humanos , Lactente , Exposição Materna , Material Particulado/análise , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , África do Sul , Nicotiana , Poluição por Fumaça de Tabaco/efeitos adversos , Poluição por Fumaça de Tabaco/análiseRESUMO
INTRODUCTION: The MATRICS consensus cognitive battery (MCCB) is the gold standard for neuropsychological assessment in psychotic disorders but is rarely used in low resource settings. This study used the MCCB to determine the prevalence, profile and associations of various exposures with cognitive impairment in Ugandan first-episode psychosis patients. METHODS: Patients and matched healthy controls were recruited at Butabika Hospital in Uganda. Clinical variables were first collated, and after the resolution of psychotic symptoms, a neuropsychological assessment of seven cognitive domains was performed using the MCCB. Cognitive impairment was defined as two standard deviations (SD) below the mean in one domain or 1SD below the mean in two domains. Descriptive statistics determined the prevalence and profile of impairment while regression models determined the association between various exposures with cognitive scores while controlling for age, sex and education. RESULTS: Neuropsychological assessment with the MCCB found the burden of cognitive impairment in first-episode psychosis patients five times that of healthy controls. The visual learning and memory domain was most impaired in first-episode psychosis patients, while it was the working memory domain for the healthy controls. Increased age was associated with impairment in the domains of the speed of processing (p < 0.001) and visual learning and memory (p = 0.001). Cassava-rich diets and previous alternative and complementary therapy use were negatively associated with impairment in the visual learning (p = 0.04) and attention/vigilance domains (p = 0.012), respectively. There were no significant associations between sex, history of childhood trauma, or illness severity with any cognitive domain. CONCLUSION: A significant burden of cognitive impairment in Ugandan first-episode psychosis patients is consistent with prior data from other contexts. However, the profile of and risk factors for impairment differ from that described in such work. Therefore, interventions to reduce cognitive impairment in FEP patients specific to this setting, including dietary modifications, are required.
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OBJECTIVES: Early detection of neurodevelopmental delay is crucial for intervention and treatment strategies. We analysed associations between newborn DNA methylation (DNAm), neonatal magnetic resonance imaging (MRI) neuroimaging data, and neurodevelopment. METHODS: Neurodevelopment was assessed in 161 children from the South African Drakenstein Child Health Study at 2 years of age using the Bayley Scales of Infant and Toddler Development III. We performed an epigenome-wide association study of neurodevelopmental delay using DNAm from cord blood. Subsequently, we analysed if associations between DNAm and neurodevelopmental delay were mediated by altered neonatal brain volumes (subset of 51 children). RESULTS: Differential DNAm at SPTBN4 (cg26971411, Δbeta = -0.024, p-value = 3.28 × 10-08), and two intergenic regions (chromosome 11: cg00490349, Δbeta = -0.036, p-value = 3.02 × 10-08; chromosome 17: cg15660740, Δbeta = -0.078, p-value = 6.49 × 10-08) were significantly associated with severe neurodevelopmental delay. While these associations were not mediated by neonatal brain volume, neonatal caudate volumes were independently associated with neurodevelopmental delay, particularly in language (Δcaudate volume = 165.30 mm3, p = 0.0443) and motor (Δcaudate volume = 365.36 mm3, p-value = 0.0082) domains. CONCLUSIONS: Differential DNAm from cord blood and increased neonatal caudate volumes were independently associated with severe neurodevelopmental delay at 2 years of age. These findings suggest that neurobiological signals for severe developmental delay may be detectable in very early life.