Metabolomic data presents challenges for epidemiological meta-analysis: a case study of childhood body mass index from the ECHO consortium.

INTRODUCTION: Meta-analyses across diverse independent studies provide improved confidence in results. However, within the context of metabolomic epidemiology, meta-analysis investigations are complicated by differences in study design, data acquisition, and other factors that may impact reproducibility. OBJECTIVE: The objective of this study was to identify maternal blood metabolites during pregnancy (> 24 gestational weeks) related to offspring body mass index (BMI) at age two years through a meta-analysis framework. METHODS: We used adjusted linear regression summary statistics from three cohorts (total N = 1012 mother-child pairs) participating in the NIH Environmental influences on Child Health Outcomes (ECHO) Program. We applied a random-effects meta-analysis framework to regression results and adjusted by false discovery rate (FDR) using the Benjamini-Hochberg procedure. RESULTS: Only 20 metabolites were detected in all three cohorts, with an additional 127 metabolites detected in two of three cohorts. Of these 147, 6 maternal metabolites were nominally associated (P < 0.05) with offspring BMI z-scores at age 2 years in a meta-analytic framework including at least two studies: arabinose (Coefmeta = 0.40 [95% CI 0.10,0.70], Pmeta = 9.7 × 10-3), guanidinoacetate (Coefmeta = - 0.28 [- 0.54, - 0.02], Pmeta = 0.033), 3-ureidopropionate (Coefmeta = 0.22 [0.017,0.41], Pmeta = 0.033), 1-methylhistidine (Coefmeta = - 0.18 [- 0.33, - 0.04], Pmeta = 0.011), serine (Coefmeta = - 0.18 [- 0.36, - 0.01], Pmeta = 0.034), and lysine (Coefmeta = - 0.16 [- 0.32, - 0.01], Pmeta = 0.044). No associations were robust to multiple testing correction. CONCLUSIONS: Despite including three cohorts with large sample sizes (N > 100), we failed to identify significant metabolite associations after FDR correction. Our investigation demonstrates difficulties in applying epidemiological meta-analysis to clinical metabolomics, emphasizes challenges to reproducibility, and highlights the need for standardized best practices in metabolomic epidemiology.

Sphingolipid classes and the interrelationship with pediatric asthma and asthma risk factors.

BACKGROUND: While dysregulated sphingolipid metabolism has been associated with risk of childhood asthma, the specific sphingolipid classes and/or mechanisms driving this relationship remain unclear. We aimed to understand the multifaceted role between sphingolipids and other established asthma risk factors that complicate this relationship. METHODS: We performed targeted LC-MS/MS-based quantification of 77 sphingolipids in plasma from 997 children aged 6 years from two independent cohorts (VDAART and COPSAC2010 ). We examined associations of circulatory sphingolipids with childhood asthma, lung function, and three asthma risk factors: functional SNPs in ORMDL3, low vitamin D levels, and reduced gut microbial maturity. Given racial differences between these cohorts, association analyses were performed separately and then meta-analyzed together. RESULTS: We observed elevations in circulatory sphingolipids with asthma phenotypes and risk factors; however, there were differential associations of sphingolipid classes with clinical outcomes and/or risk factors. While elevations from metabolites involved in ceramide recycling and catabolic pathways were associated with asthma and worse lung function [meta p-value range: 1.863E-04 to 2.24E-3], increased ceramide levels were associated with asthma risk factors [meta p-value range: 7.75E-5 to .013], but not asthma. Further investigation identified that some ceramides acted as mediators while some interacted with risk factors in the associations with asthma outcomes. CONCLUSION: This study demonstrates the differential role that sphingolipid subclasses may play in asthma and its risk factors. While overall elevations in sphingolipids appeared to be deleterious overall; elevations in ceramides were uniquely associated with increases in asthma risk factors only; while elevations in asthma phenotypes were associated with recycling sphingolipids. Modification of asthma risk factors may play an important role in regulating sphingolipid homeostasis via ceramides to affect asthma. Further function work may validate the observed associations.

Phenotypically driven subgroups of ASD display distinct metabolomic profiles.

Autism Spectrum Disorder (ASD) is a heterogeneous condition that includes a broad range of characteristics and associated comorbidities; however, the biology underlying the variability in phenotypes is not well understood. As ASD impacts approximately 1 in 100 children globally, there is an urgent need to better understand the biological mechanisms that contribute to features of ASD. In this study, we leveraged rich phenotypic and diagnostic information related to ASD in 2001 individuals aged 4 to 17 years from the Simons Simplex Collection to derive phenotypically driven subgroups and investigate their respective metabolomes. We performed hierarchical clustering on 40 phenotypes spanning four ASD clinical domains, resulting in three subgroups with distinct phenotype patterns. Using global plasma metabolomic profiling generated by ultrahigh-performance liquid chromatography mass spectrometry, we characterized the metabolome of individuals in each subgroup to interrogate underlying biology related to the subgroups. Subgroup 1 included children with the least maladaptive behavioral traits (N = 862); global decreases in lipid metabolites and concomitant increases in amino acid and nucleotide pathways were observed for children in this subgroup. Subgroup 2 included children with the highest degree of challenges across all phenotype domains (N = 631), and their metabolome profiles demonstrated aberrant metabolism of membrane lipids and increases in lipid oxidation products. Subgroup 3 included children with maladaptive behaviors and co-occurring conditions that showed the highest IQ scores (N = 508); these individuals had increases in sphingolipid metabolites and fatty acid byproducts. Overall, these findings indicated distinct metabolic patterns within ASD subgroups, which may reflect the biological mechanisms giving rise to specific patterns of ASD characteristics. Our results may have important clinical applications relevant to personalized medicine approaches towards managing ASD symptoms.

Metabo-Endotypes of Asthma Reveal Differences in Lung Function: Discovery and Validation in Two TOPMed Cohorts.

Rationale: Current guidelines do not sufficiently capture the heterogeneous nature of asthma; a more detailed molecular classification is needed. Metabolomics represents a novel and compelling approach to derive asthma endotypes (i.e., subtypes defined by functional and/or pathobiological mechanisms). Objectives: To validate metabolomic-driven endotypes of asthma and explore their underlying biology. Methods: In the Genetics of Asthma in Costa Rica Study (GACRS), untargeted metabolomic profiling, similarity network fusion, and spectral clustering was used to identify metabo-endotypes of asthma, and differences in asthma-relevant phenotypes across these metabo-endotypes were explored. The metabo-endotypes were recapitulated in the Childhood Asthma Management Program (CAMP), and clinical differences were determined. Metabolomic drivers of metabo-endotype membership were investigated by meta-analyzing findings from GACRS and CAMP. Measurements and Main Results: Five metabo-endotypes were identified in GACRS with significant differences in asthma-relevant phenotypes, including prebronchodilator (p-ANOVA = 8.3 × 10-5) and postbronchodilator (p-ANOVA = 1.8 × 10-5) FEV1/FVC. These differences were validated in the recapitulated metabo-endotypes in CAMP. Cholesterol esters, trigylcerides, and fatty acids were among the most important drivers of metabo-endotype membership. The findings suggest dysregulation of pulmonary surfactant homeostasis may play a role in asthma severity. Conclusions: Clinically meaningful endotypes may be derived and validated using metabolomic data. Interrogating the drivers of these metabo-endotypes has the potential to help understand their pathophysiology.

Nucleotide, Phospholipid, and Kynurenine Metabolites Are Robustly Associated with COVID-19 Severity and Time of Plasma Sample Collection in a Prospective Cohort Study.

Understanding the molecular underpinnings of disease severity and progression in human studies is necessary to develop metabolism-related preventative strategies for severe COVID-19. Metabolites and metabolic pathways that predispose individuals to severe disease are not well understood. In this study, we generated comprehensive plasma metabolomic profiles in >550 patients from the Longitudinal EMR and Omics COVID-19 Cohort. Samples were collected before (n = 441), during (n = 86), and after (n = 82) COVID-19 diagnosis, representing 555 distinct patients, most of which had single timepoints. Regression models adjusted for demographics, risk factors, and comorbidities, were used to determine metabolites associated with predisposition to and/or persistent effects of COVID-19 severity, and metabolite changes that were transient/lingering over the disease course. Sphingolipids/phospholipids were negatively associated with severity and exhibited lingering elevations after disease, while modified nucleotides were positively associated with severity and had lingering decreases after disease. Cytidine and uridine metabolites, which were positively and negatively associated with COVID-19 severity, respectively, were acutely elevated, reflecting the particular importance of pyrimidine metabolism in active COVID-19. This is the first large metabolomics study using COVID-19 plasma samples before, during, and/or after disease. Our results lay the groundwork for identifying putative biomarkers and preventive strategies for severe COVID-19.

Cardiometabolic Pregnancy Complications in Association With Autism-Related Traits as Measured by the Social Responsiveness Scale in ECHO.

Prior work has examined associations between cardiometabolic pregnancy complications and autism spectrum disorder (ASD) but not how these complications may relate to social communication traits more broadly. We addressed this question within the Environmental Influences on Child Health Outcomes program, with 6,778 participants from 40 cohorts conducted from 1998-2021 with information on ASD-related traits via the Social Responsiveness Scale. Four metabolic pregnancy complications were examined individually, and combined, in association with Social Responsiveness Scale scores, using crude and adjusted linear regression as well as quantile regression analyses. We also examined associations stratified by ASD diagnosis, and potential mediation by preterm birth and low birth weight, and modification by child sex and enriched risk of ASD. Increases in ASD-related traits were associated with obesity (ß = 4.64, 95% confidence interval: 3.27, 6.01) and gestational diabetes (ß = 5.21, 95% confidence interval: 2.41, 8.02), specifically, but not with hypertension or preeclampsia. Results among children without ASD were similar to main analyses, but weaker among ASD cases. There was not strong evidence for mediation or modification. Results suggest that common cardiometabolic pregnancy complications may influence child ASD-related traits, not only above a diagnostic threshold relevant to ASD but also across the population.

Low gestational vitamin D level and childhood asthma are related to impaired lung function in high-risk children.

BACKGROUND: Lung function impairment in early life often persists into adulthood. Therefore, identifying risk factors for low childhood lung function is crucial. OBJECTIVE: We examined the effect of 25-hydroxyvitamin D (25[OH]D) level and childhood asthma phenotype on childhood lung function in the Vitamin D Antenatal Asthma Reduction Trial (VDAART). METHODS: The 25(OH)D level was measured at set time points in mothers during pregnancy and in children during early life. On the basis of parental reports, children were categorized into 3 clinical phenotypes: asymptomatic/infrequent wheeze, early transient wheeze, and asthma at age 6 years. Lung function was assessed with impulse oscillometry at ages 4, 5, and 6 years and with spirometry at ages 5 and 6 years. RESULTS: A total of 570 mother-child pairs were included in this post hoc analysis. Mean gestational 25(OH)D-level quartiles were negatively associated with child respiratory resistance at 5 Hz (R5) from age 4 to 6 years (ß, -0.021 kPa/L/s; 95% CI, -0.035 to -0.007; P = .003) and positively associated with FEV1 (ß, 0.018 L; 95% CI, 0.005-0.031; P = .008) and forced vital capacity (ß, 0.022 L; 95% CI, 0.009-0.036; P = .002) from age 5 to 6 years. Children with asthma at age 6 years had lower lung function from age 4 to 6 years than the asymptomatic/infrequent wheeze group (ß, 0.065 kPa/L/s; 95% CI, 0.028 to 0.102; P < .001 for R5 and ß, -0.063 L; 95% CI, -0.099 to -0.028; P < .001 for FEV1). CONCLUSIONS: Low gestational 25(OH)D level and childhood asthma are important risk factors for decreased lung function in early childhood.

Maternal Inflammatory Biomarkers during Pregnancy and Early Life Neurodevelopment in Offspring: Results from the VDAART Study.

Maternal infection and stress during the prenatal period have been associated with adverse neurodevelopmental outcomes in offspring, suggesting that biomarkers of increased inflammation in the mothers may associate with poorer developmental outcomes. In 491 mother-child pairs from the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we investigated the association between maternal levels of two inflammatory biomarkers; interleukin-8 (IL-8) and C-Reactive Protein (CRP) during early (10-18 wks) and late (32-38 wks) pregnancy with offspring scores in the five domains of the Ages and Stages Questionnaire, a validated screening tool for assessing early life development. We identified a robust association between early pregnancy IL-8 levels and decreased fine-motor (ß: -0.919, 95%CI: -1.425, -0.414, p = 3.9 × 10-4) and problem-solving skills at age two (ß: -1.221, 95%CI: -1.904, -0.414, p = 4.9 × 10-4). Associations between IL-8 with other domains of development and those for CRP did not survive correction for multiple testing. Similarly, while there was some evidence that the detrimental effects of early pregnancy IL-8 were strongest in boys and in those who were not breastfed, these interactions were not robust to correction for multiple testing. However, further research is required to determine if other maternal inflammatory biomarkers associate with offspring neurodevelopment and work should continue to focus on the management of factors leading to increases in IL-8 levels in pregnant women.

Circulating blood metabolite trajectories and risk of rheumatoid arthritis among military personnel in the Department of Defense Biorepository.

OBJECTIVES: We sought to identify metabolic changes potentially related to rheumatoid arthritis (RA) pathogenesis occurring in the blood prior to its diagnosis. METHODS: In a US military biorepository, serum samples collected at two timepoints prior to a diagnosis of RA were identified. These were matched to controls who did not develop RA by subject age, race and time between sample collections and RA diagnosis time to stored serum samples. Relative abundances of 380 metabolites were measured using liquid chromatography-tandem mass spectrometry. We determined whether pre-RA case versus control status predicted metabolite concentration differences and differences over time (trajectories) using linear mixed models, assessing for interactions between time, pre-RA status and metabolite concentrations. We separately examined pre-RA and pre-seropositive RA cases versus matched controls and adjusted for smoking. Multiple comparison adjustment set the false discovery rate to 0.05. RESULTS: 291 pre-RA cases (80.8% pre seropositive RA) were matched to 292 controls, all with two serum samples (2.7±1.6 years; 1.0±0.9 years before RA/matched date). 52.0% were women; 52.8% were White, 26.8% Black and 20.4% other race. Mean age was 31.2 (±8.1) years at earliest blood draw. Fourteen metabolites had statistically significant trajectory differences among pre-RA subjects versus controls, including sex steroids, amino acid/lipid metabolism and xenobiotics. Results were similar when limited to pre seropositive RA and after adjusting for smoking. CONCLUSIONS: In this military case-control study, metabolite concentration trajectory differences in pre-RA cases versus controls implicated steroidogenesis, lipid/amino acid metabolism and xenobiotics in RA pathogenesis. Metabolites may have potential as biomarkers and/or therapeutic targets preceding RA diagnosis.

Leveraging cell-specific differentially methylated regions to identify leukocyte infiltration in adipose tissue.

Obesity is understood to be an inflammatory condition characterized in part by changes in resident immune cell populations in adipose tissue. However, much of this knowledge has been obtained through experimental animal models. Epigenetic mechanisms, such as DNA methylation may be useful tools for characterizing the changes in immune cell populations in human subjects. In this study, we introduce a simple and intuitive method for assessing cellular infiltration by blood into other heterogeneous, admixed tissues such as adipose tissue, and apply this approach in a large human cohort study. Associations between higher leukocyte infiltration, measured by evaluating a distance measure between the methylation signatures of leukocytes and adipose tissue, and increasing body mass index (BMI) or android fat mass (AFM) were identified and validated in independent replication samples for CD4 (pBMI = 0.009, pAFM = 0.020), monocytes (pBMI = 0.001, pAFM = 4.3 × 10-4 ), and dendritic cells (pBMI = 0.571, pAFM = 0.012). Patterns of depletion with increasing adiposity were observed for plasma B (pBMI = 0.430, pAFM = 0.004) and immature B (pBMI = 0.022, pAFM = 0.042) cells. CD4, dendritic, monocytes, immature B, and plasma B cells may be important agents in the inflammatory process. Finally, the method used to assess leukocyte infiltration in this study is straightforwardly extended to other cell types and tissues in which infiltration might be of interest.

Circulating plasma metabolites and risk of rheumatoid arthritis in the Nurses' Health Study.

OBJECTIVES: RA develops slowly over years. We tested for metabolic changes prior to RA onset using a large non-targeted metabolomics platform to identify novel pathways and advance understanding of RA development. METHODS: Two hundred and fifty-four incident RA cases with plasma samples drawn pre-RA onset in the Nurses' Health Study (NHS) cohorts were matched 1:2 to 501 controls on age, race, menopause/post-menopausal hormone use and blood collection features. Relative abundances of 360 unique, known metabolites were measured. Conditional logistic regression analyses assessed associations between metabolites and incidence of RA, adjusted for age, smoking and BMI, accounting for multiple comparisons. Subgroup analyses investigated seropositive (sero+) RA and RA within 5 years of sample collection. Significant metabolites were then tested in a female military pre-RA case-control study (n = 290). RESULTS: In the NHS, metabolites associated with RA and sero+RA in multivariable models included 4-acetamidobutanoate (odds ratio (OR) = 0.80/S.d., 95% CI: 0.66, 0.95), N-acetylputrescine (OR = 0.82, 95% CI: 0.69, 0.96), C5 carnitine (OR = 0.84, 95% CI: 0.71, 0.99) and C5:1 carnitine (OR = 0.81, 95% CI: 0.68, 0.95). These were involved primarily in polyamine and leucine, isoleucine and valine metabolism. Several metabolites associated with sero+RA within 5 years of diagnosis were replicated in the independent military cohort: C5 carnitine (OR = 0.55, 95% CI: 0.33, 0.92), C5:1 carnitine (OR = 0.62, 95% CI: 0.39, 0.99) and C3 carnitine (OR = 0.57, 95% CI: 0.36, 0.91). CONCLUSION: Several metabolites were inversely associated with incidence of RA among women. Three short-chain acylcarnitines replicated in a smaller dataset and may reflect inflammation in the 5-year period prior to sero+RA diagnosis.

Allergic disease and low ASQ communication score in children.

Autism Spectrum Disorders (ASD) are complex and multifactorial. Previous investigations have revealed associations between allergic disease and ASD, which are characterized by impaired communication skills. In this study we observed an association between allergic disease and communication skills development as assessed by the Ages and Stages Questionnaire (ASQ) communication score, as a proxy for ASD, among children who participated in the Vitamin D Antenatal Asthma Reduction Trial (VDAART). In particular, we observed significant associations between both a diagnosis of eczema at age 3 years (OR = 1.87; confidence interval [CI]: 0.97-3.47; p = 0.054) and a diagnosis of food allergy at age 6 years (OR = 3.61; 95% CI: 1.18-9.85; p = 0.015) with ASQ communication score. Plasma metabolomics analyses suggest that dysregulated tryptophan metabolism may contribute to the pathogenesis of these co-morbidities.

Metabolomic signatures of lead exposure in the VA Normative Aging Study.

BACKGROUND: Lead (Pb) is widespread and exposure to this non-essential heavy metal can cause multiple negative health effects; however the mechanisms underlying these effects remain incompletely understood. OBJECTIVES: To identify plasma metabolomic signatures of Pb exposure, as measured in blood and toenails. METHODS: In a subset of men from the VA Normative Aging Study, mass-spectrometry based plasma metabolomic profiling was performed. Pb levels were measured in blood samples and toenail clippings collected concurrently. Multivariable linear regression models, smoothing splines and Pathway analyses were employed to identify metabolites associated with Pb exposure. RESULTS: In 399 men, 858 metabolites were measured and passed QC, of which 154 (17.9%) were significantly associated with blood Pb (p < 0.05). Eleven of these passed stringent correction for multiple testing, including pro-hydroxy-pro (ß(95%CI): 1.52 (0.93,2.12), p = 7.18x10-7), N-acetylglycine (ß(95%CI): 1.44 (0.85,2.02), p = 1.12x10-6), tartarate (ß(95%CI): 0.68 (0.35,1.00), p = 4.84x10-5), vanillylmandelate (ß(95%CI): 1.05 (0.47,1.63), p = 4.44x10-7), and lysine (ß(95%CI): 1.88 (-2.8,-0.95), p = 9.10x10-5). A subset of 48 men had a second blood sample collected a mean of 6.1 years after their first. Three of the top eleven metabolites were also significant in this second blood sample. Furthermore, we identified 70 plasma metabolites associated with Pb as measured in toenails. Twenty-three plasma metabolites were significantly associated with both blood and toenail measures, while others appeared to be specific to the biosample in which Pb was measured. For example, benzanoate metabolism appeared to be of importance with the longer-term exposure assessed by toenails. DISCUSSION: Pb exposure is responsible for 0.6% of the global burden of disease and metabolomics is particularly well-suited to explore its pathogenic mechanisms. In this study, we identified metabolites and metabolomic pathways associated with Pb exposure that suggest that Pb exposure acts through oxidative stress and immune dysfunction. These findings help us to better understand the biology of this important public health burden.

Genome-wide transcriptome profiling reveals the functional impact of rare de novo and recurrent CNVs in autism spectrum disorders.

Copy-number variants (CNVs) are a major contributor to the pathophysiology of autism spectrum disorders (ASDs), but the functional impact of CNVs remains largely unexplored. Because brain tissue is not available from most samples, we interrogated gene expression in lymphoblasts from 244 families with discordant siblings in the Simons Simplex Collection in order to identify potentially pathogenic variation. Our results reveal that the overall frequency of significantly misexpressed genes (which we refer to here as outliers) identified in probands and unaffected siblings does not differ. However, in probands, but not their unaffected siblings, the group of outlier genes is significantly enriched in neural-related pathways, including neuropeptide signaling, synaptogenesis, and cell adhesion. We demonstrate that outlier genes cluster within the most pathogenic CNVs (rare de novo CNVs) and can be used for the prioritization of rare CNVs of potentially unknown significance. Several nonrecurrent CNVs with significant gene-expression alterations are identified (these include deletions in chromosomal regions 3q27, 3p13, and 3p26 and duplications at 2p15), suggesting that these are potential candidate ASD loci. In addition, we identify distinct expression changes in 16p11.2 microdeletions, 16p11.2 microduplications, and 7q11.23 duplications, and we show that specific genes within the 16p CNV interval correlate with differences in head circumference, an ASD-relevant phenotype. This study provides evidence that pathogenic structural variants have a functional impact via transcriptome alterations in ASDs at a genome-wide level and demonstrates the utility of integrating gene expression with mutation data for the prioritization of genes disrupted by potentially pathogenic mutations.

Network Analysis Reveals Protein Modules Associated with Childhood Respiratory Diseases.

Background: The first year of life is a period of rapid immune development that can impact health trajectories and the risk of developing respiratory-related diseases, such as asthma, recurrent infections, and eczema. However, the biology underlying subsequent disease development remains unknown. Methods: Using weighted gene correlation network analysis (WGCNA), we derived modules of highly correlated immune-related proteins in plasma samples from children at age 1 year (N=294) from the Vitamin D Antenatal Asthma Reduction Trial (VDAART). We applied regression analyses to assess relationships between protein modules and development of childhood respiratory diseases up to age 6 years. We then characterized genomic, environmental, and metabolomic factors associated with modules. Results: WGCNA identified four protein modules at age 1 year associated with incidence of childhood asthma and/or recurrent wheeze (Padj range: 0.02-0.03), respiratory infections (Padj range: 6.3×10-9-2.9×10-6), and eczema (Padj=0.01) by age 6 years; three modules were associated with at least one environmental exposure (Padj range: 2.8×10-10-0.03) and disrupted metabolomic pathway(s) (Padj range: 2.8×10-6-0.04). No genome-wide SNPs were identified as significant genetic risk factors for any protein module. Relationships between protein modules with clinical, environmental, and 'omic factors were temporally sensitive and could not be recapitulated in protein profiles at age 6 years. Conclusion: These findings suggested protein profiles as early as age 1 year predicted development of respiratory-related diseases through age 6 and were associated with changes in pathways related to amino acid and energy metabolism. These may inform new strategies to identify vulnerable individuals based on immune protein profiling.

Metabolite signatures associated with microRNA miR-143-3p serve as drivers of poor lung function trajectories in childhood asthma.

BACKGROUND: Lung function trajectories (LFTs) have been shown to be an important measure of long-term health in asthma. While there is a growing body of metabolomic studies on asthma status and other phenotypes, there are no prospective studies of the relationship between metabolomics and LFTs or their genomic determinants. METHODS: We utilized ordinal logistic regression to identify plasma metabolite principal components associated with four previously-published LFTs in children from the Childhood Asthma Management Program (CAMP) (n = 660). The top significant metabolite principal component (PCLF) was evaluated in an independent cross-sectional child cohort, the Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) (n = 1151) and evaluated for association with spirometric measures. Using meta-analysis of CAMP and GACRS, we identified associations between PCLF and microRNA, and SNPs in their target genes. Statistical significance was determined using an false discovery rate-adjusted Q-value. FINDINGS: The top metabolite principal component, PCLF, was significantly associated with better LFTs after multiple-testing correction (Q-value = 0.03). PCLF is composed of the urea cycle, caffeine, corticosteroid, carnitine, and potential microbial (secondary bile acid, tryptophan, linoleate, histidine metabolism) metabolites. Higher levels of PCLF were also associated with increases in lung function measures and decreased circulating neutrophil percentage in both CAMP and GACRS. PCLF was also significantly associated with microRNA miR-143-3p, and SNPs in three miR-143-3p target genes; CCZ1 (P-value = 2.6 × 10-5), SLC8A1 (P-value = 3.9 × 10-5); and TENM4 (P-value = 4.9 × 10-5). INTERPRETATION: This study reveals associations between metabolites, miR-143-3p and LFTs in children with asthma, offering insights into asthma physiology and possible interventions to enhance lung function and long-term health. FUNDING: Molecular data for CAMP and GACRS via the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI).

A Western Dietary Pattern during Pregnancy is Associated with Neurodevelopmental Disorders in Childhood and Adolescence.

Despite the high prevalence of neurodevelopmental disorders, there is a notable gap in clinical studies exploring the impact of maternal diet during pregnancy on child neurodevelopment. This observational clinical study examined the association between pregnancy dietary patterns and neurodevelopmental disorders, as well as their symptoms, in a prospective cohort of 10-year-old children (n=508). Data-driven dietary patterns were derived from self-reported food frequency questionnaires. A Western dietary pattern in pregnancy (per SD change) was significantly associated with attention-deficit / hyperactivity disorder (ADHD) (OR 1.66 [1.21 - 2.27], p=0.002) and autism diagnosis (OR 2.22 [1.33 - 3.74], p=0.002) and associated symptoms (p<0.001). Findings for ADHD were validated in three large (n=59725, n=656, n=348), independent mother-child cohorts. Objective blood metabolome modelling at 24 weeks gestation identified 15 causally mediating metabolites which significantly improved ADHD prediction in external validation. Temporal analyses across five blood metabolome timepoints in two independent mother-child cohorts revealed that the association of Western dietary pattern metabolite scores with neurodevelopmental outcomes was consistently significant in early to mid-pregnancy, independent of later child timepoints. These findings underscore the importance of early intervention and provide robust evidence for targeted prenatal dietary interventions to prevent neurodevelopmental disorders in children.

The metabolic role of vitamin D in children's neurodevelopment: a network study.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with various proposed environmental risk factors and a rapidly increasing prevalence. Mounting evidence suggests a potential role of vitamin D deficiency in ASD pathogenesis, though the causal mechanisms remain largely unknown. Here we investigate the impact of vitamin D on child neurodevelopment through an integrative network approach that combines metabolomic profiles, clinical traits, and neurodevelopmental data from a pediatric cohort. Our results show that vitamin D deficiency is associated with changes in the metabolic networks of tryptophan, linoleic, and fatty acid metabolism. These changes correlate with distinct ASD-related phenotypes, including delayed communication skills and respiratory dysfunctions. Additionally, our analysis suggests the kynurenine and serotonin sub-pathways may mediate the effect of vitamin D on early childhood communication development. Altogether, our findings provide metabolome-wide insights into the potential of vitamin D as a therapeutic option for ASD and other communication disorders.

Metabolomics and Self-Reported Depression, Anxiety, and Phobic Symptoms in the VA Normative Aging Study.

Traditional approaches to understanding metabolomics in mental illness have focused on investigating a single disorder or comparisons between diagnoses, but a growing body of evidence suggests substantial mechanistic overlap in mental disorders that could be reflected by the metabolome. In this study, we investigated associations between global plasma metabolites and abnormal scores on the depression, anxiety, and phobic anxiety subscales of the Brief Symptom Inventory (BSI) among 405 older males who participated in the Normative Aging Study (NAS). Our analysis revealed overlapping and distinct metabolites associated with each mental health dimension subscale and four metabolites belonging to xenobiotic, carbohydrate, and amino acid classes that were consistently associated across all three symptom dimension subscales. Furthermore, three of these four metabolites demonstrated a higher degree of alteration in men who reported poor scores in all three dimensions compared to men with poor scores in only one, suggesting the potential for shared underlying biology but a differing degree of perturbation when depression and anxiety symptoms co-occur. Our findings implicate pathways of interest relevant to the overlap of mental health conditions in aging veterans and could represent clinically translatable targets underlying poor mental health in this high-risk population.

Elevated third trimester corticosteroid levels are associated with fewer offspring infections.

Respiratory infections are a leading cause of morbidity and mortality in early life, and recurrent infections increase the risk of developing chronic diseases. The maternal environment during pregnancy can impact offspring health, but the factors leading to increased infection proneness have not been well characterized during this period. Steroids have been implicated in respiratory health outcomes and may similarly influence infection susceptibility. Our objective was to describe relationships between maternal steroid levels and offspring infection proneness. Using adjusted Poisson regression models, we evaluated associations between sixteen androgenic and corticosteroid metabolites during pregnancy and offspring respiratory infection incidence across two pre-birth cohorts (N = 774 in VDAART and N = 729 in COPSAC). Steroid metabolites were measured in plasma samples from pregnant mothers across all trimesters of pregnancy by ultrahigh-performance-liquid-chromatography/mass-spectrometry. We conducted further inquiry into associations of steroids with related respiratory outcomes: asthma and lung function spirometry. Higher plasma corticosteroid levels in the third trimester of pregnancy were associated with lower incidence of offspring respiratory infections (P = 4.45 × 10-7 to 0.002) and improved lung function metrics (P = 0.020-0.036). Elevated maternal androgens were generally associated with increased offspring respiratory infections and worse lung function, with some associations demonstrating nominal significance at P < 0.05, but these trends were inconsistent across individual androgens. Increased maternal plasma corticosteroid levels in the late second and third trimesters were associated with lower infections and better lung function in offspring, which may represent a potential avenue for intervention through corticosteroid supplementation in late pregnancy to reduce offspring respiratory infection susceptibility in early life.Clinical Trial Registry information: VDAART and COPSAC were originally conducted as clinical trials; VDAART: ClinicalTrials.gov identifier NCT00920621; COPSAC: ClinicalTrials.gov identifier NCT00798226.