Environment-wide Association Study Research Articles

An environment-wide association study for the identification of non-invasive factors for type 2 diabetes mellitus: Analysis based on the Henan Rural Cohort study

AimTo explore the influencing factors of Type 2 diabetes mellitus (T2DM) in the rural population of Henan Province and evaluate the predictive ability of non-invasive factors to T2DM. MethodsA total of 30,020 participants from the Henan Rural Cohort Study in China were included in this study. The dataset was randomly divided into a training set and a testing set with a 50:50 split for validation purposes. We used logistic regression analysis to investigate the association between 56 factors and T2DM in the training set (false discovery rate < 5 %) and significant factors were further validated in the testing set (P < 0.05). Gradient Boosting Machine (GBM) model was used to determine the ability of the non-invasive variables to classify T2DM individuals accurately and the importance ranking of these variables. ResultsThe overall population prevalence of T2DM was 9.10 %. After adjusting for age, sex, educational level, marital status, and body measure index (BMI), we identified 13 non-invasive variables and 6 blood biochemical indexes associated with T2DM in the training and testing dataset. The top three factors according to the GBM importance ranking were pulse pressure (PP), urine glucose (UGLU), and waist-to-hip ratio (WHR). The GBM model achieved a receiver operating characteristic (AUC) curve of 0.837 with non-invasive variables and 0.847 for the full model. ConclusionsOur findings demonstrate that non-invasive variables that can be easily measured and quickly obtained may be used to predict T2DM risk in rural populations in Henan Province.

Environment-wide association study to identify exposure pathways of bisphenol A in Korean children and adolescents: Korean National Environmental Health Survey (KoNEHS) 2018-2020

Bisphenol A (BPA) is an endocrine-disrupting chemical commonly used in manufacturing plastic products. Despite ongoing efforts and regulatory measures, BPA exposure among children persists. This study aimed to identify the modifiable factors associated with urinary BPA levels in Korean children and adolescents. We conducted an environment-wide association study (EWAS) using data from the Korean National Environmental Health Survey (KoNEHS) Cycle 4. This study included 578 preschoolers, 736 school-aged children, and 828 adolescents. A total of 117, 103, and 102 modifiable factors were selected from KoNEHS Cycle 4. Each modifiable factor associated with urinary BPA levels was tested using a multivariable linear regression model. Subsequently, multiple testing corrections were performed using false discovery rate (FDR) estimation. For the validation phase, we used the iteration of the least absolute shrinkage and selection operator (LASSO), a machine learning-based regression analysis. After the validation phase of the LASSO regression, two modifiable factors were identified as being significantly related to urinary BPA levels in preschoolers. Urinary cotinine levels and the use of slime or clay toys were positively associated with urinary BPA levels in preschoolers. However, no significant associations were observed between school-aged children and adolescents. Our results suggest novel exposure pathways to BPA in recent lifestyles and contribute to the development of effective prevention strategies. These modifiable factors provide valuable targets for interventions aimed at reducing BPA exposure in children. Further research is needed to explore additional modifiable factors and confirm our results in larger and more diverse populations.

Environment- and epigenome-wide association study of obesity in 'Children of 1997' birth cohort.

Increasing childhood obesity is a global issue requiring potentially local solutions to ensure it does not continue into adulthood. We systematically identified potentially modifiable targets of obesity at the onset and end of puberty in Hong Kong, the most economically developed major Chinese city. We conducted an environment-wide association study (EWAS) and an epigenome-wide association study of obesity to systematically assess associations with body mass index (BMI) and waist-hip ratio (WHR) in Hong Kong's population-representative 'Children of 1997' birth cohort. Univariable linear regression was used to select exposures related to obesity at ~11.5 years (BMI and obesity risk n ≤ 7119, WHR n = 5691) and ~17.6 years (n = 3618) at Bonferroni-corrected significance, and multivariable regression to adjust for potential confounders followed by replicated multivariable regression (n = 308) and CpG by CpG analysis (n = 286) at ~23 years. Findings were compared with evidence from published randomized controlled trials (RCTs) and Mendelian randomization (MR) studies. At ~11.5 and~17.6 years the EWAS identified 14 and 37 exposures associated with BMI, as well as 7 and 12 associated with WHR, respectively. Most exposures had directionally consistent associations at ~23 years. Maternal second-hand smoking, maternal weight, and birth weight were consistently associated with obesity. Diet (including dairy intake and artificially sweetened beverages), physical activity, snoring, binge eating, and earlier puberty were positively associated with BMI at ~17.6 years, while eating before sleep was inversely associated with BMI at ~17.6 years. Findings for birth weight, dairy intake, and binge eating are consistent with available evidence from RCTs or MR studies. We found 17 CpGs related to BMI and 17 to WHR. These novel insights into potentially modifiable factors associated with obesity at the outset and the end of puberty could, if causal, inform future interventions to improve population health in Hong Kong and similar Chinese settings. This study including the follow-up survey and epigenetics testing was supported by the Health and Medical Research Fund Research Fellowship, Food and Health Bureau, Hong Kong SAR Government (#04180097). The DNA extraction of the samples used for epigenetic testing was supported by CFS-HKU1.

Modifiable factors associated with cognitive performance in Chinese adolescents: a national environment-wide association study.

Growing evidence exists about the candidate factors of childhood cognitive performance, but mainly limited to single-exposure studies. We sought to systematically and simultaneously identify and validate a wide range of potential modifiable factors for childhood cognitive performance. We used data from five waves of data from the China Family Panel Studies (CFPS-2010, 2012, 2014, 2016 and 2018). Our analytical sample was restricted to those children aged 2-5 at baseline with valid exposure information. A total of 80 modifiable factors were identified. Childhood cognitive performance was assessed using vocabulary and mathematics test at wave 5. We used an environment-wide association study (EnWAS) to screen all exposure-outcome associations independently and used the least absolute shrinkage and selection operator (LASSO) variable selection algorithm to identify factors associated with cognitive performance. Multivariable linear model was then used to evaluate causal relationships between identified factors and cognitive performance. Of the 1305 participants included in the study (mean ± SD, 3.5 ± 1.1years age at baseline, 45.1% girls). Eight factors were retained in the LASSO regression analysis. Six factors across community characteristics (percentage of poverty in the community; percentage of children in the community), household characteristics (family size), child health and behaviors (mobile internet access), parenting behaviors and cognitive enrichment (parental involvement in child' s education), and parental wellbeing (paternal happiness) domains were significantly associated with childhood cognition. Using a three-stage approach, this study validates several actionable targets for improving childhood cognitive performance.

Identifying environmental risk factors for post-acute sequelae of SARS-CoV-2 infection: An EHR-based cohort study from the recover program.

Post-acute sequelae of SARS-CoV-2 infection (PASC) affects a wide range of organ systems among a large proportion of patients with SARS-CoV-2 infection. Although studies have identified a broad set of patient-level risk factors for PASC, little is known about the association between "exposome"-the totality of environmental exposures and the risk of PASC. Using electronic health data of patients with COVID-19 from two large clinical research networks in New York City and Florida, we identified environmental risk factors for 23 PASC symptoms and conditions from nearly 200 exposome factors. The three domains of exposome include natural environment, built environment, and social environment. We conducted a two-phase environment-wide association study. In Phase 1, we ran a mixed effects logistic regression with 5-digit ZIP Code tabulation area (ZCTA5) random intercepts for each PASC outcome and each exposome factor, adjusting for a comprehensive set of patient-level confounders. In Phase 2, we ran a mixed effects logistic regression for each PASC outcome including all significant (false positive discovery adjusted p-value < 0.05) exposome characteristics identified from Phase I and adjusting for confounders. We identified air toxicants (e.g., methyl methacrylate), particulate matter (PM2.5) compositions (e.g., ammonium), neighborhood deprivation, and built environment (e.g., food access) that were associated with increased risk of PASC conditions related to nervous, blood, circulatory, endocrine, and other organ systems. Specific environmental risk factors for each PASC condition and symptom were different across the New York City area and Florida. Future research is warranted to extend the analyses to other regions and examine more granular exposome characteristics to inform public health efforts to help patients recover from SARS-CoV-2 infection.

Environment-wide association study of elevated liver enzymes: results from the Korean National Environmental Health Survey 2018-2022.

Environmental exposure is characterized by low concentration, chronic, and complex exposure. Traditional epidemiological studies show limitations in reflecting these characteristics since they usually focus on a single or very limited number of exposure factors at a time. In this study, we adopted the methodology of environment-wide association study (EWAS) to figure out the association of human liver function with various environmentally hazardous substances. We analyzed 2,961 participants from the Korean National Environmental Health Survey Cycle 4 (2018-2020). Using generalized linear model (GLM) analysis, we analyzed the association of 72 variables with 3 liver function indices (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and gamma glutamyl transferase [GGT]). Finally, we visualized our results with Manhattan plot. In GLM analysis, perfluorooctanesulfonate were positively associated with ALT (odds ratio [OR]: 2.2; 95% confidence interval [CI]: 1.39-3.46; p adjusted = 0.0147) and perfluorodecanoic acid showed positive association with GGT (OR: 2.73; 95% CI: 1.36-5.5; p adjusted = 0.0256). Plasma mercury showed positive association with GGT (OR: 1.45; 95% CI: 1.14-1.84; p adjusted = 0.0315). Using a plastic container while keeping food in the refrigerator was associated with elevated GGT compared to using a glass container (OR: 1.51; 95% CI: 1.16-1.95; p adjusted = 0.0153). 2-ethyl-5-oxohexyl phthalate, showed a negative trend with all 3 indices, with AST (OR: 0.54; 95% CI: 0.39-0.73; p adjusted = 0.00357), ALT (OR: 0.5; 95% CI: 0.34-0.75; p adjusted = 0.036), GGT (OR: 0.55; 95% CI: 0.4-0.76; p adjusted = 0.00697). Bisphenol S and frequent use of sunblock cream showed negative association with ALT (OR: 0.77; 95% CI: 0.66-0.89), and GGT (OR: 0.25; 95% CI: 0.11-0.55), respectively. We conducted an exploratory study on environmental exposure and human liver function. By using EWAS methodology, we identified 7 factors that could have potential association with liver function.

An environment wide association study on body mass index in adolescents using 2003-2004 and 2013-2014 NHANES data

BACKGROUND AND AIM: Excess weight is a global public health challenge affecting millions of people, including younger age groups. The human exposome concept presents a novel opportunity to comprehensively characterize all non-genetic disease determinants at particularly susceptible time windows. Our study aimed to describe the association between multiple lifestyle and nutritional exposures and body mass index (BMI) in adolescents using the exposome framework METHODS: We conducted an environment-wide association study using the U.S. National Health and Nutrition Examination Survey (NHANES) survey of 2003-2004 for discovery of associations between the study population characteristics and BMI and the 2013-2014 survey to replicate the analysis. We included non-diabetic and non-pregnant adolescents aged 12-18 years-old. We analyzed variables available in both survey rounds, with 20% of missing values in relation to BMI z-scores. We performed univariable and multivariable linear regression analysis adjusted for age, sex, race-ethnicity, education, smoking, and income to poverty ratio. RESULTS:A total of 1899 (18.4% overweight and 18.1% obese) and 1224 (18.5% overweight and 20.6% obese) participants were identified in the target study population of the discovery and replication dataset, respectively. Retained exposure factors included 63 dietary and 50 clinical variables. After correction of false-discovery rate (FDR), univariable regression identified 10 and 13 clinical variables in the discovery and replication dataset, respectively. Multivariable regression identified 4 clinical variables in discovery dataset (uric acid; alanine aminotransferase; gamma glutamyl transferase and triglycerides) of which only uric acid remained significant in the replication dataset after FDR correction. CONCLUSIONS:Associations between BMI and different nutritional and clinical factors were explored and identified in adolescents. Future studies are warranted to investigate the possible role of uric acid as an early-stage biomarker of increased BMI and associated pathologies among adolescents and to replicate these findings to other populations. KEYWORDS: exposome, environment-wide association study, biomarker

Environmental chemicals and cross-sectional cognition among adults in the National Health and Nutrition Examination Survey

BACKGROUND AND AIM: Cognitive impairment among older adults is a growing public health challenge and environmental chemicals may be modifiable risk factors. A wide array of chemicals has not been tested for association with cognition in an environment-wide association framework. METHODS: In the US National Health and Nutrition Examination Survey (NHANES) 1999-2002 and 2011-2014 cross-sectional cycles, cognition was assessed using the Digit Symbol Substitution Test (DSST, scores 0-117) among participants 60 years of age and older. Concentrations of environmental chemicals were measured in blood or urine. Chemicals with at least 50% of measures greater than the limit of detection were included (nchemicals=124, nclasses=16). We tested for differences in cognition by natural log transformed concentration of each chemical using parallel multivariable linear regression models accounting for age, sex, race/ethnicity, and educational attainment. We calculated false discovery rates (FDR). RESULTS:Participants with complete cognition/demographic measures and at least one chemical measure (n=5,670) were mean age 70.3 years, 51% female, 43.7% college educated, and 53.2% non-Hispanic White. The mean DSST score was 43.6 (18.1 standard deviation) and 24.2% were cognitively impaired (DSST28). In adjusted analyses, 75% higher lipid adjusted blood concentration of the pesticide DDT was associated with 1.4 points lower DSST score (95% Confidence interval (CI):-2.1,-0.7, FDR:0.0001). Similarly, 75% higher heptachlor concentration was associated with 0.9 points lower DSST score (95%CI:-1.6,-0.1, FDR:0.02). For metals, we observed 75% higher blood cadmium levels were associated with 0.7 points lower DSST score (95%CI:-1.1,-0.4, FDR:5*10-5) and 75% higher blood lead levels were associated with 0.6 points lower DSST score (95%CI:-0.9,-0.2, FRD:0.002). Among perfluoroalkyl substances, 75% higher urinary concentration of perfluoroundecanoic acid was associated with 0.5 points lower DSST score (95%CI:-1.0,0.07, FDR: 0.09). CONCLUSIONS:Exposure to environmental chemicals, particularly pesticides and metals, may be modifiable factors for reduced cognition among older adults. KEYWORDS: cognition, exposome, environment-wide association study, dementia

Expanding the environmental scope: an environment-wide association study for mental well-being

BackgroundIdentifying modifiable factors associated with well-being is of increased interest for public policy guidance. Developments in record linkage make it possible to identify what contributes to well-being from a myriad of factors. To this end, we link two large-scale data resources; the Geoscience and Health Cohort Consortium, a collection of geo-data, and the Netherlands Twin Register, which holds population-based well-being data.ObjectiveWe perform an Environment-Wide Association Study (EnWAS), where we examine 139 neighbourhood-level environmental exposures in relation to well-being.MethodsFirst, we performed a generalized estimation equation regression (N = 11,975) to test for the effects of environmental exposures on well-being. Second, to account for multicollinearity amongst exposures, we performed principal component regression. Finally, using a genetically informative design, we examined whether environmental exposure is driven by genetic predisposition for well-being.ResultsWe identified 21 environmental factors that were associated with well-being in the domains: housing stock, income, core neighbourhood characteristics, livability, and socioeconomic status. Of these associations, socioeconomic status and safety are indicated as the most important factors to explain differences in well-being. No evidence of gene-environment correlation was found.SignificanceThese observed associations, especially neighbourhood safety, could be informative for policy makers and provide public policy guidance to improve well-being. Our results show that linking databases is a fruitful exercise to identify determinants of mental health that would remain unknown by a more unilateral approach.

Systematic identification and replication of factors associated with human papillomavirus vaccine initiation among adolescents in the United States using an environment-wide association study approach

ObjectiveHuman papillomavirus (HPV) vaccination coverage is low among adolescents in the USA. Identification of factors associated with HPV vaccine initiation (receipt of ≥1 dose) is critical for improving uptake. Our...

Home-based informal jewelry production increases exposure of working families to cadmium

Trace element concentrations in biological fluids may vary according to the individual exposome, especially when considering specific external factors of the environment, such as occupational activities. The aim of this study was to determine concentrations of Potentially Toxic Elements (PTEs: As, Cr, Cd, Cu, Mn, Ni, Pb, Zn) in urine samples of informal jewelry workers and in jewelry and soldering powder. Fifty-two families from Brazil comprised the Exposed (n = 113) and Control (n = 79) groups. PTE concentrations in urine samples (n = 192) of workers, controls and their family members were determined by ICP-MS. Soldering powder samples (n = 7) and jewelry pieces (n = 54) were measured for PTEs by field-portable X-ray fluorescence. Levels of PTEs in urine and occupational exposure associations were determined. The environment-wide association study (EWAS) approach was applied to test the influence of occupational activities on participant exposure. Mean PTE concentrations were within the limits recommended in urine by Brazilian occupational guidelines. However, As, Cd, Ni and Zn concentrations in some samples exceeded acceptable values for environmental exposure in the U.S and Canada, as well as Brazilian occupational limits. Cd concentrations were higher for women (0.19 μg g−1 creatinine; p = 0.01), adult workers (0.25 μg g−1 creatinine; p = 0.0002) and smokers (0.27 μg g−1creatinine; p = 0.0001). The difference between the Exposed (0.17 μg g−1creat.) and Control groups (0.10 μg g−1creat.) for Cd was significant among non-smokers. Workers engaged in soldering and assemblers had higher Cd concentrations (0.61 and 0.18 μg g−1 creatinine, respectively) than individuals not working with jewelry production (0.12 μg g−1 creat). PTEs in some jewelry and all soldering powder exceeded Brazilian limits. Considering this exposure scenario, informal jewelry production increased urinary cadmium levels in workers. Occupational exposure to this element in the household environment should be explored, as it may pose a health risk to family members and workers alike.

A systematic comprehensive longitudinal evaluation of dietary factors associated with acute myocardial infarction and fatal coronary heart disease

Environmental factors, and in particular diet, are known to play a key role in the development of Coronary Heart Disease. Many of these factors were unveiled by detailed nutritional epidemiology studies, focusing on the role of a single nutrient or food at a time. Here, we apply an Environment-Wide Association Study approach to Nurses’ Health Study data to explore comprehensively and agnostically the association of 257 nutrients and 117 foods with coronary heart disease risk (acute myocardial infarction and fatal coronary heart disease). After accounting for multiple testing, we identify 16 food items and 37 nutrients that show statistically significant association – while adjusting for potential confounding and control variables such as physical activity, smoking, calorie intake, and medication use – among which 38 associations were validated in Nurses’ Health Study II. Our implementation of Environment-Wide Association Study successfully reproduces prior knowledge of diet-coronary heart disease associations in the epidemiological literature, and helps us detect new associations that were only marginally studied, opening potential avenues for further extensive experimental validation. We also show that Environment-Wide Association Study allows us to identify a bipartite food-nutrient network, highlighting which foods drive the associations of specific nutrients with coronary heart disease risk.

Diabetic Retinopathy Environment-Wide Association Study (EWAS) in NHANES 2005-2008.

Several circulating biomarkers are reported to be associated with diabetic retinopathy (DR). However, their relative contributions to DR compared to known risk factors, such as hyperglycaemia, hypertension, and hyperlipidaemia, remain unclear. In this data driven study, we used novel models to evaluate the associations of over 400 laboratory parameters with DR compared to the established risk factors. Methods: we performed an environment-wide association study (EWAS) of laboratory parameters available in National Health and Nutrition Examination Survey (NHANES) 2007–2008 in individuals with diabetes with DR as the outcome (test set). We employed independent variable (feature) selection approaches, including parallelised univariate regression modelling, Principal Component Analysis (PCA), penalised regression, and RandomForest™. These models were replicated in NHANES 2005–2006 (replication set). Our test and replication sets consisted of 1025 and 637 individuals with available DR status and laboratory data respectively. Glycohemoglobin (HbA1c) was the strongest risk factor for DR. Our PCA-based approach produced a model that incorporated 18 principal components (PCs) that had an Area under the Curve (AUC) 0.796 (95% CI 0.761–0.832), while penalised regression identified a 9-feature model with 78.51% accuracy and AUC 0.74 (95% CI 0.72–0.77). RandomForest™ identified a 31-feature model with 78.4% accuracy and AUC 0.71 (95% CI 0.65–0.77). On grouping the selected variables in our RandomForest™, hyperglycaemia alone achieved AUC 0.72 (95% CI 0.68–0.76). The AUC increased to 0.84 (95% CI 0.78–0.9) when the model also included hypertension, hypercholesterolemia, haematocrit, renal, and liver function tests.

Early-Life Factors and Risk of Multiple Sclerosis: An MR-EWAS

Background: Although several risk factors are associated with multiple sclerosis (MS) in adulthood, evidence for risk factors acting from birth to adolescence is scarce. Methods: We conceived a 2-step study design, where signals from an Environment-Wide Association Study are prioritized for follow-up in a Mendelian Randomization study (MR-EWAS), to examine the association of early-life factors with risk of MS. The EWAS was conducted in UK Biobank, where we agnostically selected all the available risk factors acting from the perinatal period until the adolescence, including perinatal factors, anthropometric characteristics during childhood, male and female sexual factors, and skin phenotypic characteristics. We prioritized statistically significant risk factors to perform a 2-sample MR study using publicly available summary-level genetic data. We also calculated the power of the 2-step MR-EWAS approach under several scenarios and compared it against a 1-step hypothesis-free MR approach to detect risk factors of MS. Results: In the EWAS, an increase per 1 year in age at menarche was associated with a lower risk of MS (OR = 0.93; 95% CI: 0.90–0.96) and a plumper than average body size at the age of 10 was associated with a higher risk of MS (OR = 1.42; 95% CI: 1.24–1.61). Individuals getting very tanned or moderately tanned were at higher risk of MS compared with individuals that never tan or get mildly to occasionally tanned (OR = 0.86; 95% CI: 0.79–0.94). The MR analysis supported the association of age at menarche and childhood body mass index (BMI) without presence of pleiotropic effects. In the multivariable MR analysis, the association of age at menarche was not statistically significant after adjusting for childhood BMI. The MR analysis for ease of tanning did not reveal a statistically significant association. In multiple scenarios, the power of MR-EWAS approach was larger than the power of a hypothesis-free MR approach. Conclusions: We introduced the MR-EWAS, a 2-step approach that is more powerful compared with the hypothesis-free MR approach under certain scenarios, to test potential causal signals. Our comprehensive assessment of early-life risk factors of MS highlighted a potential causal role of early menarche and elevated childhood BMI for risk of MS.

Averaging causal estimators in high dimensions

Abstract There has been increasing interest in recent years in the development of approaches to estimate causal effects when the number of potential confounders is prohibitively large. This growth in interest has led to a number of potential estimators one could use in this setting. Each of these estimators has different operating characteristics, and it is unlikely that one estimator will outperform all others across all possible scenarios. Coupling this with the fact that an analyst can never know which approach is best for their particular data, we propose a synthetic estimator that averages over a set of candidate estimators. Averaging is widely used in statistics for problems such as prediction, where there are many possible models, and averaging can improve performance and increase robustness to using incorrect models. We show that these ideas carry over into the estimation of causal effects in high-dimensional scenarios. We show theoretically that averaging provides robustness against choosing a bad model, and show empirically via simulation that the averaging estimator performs quite well, and in most cases nearly as well as the best among all possible candidate estimators. Finally, we illustrate these ideas in an environmental wide association study and see that averaging provides the largest benefit in the more difficult scenarios that have large numbers of confounders.

Environment-wide association study on childhood obesity in the U.S.

BackgroundChildhood obesity is a national public health issue with increasing prevalence. It has been linked to diet, lack of physical activity, and genetic susceptibility, with more recent evidence that it could also result from environmental factors. Studies linking it to environmental factors are limited, unsystematic, incomprehensive, and inconclusive. ObjectiveTo conduct an environment-wide association study (EWAS) to comprehensively investigate all the environmental factors available in a nationally representative sample of children to determine factors associated with childhood obesity. MethodsWe utilized the 1999–2016 National Health and Nutrition Examination Survey (NHANES) datasets and included all children/adolescents (6–17 years). Obesity was measured using body mass index and waist to height ratio. A multinomial and binary logistic regression were used adjusting for age, sex, race/ethnicity, creatinine, calorie intake, physical activity, screen time, limitation to physical activities, and socioeconomic status. We then controlled for multiple hypothesis testing and validated our findings on a different cohort of children. ResultsWe found that metals such as beryllium (OR: 3.305 CI: 1.460–7.479) and platinum (OR: 1.346 CI: 1.107–1.636); vitamins such as gamma-tocopherol (OR: 8.297 CI: 5.683–12.114) and delta-tocopherol (OR: 1.841 CI:1.476–2.297); heterocyclic aromatic amines such as 2-Amino-9H-pyrido (2,3-b) indole (OR: 1.323 CI: 1.083–1.617) and 2-Amino-3-methyl-9H-pyriodo(2,3-b)indole (OR: 2.799 CI: 1.442–5.433); polycyclic aromatic amines such as 9- fluorene (OR: 1.509 CI: 1.230–1.851) and 4-phenanthrene (OR: 2.828 CI: 1.632–4.899); and caffeine metabolites such as 1,3,7-trimethyluric acid (OR: 1.22 CI: 1.029–1.414) and 1,3,7-trimethylxanthine (OR: 1.258 CI: 1.075–1.473) were positively and significantly associated with childhood obesity. ConclusionFollowing the unique concept of EWAS, certain environmental factors were associated with childhood obesity. Further studies are required to confirm these associations while investigating their mechanisms of action.

Environment-Wide Association Study of CKD.

Exposure to environmental chemicals has been recognized as one of the possible contributors to CKD. We aimed to identify environmental chemicals that are associated with CKD. We analyzed the data obtained from a total of 46,748 adults who participated in the National Health and Nutrition Examination Survey (1999-2016). Associations of chemicals measured in urine or blood (n=262) with albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g), reduced eGFR (<60 ml/min per 1.73 m2), and a composite of albuminuria or reduced eGFR were tested and validated using the environment-wide association study approach. Among 262 environmental chemicals, seven (3%) chemicals showed significant associations with increased risk of albuminuria, reduced eGFR, or the composite outcome. These chemicals included metals and other chemicals that have not previously been associated with CKD. Serum and urine cotinines, blood 2,5-dimethylfuran (a volatile organic compound), and blood cadmium were associated with albuminuria. Blood lead and cadmium were associated with reduced eGFR. Blood cadmium and lead and three volatile compounds (blood 2,5-dimethylfuran, blood furan, and urinary phenylglyoxylic acid) were associated with the composite outcome. A total of 23 chemicals, including serum perfluorooctanoic acid, seven urinary metals, three urinary arsenics, urinary nitrate and thiocyanate, three urinary polycyclic aromatic hydrocarbons, and seven volatile organic compounds, were associated with lower risks of one or more manifestations of CKD. A number of chemicals were identified as potential risk factors for CKD among the general population.

Metabolites, Nutrients, and Lifestyle Factors in Relation to Coffee Consumption: An Environment-Wide Association Study.

Coffee consumption has been inversely associated with various diseases; however, the underlying mechanisms are not entirely clear. We used data of 17,752 Third National Health and Nutrition Examination Survey participants to investigate the association of 245 metabolites, nutrients, and lifestyle factors with coffee consumption. We used data from the first phase (n = 8825) to identify factors with a false discovery rate of <5%. We then replicated our results using data from the second phase (n = 8927). Regular coffee consumption was positively associated with active and passive smoking, serum lead and urinary cadmium concentrations, dietary intake of potassium and magnesium, and aspirin intake. In contrast, regular coffee consumption was inversely associated with serum folate and red blood cell folate levels, serum vitamin E and C, and beta-cryptoxanthin concentrations, Healthy Eating Index score, and total serum bilirubin. Most of the aforementioned associations were also observed for caffeinated beverage intake. In our assessment of the association between coffee consumption and selected metabolites, nutrients, and lifestyle factors, we observed that regular coffee and caffeinated beverage consumption was strongly associated with smoking, serum lead levels, and poorer dietary habits.

Environment-wide association study to comprehensively test and validate associations between nutrition and lifestyle factors and testosterone deficiency: NHANES 1988-1994 and 1999-2004.

Testosterone (T) plays an important role in men's health and its deficiency is linked with poorer health. However, the role of nutritional and lifestyle factors in T regulation and production remains unclear. The objectives are to comprehensively test the cross-sectional associations of nutritional and lifestyle factors with T deficiency and to validate the associations in the NHANES survey. We performed weighted multivariable logistic regression analysis to examine the association of 173 nutritional and lifestyle factors with T deficiency (total testosterone ≤ 3.5ng/mL) in NHANES III as the discovery set (mean age 41). We controlled for multiple comparisons with a false discovery rate (FDR) < 5% and replicated in NHANES 1999-2004 (mean age 44). We identified seven nutritional factors as being inversely associated with T deficiency in NHANES 1999-2004, namely dietary intake of vitamin A, protein, saturated fatty acids, monounsaturated fatty acids, total fats, saturated fatty acid 16:0, and phosphorus. In a multivariable model, only vitamin A intake remained significantly associated with T deficiency (OR 0.97, 95% CI 0.94-0.99). Principal component analysis suggested that the two principal components, (1) dietary fats, protein, and phosphorous and (2) total vitamin A, may be associated with T deficiency. Our systematic evaluation provided new insight into the modifiable factors that could play a role in the regulation of T production. This study has the potential to contribute to the current body of literature which seeks to formulate a clinical definition of T deficiency after taking into account nutritional and lifestyle factors.

Childhood type 1 diabetes: an environment-wide association study across England

Aims/hypothesisType 1 diabetes is an autoimmune disease affecting ~400,000 people across the UK. It is likely that environmental factors trigger the disease process in genetically susceptible individuals. We assessed the associations between a wide range of environmental factors and childhood type 1 diabetes incidence in England, using an agnostic, ecological environment-wide association study (EnWAS) approach, to generate hypotheses about environmental triggers.MethodsWe undertook analyses at the local authority district (LAD) level using a national hospital episode statistics-based incident type 1 diabetes dataset comprising 13,948 individuals with diabetes aged 0–9 years over the period April 2000 to March 2011. We compiled LAD level estimates for a range of potential demographic and environmental risk factors including meteorological, land use and environmental pollution variables. The associations between type 1 diabetes incidence and risk factors were assessed via Poisson regression, disease mapping and ecological regression.ResultsCase counts by LAD varied from 1 to 236 (median 33, interquartile range 24–46). Overall type 1 diabetes incidence was 21.2 (95% CI 20.9, 21.6) per 100,000 individuals. The EnWAS and disease mapping indicated that 15 out of 53 demographic and environmental risk factors were significantly associated with diabetes incidence, after adjusting for multiple testing. These included air pollutants (particulate matter, nitrogen dioxide, nitrogen oxides, carbon monoxide; all inversely associated), as well as lead in soil, radon, outdoor light at night, overcrowding, population density and ethnicity. Disease mapping revealed spatial heterogeneity in type 1 diabetes risk. The ecological regression found an association between type 1 diabetes and the living environment domain of the Index of Multiple Deprivation (RR 0.995; 95% credible interval [CrI] 0.991, 0.998) and radon potential class (RR 1.044; 95% CrI 1.015, 1.074).Conclusions/interpretationOur analysis identifies a range of demographic and environmental factors associated with type 1 diabetes in children in England.