Established Environmental Risk Factors Research Articles

Early Life and Childhood Environmental Exposures, More Than Genetic Predisposition, Influence Age of Diagnosis in a Diverse Cohort of 2952 Patients With IBD

Background and AimsInflammatory bowel disease (IBD) develops from a combination of genetic and environmental factors. The aim of this study was to determine the contribution of established environmental risk factors and genetic risk on age of IBD diagnosis in a diverse cohort. MethodsIBD patients in clinic completed detailed questionnaires. Blood was drawn for genetic analysis. Environmental risk factors and age of diagnosis were analyzed by ethnicity (Hispanic/Latinx or non-Hispanic White [NHW] individuals) and IBD subtype (ulcerative colitis or Crohn’s disease [CD]). Weighted genetic risk scores and environmental risk scores were developed. We examined the relationship between environmental risk scores, genetic risk scores, and age of diagnosis. ResultsA total of 2952 patients were included: 58.9% had CD. A total of 46.83% were of Hispanic background. Early life exposures like cesarean delivery and being born in a developed country were associated with a younger age of IBD diagnosis. Childhood exposures such as frequent plastic water bottle use and having more than 1 bathroom at home were associated with a younger age of IBD. Hispanic and NHW individuals shared similar susceptibilities to environmental exposures. Environmental factors explained 21% of the variance in age of CD diagnosis and 39% in ulcerative colitis. In models incorporating genetic risk score and environmental risk score, the environment was the only significant factor associated with younger age of IBD diagnosis in all groups. ConclusionsEarly life and childhood exposures impact IBD diagnosis and influence Hispanic and NHW individuals similarly. A cumulative environmental risk score contributes more to age of IBD diagnosis than genetic risk.

Cholecalciferol Supplementation Induced Up-Regulation of SARAF Gene and Down-Regulated miR-155-5p Expression in Slovenian Patients with Multiple Sclerosis.

Multiple sclerosis is a common immune-mediated inflammatory and demyelinating disease. Lower cholecalciferol levels are an established environmental risk factor in multiple sclerosis. Although cholecalciferol supplementation in multiple sclerosis is widely accepted, optimal serum levels are still debated. Moreover, how cholecalciferol affects pathogenic disease mechanisms is still unclear. In the present study, we enrolled 65 relapsing-remitting multiple sclerosis patients who were double-blindly divided into two groups with low and high cholecalciferol supplementation, respectively. In addition to clinical and environmental parameters, we obtained peripheral blood mononuclear cells to analyze DNA, RNA, and miRNA molecules. Importantly, we investigated miRNA-155-5p, a previously published pro-inflammatory miRNA in multiple sclerosis known to be correlated to cholecalciferol levels. Our results show a decrease in miR-155-5p expression after cholecalciferol supplementation in both dosage groups, consistent with previous observations. Subsequent genotyping, gene expression, and eQTL analyses reveal correlations between miR-155-5p and the SARAF gene, which plays a role in the regulation of calcium release-activated channels. As such, the present study is the first to explore and suggest that the SARAF miR-155-5p axis hypothesis might be another mechanism by which cholecalciferol supplementation might decrease miR-155 expression. This association highlights the importance of cholecalciferol supplementation in multiple sclerosis and encourages further investigation and functional cell studies.

Excess mortality attributed to heat and cold: a health impact assessment study in 854 cities in Europe

Heat and cold are established environmental risk factors for human health. However, mapping the related health burden is a difficult task due to the complexity of the associations and the differences in vulnerability and demographic distributions. In this study, we did a comprehensive mortality impact assessment due to heat and cold in European urban areas, considering geographical differences and age-specific risks. We included urban areas across Europe between Jan 1, 2000, and Dec 12, 2019, using the Urban Audit dataset of Eurostat and adults aged 20 years and older living in these areas. Data were extracted from Eurostat, the Multi-country Multi-city Collaborative Research Network, Moderate Resolution Imaging Spectroradiometer, and Copernicus. We applied a three-stage method to estimate risks of temperature continuously across the age and space dimensions, identifying patterns of vulnerability on the basis of city-specific characteristics and demographic structures. These risks were used to derive minimum mortality temperatures and related percentiles and raw and standardised excess mortality rates for heat and cold aggregated at various geographical levels. Across the 854 urban areas in Europe, we estimated an annual excess of 203 620 (empirical 95% CI 180 882-224 613) deaths attributed to cold and 20 173 (17 261-22 934) attributed to heat. These corresponded to age-standardised rates of 129 (empirical 95% CI 114-142) and 13 (11-14) deaths per 100 000 person-years. Results differed across Europe and age groups, with the highest effects in eastern European cities for both cold and heat. Maps of mortality risks and excess deaths indicate geographical differences, such as a north-south gradient and increased vulnerability in eastern Europe, as well as local variations due to urban characteristics. The modelling framework and results are crucial for the design of national and local health and climate policies and for projecting the effects of cold and heat under future climatic and socioeconomic scenarios. Medical Research Council of UK, the Natural Environment Research Council UK, the EU's Horizon 2020, and the EU's Joint Research Center.

Polygenic risk scores for schizophrenia and major depression are associated with socio-economic indicators of adversity in two British community samples

Schizophrenia (SCZ) and major depressive disorder (MDD) are complex psychiatric disorders which contribute substantially to the global burden of disease. Both psychopathologies are heritable with some genetic overlap between them. Importantly, SCZ and MDD have also been found to be associated with environmental risk factors. However, rather than being independent of genetic influences, exposure to environmental risk factors may be under genetic control, known as gene-environment correlation (rGE). In this study we investigated rGE in relation to polygenic risk scores for SCZ and MDD in adults, derived from large genome-wide association studies, across two different British community samples: Understanding Society (USoc) and the National Child Development Study (NCDS). We tested whether established environmental risk factors for SCZ and/or MDD are correlated with polygenic scores in adults and whether these associations differ between the two disorders and cohorts. Findings partially overlapped between disorders and cohorts. In NCDS, we identified a significant correlation between the genetic risk for MDD and an indicator of low socio-economic status, but no significant findings emerged for SCZ. In USoc, we replicated associations between indicators of low socio-economic status and the genetic propensity for MDD. In addition, we identified associations between the genetic susceptibility for SCZ and being single or divorced. Results across both studies provide further evidence that the genetic risk for SCZ and MDD were associated with common environmental risk factors, specifically MDD’s association with lower socio-economic status.

Polygenic scores for schizophrenia and major depression are associated with psychosocial risk factors in children: evidence of gene-environment correlation.

Whilst genetic and environmental risk factors for schizophrenia (SCZ) and major depressive disorder (MDD) have been established, it is unclear whether exposure to environmental risk factors is genetically confounded by passive, evocative or active gene-environment correlation (rGE). This study aims to investigate: (a) whether the genetic risk for SCZ/MDD in children is correlated with established environmental and psychosocial risk factors in two British community samples, the 1958 National Child Development Study (NCDS) and the Millennium Cohort Study (MCS), (b) whether these associations vary between both psychopathologies, and (c) whether findings differ across the two cohorts which were born 42 years apart. Polygenic risk scores (PRS) from existing large genome-wide associations studies (GWAS) were applied to test the correlation between the child genetic risk for SCZ/MDD and known environmental risk factors. In addition, parental and child genetic data from MCS were used to distinguish between passive and evocative rGE. The child polygenic risk for SCZ and MDD was correlated with single parenthood in MCS. Moreover, the lack of father's involvement in child care was associated with the genetic risk for SCZ in NCDS. However, we also found associations between several indicators of low socioeconomic status and heightened genetic risk for MDD in children in both cohorts. Further, the genetic risk for MDD was associated with parental lack of interest in the child's education in NCDS as well as more maternal smoking and less maternal alcohol consumption during childhood in MCS. According to sensitivity analyses in MCS (controlling for parental genotype), more than half of our significant correlations reflected passive rGE. Findings suggest that several established environmental and psychosocial risk factors for SCZ and MDD are at least partially associated with children's genetic risk for these psychiatric disorders.

Association of Cyberbullying Experiences and Perpetration With Suicidality in Early Adolescence

Adolescent suicidality (ie, suicidal ideation or attempts) is a major public health concern. Cyberbullying experiences and perpetration have become increasingly prevalent and are associated with mental health burden, but their roles as independent suicidality risk factors remain unclear. Data are needed to clarify their contribution to teen suicidality to inform suicide prevention efforts. To examine whether cyberbullying experiences and perpetration are distinct stressors divergent from other forms of peer aggression experiences in their association with suicidality in early adolescence. This cross-sectional analysis used data collected between July 2018 and January 2021 from the Adolescent Brain Cognitive Development (ABCD) study, a large, diverse sample of US children aged 10 to 13 years. Youth reports of cyberbullying experiences or perpetration. The main outcome was youth-reported suicidality (past or present, as reported in the ABCD 2-year follow-up assessment). Covariates included demographics, established environmental risk and protective factors for youth suicidality, psychopathology, and experiences or perpetration of offline peer aggression. A total of 10 414 ABCD participants were included in this study. Participants had a mean (SD) age of 12.0 (0.7) years and 4962 (47.6%) were female; 796 (7.6%) endorsed suicidality. A total of 930 (8.9%) reported experiencing cyberbullying and 96 (0.9%) reported perpetrating cyberbullying. Of the perpetrators, 66 (69.0%) also endorsed experiencing cyberbullying. Controlling for demographics, experiencing cyberbullying was associated with suicidality (odds ratio [OR], 4.2 [95% CI, 3.5-5.1]; P < .001), whereas perpetrating cyberbullying was not (OR, 1.3 [95% CI, 0.8-2.3]; P = .30). Experiencing cyberbullying remained associated with suicidality when accounting for negative life events, family conflict, parental monitoring, school environment, and racial and ethnic discrimination (OR, 2.5 [95% CI, 2.0-3.0]; P < .001) and when further covarying for internalizing and externalizing psychopathology (OR, 1.8 [95% CI, 1.4-2.4]; P < .001). Both being a target and being a perpetrator of offline peer aggression were associated with suicidality (OR, 1.5 [95% CI, 1.1-2.0] for both), controlling for all covariates described earlier. Cyberbullying experiences remained associated with suicidality (OR, 1.7 [95% CI, 1.3-2.2]; P < .001, controlling for all covariates) when included with offline peer aggression experiences and perpetration. In this cross-sectional study, experiencing-but not perpetrating-cyberbullying was associated with suicidality in early adolescence. This association was significant over and above other suicidality risk factors, including offline peer aggression experiences or perpetration. These findings can inform adolescent suicide prevention strategies, and they suggest that clinicians and educational staff working with this population should routinely evaluate for adolescents' experience with cyberbullying.

Association between germline pathogenic variants and breast cancer risk in Japanese women: The HERPACC study.

Approximately 5%–10% of breast cancers are hereditary, caused by germline pathogenic variants (GPVs) in breast cancer predisposition genes. To date, most studies of the prevalence of GPVs and risk of breast cancer for each gene based on cases and noncancer controls have been conducted in Europe and the United States, and little information from Japanese populations is available. Furthermore, no studies considered confounding by established environmental factors and single‐nucleotide polymorphisms (SNPs) identified in genome‐wide association studies (GWAS) together in GPV evaluation. To evaluate the association between GPVs in nine established breast cancer predisposition genes including BRCA1/2 and breast cancer risk in Japanese women comprehensively, we conducted a case‐control study within the Hospital‐based Epidemiologic Research Program at Aichi Cancer Center (629 cases and 1153 controls). The associations between GPVs and the risk of breast cancer were assessed by odds ratios (OR) and 95% confidence intervals (CI) using logistic regression models adjusted for potential confounders. A total of 25 GPVs were detected among all cases (4.0%: 95% CI: 2.6–5.9), whereas four individuals carried GPVs in all controls (0.4%). The OR for breast cancer by all GPVs and by GPVs in BRCA1/2 was 12.2 (4.4–34.0, p = 1.74E‐06) and 16.0 (4.2–60.9, p = 5.03E‐0.5), respectively. A potential confounding with GPVs was observed for the GWAS‐identified SNPs, whereas not for established environmental risk factors. In conclusion, GPVs increase the risk of breast cancer in Japanese women regardless of environmental factors and GWAS‐identified SNPs. Future studies investigating interactions with environment and SNPs are warranted.

Timing of maternal immune activation and sex influence schizophrenia-relevant cognitive constructs and neuregulin and GABAergic pathways

Maternal immune activation (MIA) during pregnancy is an established environmental risk factor for schizophrenia. Timing of immune activation exposure as well as sex of the exposed offspring are critical factors in defining the effects of MIA. However, the specificity of MIA on the component structure of schizophrenia, especially cognition, has been difficult to assess due to a lack of translational validity of maze-like testing paradigms. We aimed to assess cognitive domains relevant to schizophrenia using highly translational touchscreen-based tasks in male and female mice exposed to the viral mimetic, poly(I:C) (5 mg/k, i.p.), during early (gestational day (GD) 9–11) and late (GD13-15) gestational time points. Gene expression of schizophrenia candidate pathways were assessed in fetal brain immediately following poly(I:C) exposure and in adulthood to identify its influence on neurodevelopmental processes.Sex and window specific alterations in cognitive performance were found with the early window of MIA exposure causing female-specific disruptions to working memory and reduced perseverative behaviour, while late MIA exposure caused male-specific changes to working memory and deficits in reversal learning. GABAergic specification marker, Nkx2.1 gene expression was reduced in fetal brains and reelin expression was reduced in adult hippocampus of both early and late poly(I:C) exposed mice. Neuregulin and EGF signalling were initially upregulated in the fetal brain, but were reduced in the adult hippocampus, with male mice exposed in the late window showing reduced Nrg3 expression. Serine racemase was reduced in both fetal and adult brain, but again, adult reductions were specific to male mice exposed at the late time point. Overall, we show that cognitive constructs relevant to schizophrenia are altered by in utero exposure to maternal immune activation, but are highly dependent on the timing of infection and the sex of the offspring. Glutamatergic and epidermal growth factor pathways were similarly altered by MIA in a timing and sex dependent manner, while MIA-induced GABAergic deficits were independent of timing or sex.

P70.05 Identification of Germline Mutations in Young Never Smokers With Lung Adenocarcinoma by Whole Exome Sequencing

Recently, an increasing number of young never-smokers were diagnosed with lung cancer. Although environmental risk factors such as second-hand smoke, radon, and indoor air pollutants might cause never-smoking lung cancer, a large proportion of these patients do not have a definite association with established environmental risk factors. The aim of this study was to investigate the genetic predisposition of lung cancer in these patients and discover candidate pathogenic variants for lung adenocarcinoma in young never-smokers.

A Personal Breast Cancer Risk Stratification Model Using Common Variants and Environmental Risk Factors in Japanese Females.

Simple SummaryBreast cancer remains the most common cancer in females, warranting the development of new approaches to prevention. One such approach is personalized prevention using genetic risk models. Here, we developed a risk model using both genetic and environmental risk factors. Results showed that a genetic risk score defined by the number of risk alleles for 14 breast cancer risk SNPs clearly stratified breast cancer risk. Moreover, the combination of this genetic risk score model with an environmental risk model which included established environmental risk factors showed significantly better C-statistics than the environmental risk model alone. This genetic risk score model in combination with the environmental model may be suitable for stratifying individual breast cancer risk, and may form the basis for a new personalized approach to breast cancer prevention.Personalized approaches to prevention based on genetic risk models have been anticipated, and many models for the prediction of individual breast cancer risk have been developed. However, few studies have evaluated personalized risk using both genetic and environmental factors. We developed a risk model using genetic and environmental risk factors using 1319 breast cancer cases and 2094 controls from three case–control studies in Japan. Risk groups were defined based on the number of risk alleles for 14 breast cancer susceptibility loci, namely low (0–10 alleles), moderate (11–16) and high (17+). Environmental risk factors were collected using a self-administered questionnaire and implemented with harmonization. Odds ratio (OR) and C-statistics, calculated using a logistic regression model, were used to evaluate breast cancer susceptibility and model performance. Respective breast cancer ORs in the moderate- and high-risk groups were 1.69 (95% confidence interval, 1.39–2.04) and 3.27 (2.46–4.34) compared with the low-risk group. The C-statistic for the environmental model of 0.616 (0.596–0.636) was significantly improved by combination with the genetic model, to 0.659 (0.640–0.678). This combined genetic and environmental risk model may be suitable for the stratification of individuals by breast cancer risk. New approaches to breast cancer prevention using the model are warranted.

Ethnicity Influences Risk of Inflammatory Bowel Disease (IBD)-Associated Colon Cancer: A Cross-sectional Analysis of Dysplasia Prevalence and Risk Factors in Hispanics and Non-Hispanic Whites With IBD

BackgroundInflammatory bowel disease (IBD) is an emerging disease in Hispanics. In this study, we examine the prevalence of IBD-related colon dysplasia (IBD-dys) in Hispanics versus non-Hispanic whites (NHWs) and compare differences in established clinical and environmental risk factors.MethodsWe performed a cross-sectional analysis on adult Hispanics and NHWs with IBD who met criteria for colorectal cancer surveillance and were followed at our center between 2008 and 2018. Clinical variables and IBD phenotype were recorded. Lifestyle IBD-dys risk factors were examined, including smoking and lack of physical activity. Using multivariable regression, we compared the prevalence of IBD-dys in Hispanics versus NHW, using relevant covariates. Receiver operating characteristic and area under the curve were performed to find the best fitting model.ResultsA total of 445 IBD patients were included (148 Hispanics and 297 NHWs). IBD phenotype was similar between groups, except that Hispanics had shorter disease duration, a lower frequency of Crohn’s disease-related complications, and lower reported use of steroids. Frequency of surveillance colonoscopies was similar between Hispanics and NHW. There were no differences in median body mass index between Hispanics and NHW [26.5 (IQR 6.0) vs 25.0 (IQR 6.0), P = 0.40]. Hispanics were less likely than NHW to consume alcohol but smoking history was similar between groups. Three out of 148 Hispanic patients had IBD-dys (2.02%) compared to 29 out of 297 NHWs (9.76%). Adjusting for disease duration, primary sclerosing cholangitis, family history of colon cancer, and smoking, Hispanics had a lower prevalence of IBD-dys compared to NHW [ORadjusted = 0.207 (95% CI 0.046–0.938), P = 0.008].ConclusionsHispanics with IBD undergoing surveillance had a lower prevalence of IBD-dys than their NHW counterparts, despite similar risk factors. Future studies should examine dietary and microbial factors that may explain differences in risk.

Prenatal Stress Impairs Spinal Cord Oligodendrocyte Maturation via BDNF Signaling in the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis

One of the most substantial and established environmental risk factors for neurological and psychiatric disorders is stress exposure, whose detrimental consequences hinge on several variables including time. In this regard the gestational period is known to present an intrinsic vulnerability to environmental insults and thus stressful events during pregnancy can lead to severe consequences on the offspring’s brain development with long-term repercussions throughout adulthood. On this basis, we investigated the long-lasting impact of prenatal stress exposure on the susceptibility to the experimental autoimmune encephalomyelitis (EAE), a well-established murine model of multiple sclerosis. Although stress is considered a triggering factor for this chronic, progressive, autoimmune disease, little is known about the underlying mechanisms. To this end, EAE was induced by immunization with MOG35-55/CFA and pertussis toxin administration in adult female C57BL/6 mice born from control or stressed dams exposed to restraint stress during the last days of gestation. Our results demonstrate that gestational stress induces a marked increase in the severity of EAE symptoms in adulthood. Further, we highlight an altered maturation of oligodendrocytes in the spinal cord of prenatally stressed EAE mice, as indicated by the higher levels of GPR17, a marker of immature oligodendrocyte precursor cells. These behavioral and molecular alterations are paralleled by changes in the expression and signaling of the neurotrophin BDNF, an important mediator of neural plasticity that may contribute to stress-induced impaired remyelination. Since several already marketed drugs are able to modulate BDNF levels, these results pave the way to the possibility of repositioning these drugs in multiple sclerosis.

Primary CNS tumors in adults and environmental factors: an update

The incidence of adult primary brain tumors is increasing in some European countries. High-dose ionizing irradiation, rare genetic syndromes, and genetic predisposition in 5 % of families are a few established environmental risk factors for brain tumor. Mobile phone use that causes near brain exposure to radiofrequency electromagnetic waves and thus creates risks of CNS tumors has been the focus of many studies. Nine meta-analyses were available on this subject. The Interphone multi-center case-control study is the largest one to date; it included 2.708 glioma and 2.409 meningioma cases and matched controls in 13 countries. Studies exploring metals (cadmium, lead), pesticides, outdoor pollution, virus, and risk of glioma created by exposure to them were reviewed. Interphone study did not show increased risk of glioma or meningioma in mobile-phone users. One recent meta-analysis in 2017 found that prolonged exposure i.e.,&gt; 10 years of all phone types was associated with increased risk of ipsilateral CNS tumor locations. In another meta-analysis, long-term use of mobile-phones was found to be a risk factor for low-grade glioma. In case of all durations regarding mobile phone use and both sides of the head, the results of pooling data were more discordant. A large prospective study in 2014 showed that long term use vs never use increased risks of acoustic neurinoma (10+ years: RR = 2.46, 95 % CI = 1.07–5.64, P = 0.03), but not of glioma or meningioma. Studies of other risk factors showed no/weak/contradictory association with brain tumor risk. In the absence of robust and consistent evidence, a causal relation between radiofrequency exposure and CNS tumors was not found. Large prospective studies of this kind regarding a disease with low incidence require a high number of participants and a long follow-up period.

Первичные опухоли центральной нервной системы у взрослого населения и факторы окружающей среды: обновленный обзор существующих публикаций

The incidence of adult primary brain tumors is increasing in some European countries. High-dose ionizing irradiation, rare genetic syndromes, and genetic predisposition in 5 % of families are a few established environmental risk factors for brain tumor. Mobile phone use that causes near brain exposure to radiofrequency electromagnetic waves and thus creates risks of CNS tumors has been the focus of many studies. Nine meta-analyses were available on this subject. The Interphone multi-center case-control study is the largest one to date; it included 2.708 glioma and 2.409 meningioma cases and matched controls in 13 countries. Studies exploring metals (cadmium, lead), pesticides, outdoor pollution, virus, and risk of glioma created by exposure to them were reviewed. Interphone study did not show increased risk of glioma or meningioma in mobile-phone users. One recent meta-analysis in 2017 found that prolonged exposure i.e.,&gt; 10 years of all phone types was associated with increased risk of ipsilateral CNS tumor locations. In another meta-analysis, long-term use of mobile-phones was found to be a risk factor for low-grade glioma. In case of all durations regarding mobile phone use and both sides of the head, the results of pooling data were more discordant. A large prospective study in 2014 showed that long term use vs never use increased risks of acoustic neurinoma (10+ years: RR = 2.46, 95 % CI = 1.07–5.64, P = 0.03), but not of glioma or meningioma. Studies of other risk factors showed no/weak/contradictory association with brain tumor risk. In the absence of robust and consistent evidence, a causal relation between radiofrequency exposure and CNS tumors was not found. Large prospective studies of this kind regarding a disease with low incidence require a high number of participants and a long follow-up period.

Evidence for an interrelated cluster of Hallucinatory experiences in the general population: an incidence study.

Although hallucinations have been studied in terms of prevalence and its associations with psychopathology and functional impairment, very little is known about sensory modalities other than auditory (i.e. haptic, visual and olfactory), as well the incidence of hallucinations, factors predicting incidence and subsequent course. We examined the incidence, course and risk factors of hallucinatory experiences across different modalities in two unique prospective general population cohorts in the same country using similar methodology and with three interview waves, one over the period 1996-1999 (NEMESIS) and one over the period 2007-2015 (NEMESIS-2). In NEMESIS-2, the yearly incidence of self-reported visual hallucinations was highest (0.33%), followed by haptic hallucinations (0.31%), auditory hallucinations (0.26%) and olfactory hallucinations (0.23%). Rates in NEMESIS-1 were similar (respectively: 0.35%, 0.26%, 0.23%, 0.22%). The incidence of clinician-confirmed hallucinations was approximately 60% of the self-reported rate. The persistence rate of incident hallucinations was around 20-30%, increasing to 40-50% for prevalent hallucinations. Incident hallucinations in one modality were very strongly associated with occurrence in another modality (median OR = 59) and all modalities were strongly associated with delusional ideation (median OR = 21). Modalities were approximately equally strongly associated with the presence of any mental disorder (median OR = 4), functioning, indicators of help-seeking and established environmental risk factors for psychotic disorder. Hallucinations across different modalities are a clinically relevant feature of non-psychotic disorders and need to be studied in relation to each other and in relation to delusional ideation, as all appear to have a common underlying mechanism.

Dental X-Rays and the Risk of Thyroid Cancer and Meningioma: A Systematic Review and Meta-Analysis of Current Epidemiological Evidence.

Background: Exposure to moderate-to-high doses of ionizing radiation is the only established environmental risk factor for thyroid cancer and brain and central nervous system tumors. Considering the high lifetime prevalence and frequency of exposure to dental X-rays, the most common source of diagnostic radiation exposure in the general population, even a small associated increase in cancer risk would be of considerable public health importance. With the objective to inform clinical practice and guidelines, we synthesized the current epidemiological evidence on the association between dental X-rays and the risk of thyroid cancer, meningioma, and other cancers of the head and neck region. Methods: The Medline, Embase, and Web of Science databases were searched to identify eligible studies. Summary odds ratio/relative risk estimates and confidence intervals were extracted, and pooled risk ratios (RRs) for each cancer were calculated using random effects meta-analysis. Results: The literature search identified 5537 publications; of these, 26 studies including 10,868 cancer patients were included in the synthesis. The random effects meta-analyses, based on seven studies of thyroid cancer (six case/control, one cohort) and eight studies of meningioma (all case/control), showed that multiple (or repeated) exposures to dental X-rays were significantly associated with an increased risk of thyroid cancer (pooled RR = 1.87 [95% confidence interval, CI 1.11-3.15]) and meningioma (pooled RR = 1.53 [CI 1.26-1.85]). There was no association with glioma, and there were too few studies of other cancers of the head and neck region to conduct a meaningful meta-analysis. Conclusions: Based on a meta-analysis of retrospective case/control studies, these findings provide some support to the hypothesis that multiple (or repeated) exposures to dental X-rays may be associated with an increased risk of thyroid cancer and meningioma. These studies did not include individual organ doses and ages at exposure, and are subject to recall bias and other limitations. Furthermore, the thyroid exposure has decreased dramatically over time from the use of thyroid shields and improved technology/equipment. Prospective studies, based on dental X-ray records and patient follow-up, are needed to test the hypothesis further and clarify the possible cancer risk associated with dental radiography, as although the risk at the individual level, particularly with improved technology/equipment, is likely to be very low, the proportion of the population exposed is high. Considering that about one-third of the general population in developed countries is routinely exposed to one or more dental X-rays per year, these findings manifest the need to reduce diagnostic radiation exposure as much as possible.

M18 GENOME-WIDE STUDY OF GENE-BASED INTERACTIONS WITH FOUR ENVIRONMENTAL RISK FACTORS FOR AGGRESSIVE BEHAVIOR IN CHILDREN AND ADOLESCENTS IMPLICATES OPIOID SIGNALING

Background: Aggressive behavior in children and adolescents is caused by complex interactions of genetic and environmental factors (GxE-interactions). In this respect, environmental adversities lead to aggression in some individuals depending on their genetic make-up. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we conducted a genome-wide study of gene-based interactions with four established environmental risk factors for aggressive behavior. Methods: Genome-wide genotyping data were available for 8941 children and adolescents. For up to 5214 of these, we had data for eight disruptive behavior-related traits that measure aggression. Environmental adversities were maternal paracetamol use, life events and smoking during pregnancy, and child maltreatment after birth. Following GxE-interaction analyses, we investigated whether specific canonical pathways were enriched in our data. Results: We discovered 686 significant gene-based GxEinteractions (involving 589 unique genes) that survived correction for multiple testing ( α≈7.90E-08) and explained up to 39% of the phenotypic variance associated with each interaction. In total, 326 genes interacted with maternal smoking, 272 genes with maternal life events, 73 genes with paracetamol use, and 2 genes with child maltreatment. Across all interactions, the top 5 genes were AKR1C1, CSMD1, FBXL14, PODNL1, and TMEM132D. Further, opioid signaling emerged as the only canonical pathway that was significantly enriched in multiple sets of GxE-implicated genes. Discussion: The interaction of multiple genes with four environmental factors is related to aggressive behavior in children and adolescents. Some of these genes have been previously implicated in aggression, including NOS1AP, NOS3, RBFOX1, and TMEM132D. In addition, opioid signaling is a key molecular cascade underlying the identified GxEinteractions.

Abstract SY26-02: Sherlock-Lung: Tracing lung cancer mutational processes in never smokers

Abstract Globally, about 2 million people are diagnosed with lung cancer annually, making it the most common type of cancer in the world. In addition, lung cancer is the leading cause of cancer death among both men and women, accounting for ~25% of all cancer deaths in the United States and ~19% of cancer deaths worldwide. Although tobacco smoking is the most common cause of lung cancer, it is estimated that 10-25% of all patients diagnosed with lung cancer worldwide are never smokers, with higher proportions in Asians and women. Compared to former and current smokers with lung cancer, lung cancers in never smokers tend to present at an earlier age and more frequently have adenocarcinoma histology. Although a few risk factors are known to contribute to the etiology of lung cancer in never smokers, a large fraction of cancer cases cannot be explained by established environmental and genetic risk factors, highlighting the need for research in this area. One promising approach to identify the etiological factors involved in lung tumorigenesis in never smokers is based on the study of the “mutational signatures” that the exogenous and endogenous processes leave on the tumor tissue and surrounding areas. Somatic mutations accumulate throughout individuals’ lifetime, as a result of the balance between DNA damage and DNA repair. Mutational sources can change over time and mutational signatures can provide information on the tumor evolutionary trajectory, tracking activities of mutational processes. We designed “Sherlock-Lung” to identify mutational signatures in lung cancers from never smokers and order them based on their clonal and subclonal localization to have an insight on the factors involved in the initiation of the tumors. Prevention and treatment strategies are likely to be more effective when targeting the tumor initiating factors rather than those responsible for the tumor progression. Here, we present the Sherlock-Lung study design, which includes a combination of lung cancer cases from populations highly exposed to lung cancer risk factors and populations with unknown exposures. We also present preliminary data from this study and what we have learned from whole genome sequencing analysis of the mutational landscape of lung cancers from smokers and nonsmokers and from different histological subtypes. For example, although the mutational signature associated with tobacco smoking is largely clonal in all lung cancers from smokers, consistent with an initiating role of tobacco smoking in lung tumorigenesis, the mutational signatures distribution varies across histological subtypes. Moreover, the frequency of mutations in major cancer driver genes varies dramatically between smokers and never smokers, and mutational signatures distribution appears to differ between tumors with and without specific driver genes. In never smokers, without the dominant mutational source of tobacco smoking, other signatures emerged, e.g., that associated with reactive oxygen species. Although this approach has already revealed important information on the etiological processes involved in tumorigenesis of lung cancer and other cancer types, there is a growing list of open questions and challenges that need to be addressed. In population studies, careful exposure assessment to identify and validate new mutational signatures and the inclusion of study subjects from different geographical locations and ethnicities are critical. Citation Format: Maria Teresa Landi, Tongwu Zhang, Montserrat Garcia-Closas, Yohan Bossé, Jianxin Shi, Bin Zhu, Qing Lan, Nathaniel Rothman, Jiyeon Choi, Neil E. Caporaso, Wei Zhao, Chongyi Chen, Eytan Ruppin, Jennifer Rosenbaum, Dmitry Gordenin, Sai Yendamuri, Chris Amos, Paul Brennan, David C. Christiani, Geoff Liu, Bonnie Gould Rothberg, Matthew Schabath, Han Liang, Ludmil Alexandrov, David Wedge, Stephen Chanock. Sherlock-Lung: Tracing lung cancer mutational processes in never smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY26-02.

Is urban living good for mental health?

The questions of urban living, mental health and well-being are complex issues correlated to many interacting factors. The purpose of this review is to provide data on mental health challenges of urban life and perspectives to address these challenges. Urbanization may cause mental health problems, such as psychotic experiences, depression and stress-related disorders, particularly in vulnerable individuals. Challenges of urban living are even greater in developing countries, because of other urgent problems these countries are facing. New findings identified distinct neural mechanisms for an established environmental risk factor, linking the urban environment to social stress processing. Nature-based solutions may be helpful in preventing mental disorders and in alleviating psychological symptoms. The data of impact of urban living on mental health are still controversial and mechanism of association is unclear. Urban living may be related to biological or social/environmental factors or both. Most probably, urbanicity has a synergistic effect with genetic vulnerability. Interdisciplinary and intersectoral actions are needed to meet urban living challenges, such as providing access to green space and mental health services, decrease of poverty, homelessness and emerging problems of immigration to cities.

Gene-Environment Interactions and the Risk of Barrett's Esophagus in Three US Cohorts.

Several single-nucleotide polymorphisms (SNPs) have been associated with Barrett's esophagus (BE) risk. In addition, environmental factors including smoking, alcohol consumption, and heartburn increase BE risk. However, data on potential interactions between these genetic and environmental factors on BE risk are scant. Understanding how genes and environmental risk factors interact may provide key insight into the pathophysiology of BE, and potentially identify opportunities for targeted prevention and treatment. The objectives of this study were to examine the main effects and the potential effect modification between known genetic loci (SNPs) and established environmental risk factors for BE. We performed a nested case-control study using data on 401 incident BE cases and 436 age-matched controls from the Nurses' Health Study, Nurses' Health Study II, and Health Professionals Follow-up Study cohorts, who gave blood and completed biennial questionnaires. Overall, we genotyped 46 SNPs identified in previous BE genome-wide association studies as well as SNPs in candidate genes related to BE susceptibility (i.e., related to excess body fat, fat distribution, factors associated with insulin resistance, and inflammatory mediators). A genetic risk score (GRS) was constructed to evaluate the combined effect of the selected SNPs on BE risk. Interactions between SNPs and BE risk factors were also assessed. We observed a suggestive, but not statistically significant, association between our GRS and BE risk: a one-allele increase in the unweighted GRS increased the risk of BE by a factor of 1.20 (95% confidence interval = 1.00-1.44; P = 0.057). We did not observe any meaningful multiplicative interactions between smoking, alcohol consumption, or heartburn duration and BE genotypes. When we assessed the joint effect of weighted GRS and BE risk factors, we did not observe any significant interaction with alcohol and heartburn duration, whereas smoking showed a significant multiplicative interaction (P = 0.016). Our results suggest that SNPs associated with BE at genome-wide significant levels can be combined into a GRS with a potential positive association with BE risk.