Significant Gene-environment Interaction Research Articles

Maternal seafood intake, dietary contaminant exposure, and risk of juvenile idiopathic arthritis: exploring gene-environment interactions.

Juvenile idiopathic arthritis (JIA) originates from a complex interplay between genetic and environmental factors. We investigated the association between seafood intake and dietary contaminant exposure during pregnancy and JIA risk, to identify sex differences and gene-environment interactions. We used the Norwegian Mother, Father, and Child Cohort Study (MoBa), a population-based prospective pregnancy cohort (1999-2008). JIA patients were identified through the Norwegian Patient Registry, with remaining mother-child pairs serving as controls. We assessed maternal seafood intake and dietary contaminants typically found in seafood using a food frequency questionnaire completed during pregnancy, mainly comparing high (≥90th percentile, P90) vs low (<P90) intake. Multivariable logistic regression calculated adjusted odds ratios (aOR), including sex-stratification analyses. A polygenic risk score (PRS) for JIA was used in a subsample to assess gene-environment interactions. We identified 217 JIA patients and 71,884 controls. High vs low maternal intake of lean/semi-oily fish was associated with JIA (aOR 1.51, 95% CI 1.02-2.22), especially among boys (aOR 2.13, 95% CI 1.21-3.75). A significant gene-environment interaction was observed between total fish intake and PRS, with high fish intake associated with JIA primarily in those with low PRS (p<0.03). We found no associations between high vs low exposure to other types of seafood or environmental contaminants and JIA. We found a modestly increased risk of JIA associated with high intake of lean/semi-oily fish during pregnancy, not explained by estimated exposure to dietary contaminants. Our data suggest a more pronounced association in children with a lower genetic predisposition for JIA.

Gene-environment interactions in the influence of maternal education on adolescent neurodevelopment using ABCD study.

Maternal education was strongly correlated with adolescent brain morphology, cognitive performances, and mental health. However, the molecular basis for the effects of maternal education on the structural neurodevelopment remains unknown. Here, we conducted gene-environment-wide interaction study using the Adolescent Brain Cognitive Development cohort. Seven genomic loci with significant gene-environment interactions (G×E) on regional gray matter volumes were identified, with enriched biological functions related to metabolic process, inflammatory process, and synaptic plasticity. Additionally, genetic overlapping results with behavioral and disease-related phenotypes indicated shared biological mechanism between maternal education modified neurodevelopment and related behavioral traits. Finally, by decomposing the multidimensional components of maternal education, we found that socioeconomic status, rather than family environment, played a more important role in modifying the genetic effects on neurodevelopment. In summary, our study provided analytical evidence for G×E effects regarding adolescent neurodevelopment and explored potential biological mechanisms as well as social mechanisms through which maternal education could modify the genetic effects on regional brain development.

Genetic Determinants of Thiazide-Induced Hyperuricemia, Hyperglycemia, and Urinary Electrolyte Disturbances - A Genome-Wide Evaluation of the UK Biobank.

Thiazide diuretics, widely used in hypertension, cause a variety of adverse reactions, including hyperglycemia, hyperuricemia, and electrolyte abnormalities. In this study, we aimed to identify genetic variants that interact with thiazide-use to increase the risk of these adverse reactions. Using UK Biobank data, we first performed genomewide variance quantitative trait locus (vQTL) analysis of ~ 6.2 million SNPs on 95,493 unrelated hypertensive White British participants (24,313 on self-reported bendroflumethiazide treatment at recruitment) for 2 blood (glucose and urate) and 2 urine (potassium and sodium) biomarkers. Second, we conducted direct gene-environment interaction (GEI) tests on the significant (P < 2.5 × 10-9) vQTLs, included a second UK Biobank cohort comprising 13,647 unrelated hypertensive White British participants (3,478 on thiazides other than bendroflumethiazide) and set significance at P = 0.05 divided by the number of vQTL SNPs tested for GEIs. The vQTL analysis identified eight statistically significant SNPs for blood glucose (5 SNPs) and serum urate (3 SNPs), with none being identified for the urinary biomarkers. Two of the SNPs (1 glucose SNP: CDKAL1 intron rs35612982, GEI P = 6.24 × 10-3; and 1 serum urate SNP: SLC2A9 intron rs938564, GEI P = 4.51 × 10-4) demonstrated significant GEI effects in the first, but not the second, cohort. Both genes are biologically plausible candidates, with the SLC2A9-mediated interaction having been previously reported. In conclusion, we used a two-stage approach to detect two biologically plausible genetic loci that can interact with thiazides to increase the risk of thiazide-associated biochemical abnormalities. Understanding how environmental exposures (including medications such as thiazides) and genetics interact, is an important step toward precision medicine and improved patient outcomes.

Prevalence, associated factors, and gene polymorphisms of obesity in Tibetan adults in Qinghai, China

ObjectivesTo explore the prevalence and associated factors of obesity in Tibetan adults in Qinghai, China, and to determine the association between the FTO (rs1121980 and rs17817449) and MC4R gene (rs17782313 and rs12970134) polymorphisms with obesity.MethodsA cross-sectional survey was conducted in 2015 in Qinghai to selected Tibetan adults aged 20 to 80 years. Prevalence of obesity (BMI ≥ 28 kg/m2) and overweight (BMI 24 ~ 27.9 kg/m2) were evaluated. Multivariable logistic models were used to determine the associated factors. Pair-matched subjects of obesity cases and normal-weight controls were selected for the gene polymorphism analyses. Conditional logistic models were used to assess the association between gene polymorphisms with obesity. Additive and multiplicative gene-environment interactions were tested.ResultsA total of 1741 Tibetan adults were enrolled. The age- and sex- standardized prevalence of obesity and overweight was 18.09% and 31.71%, respectively. Male sex, older age, heavy level of leisure-time exercise, current smoke, and heavy level of occupational physical activity were associated with both obesity and overweight. MC4R gene polymorphisms were associated with obesity in Tibetan adults. No significant gene-environment interaction was detected.ConclusionThe prevalence of obesity and overweight in Tibetan adults was high. Both environmental and genetic factors contributed to the obesity prevalent.

Interplay between polygenic risk for mood disorders and stressful life events in bipolar disorder

BackgroundAlthough genetic and environmental factors are involved in the aetiology of bipolar disorder [BD], studies focused on their interplay are lacking. The current investigation examines interactions and correlations between polygenic risk scores [PRS] for BD and major depressive disorder [MDD] with stressful life events [SLEs] in liability for BD. MethodsThis study used data from 1715 participants (862 bipolar cases and 853 controls) taken from UK and Canadian samples. The List of Threatening Experiences Questionnaire recorded SLEs that occurred 6 months before interview for controls and 6 months prior to the first (Canadian sample) and worst (UK sample) depressive and manic episodes for bipolar cases. PRS-BD and PRS-MDD were calculated from the Psychiatric Genomics Consortium. ResultsFor the worst depressive episode, the PRS-MDD was significantly correlated with total number of SLEs (β = 0.13, 95 % CI:0.04–0.22, p = 0.003) and dependent SLEs (β = 0.09, 95 % CI:0.02–0.16, p = 0.007). After correction for multiple testing nominally significant correlations were detected for PRS-BD with total number of SLEs (β = 0.11, 95 % CI:0.02–0.20, p = 0.015) and dependent SLEs (β = 0.08, 95 % CI:0.01–0.15, p = 0.019). Among bipolar cases, these associations were slightly stronger but were only of nominal significance for total number of SLEs (PRS-MDD: β = 0.19, 95 % CI:0.04–0.35, p = 0.015; PRS-BD: β = 0.16, 95 % CI:0.01–0.32, p = 0.042) and dependent SLEs (PRS-MDD: β = 0.14, 95 % CI:0.03–0.26, p = 0.015; PRS-BD: β = 0.12, 95 % CI:0.004–0.24, p = 0.043). No other significant gene-environment correlations or interactions were found. LimitationsUse of a larger sample size would be beneficial. ConclusionsThe relationship between SLEs and genetic risk for mood disorders may be best explained through correlations rather than interactions.

Association between birth by caesarian section and anxiety, self-harm: a gene-environment interaction study using UK Biobank data

BackgroundLimited efforts have been paid to explore the underlying genetic mechanisms of birth by caesarian section (CS) affecting the risks of adult anxiety and self-harm.MethodsUsing UK Biobank cohort, the logistic regression model was first applied to evaluate the associations of adult anxiety and self-harm with birth by CS. Using birth by CS as exposure variables, genome-wide by environment interaction study (GWEIS) was then applied by PLINK2.0 to identify associated genes interacting with birth by CS for anxiety and self-harm.ResultsIn the observational study, significant associations were observed between birth by CS and anxiety (odds ratio (OR) = 1.24; 95% confidence interval (CI), 1.12–1.38; P = 4.86 × 10− 5), and self-harm (OR = 1.12; 95% CI, 1.01–1.24; P = 2.90 × 10− 2). GWEIS revealed multiple suggestive genes interacted with birth by CS for anxiety, such as DKK2 (rs13137764, P = 1.24 × 10− 9, adjusted P = 2.68 × 10− 7) and ATXN1 (rs62389045, P = 4.38 × 10− 8, adjusted P = 3.55 × 10− 6). For self-harm, significant gene-environment interactions of birth by CS on self-harm were detected, such as ALDH1A2 (rs77828167, P = 1.62 × 10− 8; rs116899929, P = 1.92 × 10− 8) and DAB1 (rs116124269, P = 3.20 × 10− 8; rs191070006, P = 3.63 × 10− 8).ConclusionsOur results suggested that birth by CS was associated with the risk of adult anxiety and self-harm. We also discovered some genes interacted with birth by CS might influence the risk of anxiety and self-harm, which may provide novel clues for the pathogenesis of those mental disorders.

Gene-environment interaction in the association of residential greenness and 25(OH) vitamin D

There is increasing awareness for beneficial health effects of green space surrounding the home, but the underlying mechanisms are not yet fully understood and challenging to study given the correlation with other exposures. Here, the association of residential greenness and vitamin D including a gene-environment interaction is investigated. 25-hydroxyvitamin D (25(OH)D) was measured by electrochemiluminescence at ages 10 and 15 years in participants of two German birth cohorts GINIplus and LISA. Greenness was measured using the Landsat-derived Normalized Difference Vegetation Index (NDVI) in a 500 m buffer surrounding the home. Linear and logistic regression models were applied at both time points adjusted for several covariates (N10Y = 2,504, N15Y = 2,613). In additional analyses vitamin D-related genes, physical activity, time spent outdoors, supplements, and measurement season were investigated as potential confounders or effect modifiers. A 1.5-SD increase in NDVI was significantly associated with increased 25(OH)D values at ages 10 and 15 years (β10y = 2.41 nmol/l, p=<0.01; β15y = 2.03 nmol/l, p = 0.02). In stratified analyses, the associations were not seen in participants spending more than 5 h/day outside in summer, having a high physical activity level, taking supplements, or being examined during the winter season. In a subset (n = 1,732) with genetic data, a significant gene-environment interaction of NDVI with CYP2R1, an upstream gene in 25(OH)D synthesis, was observed at age 10 years. When investigating 25(OH)D sufficiency, defined as values above 50 nmol/l, a 1.5-SD increase in NDVI was associated with significantly higher odds of having sufficient 25 (OH)D levels at age 10 years (OR = 1.48, 1.19–1.83). In conclusion, robust associations between residential greenness and 25 (OH)D levels were observed in children and adolescents independent of other confounders and additionally supported by the presence of a gene-environment interaction. Effects of NDVI were stronger in those having lower vitamin D levels at age 10 years due to their covariate profile or genetically lower 25(OH)D synthesis.

Longitudinal Influences of DRD4 Polymorphism and Early Maternal Caregiving on Personality Development and Problem Behavior in Middle Childhood and Adolescence.

Most studies examining gene-environment effects on self-regulation focus on outcomes early childhood or adulthood. However, only a few studies investigate longitudinal effects during middle childhood and adolescence and compare two domains of early caregiving. In a longitudinal follow-up with a sample of N = 87, we studied the effects of differences in the DRD4 tandem repeat polymorphisms and two domains of early maternal caregiving quality on children’s personality development using Block’s California Child Q-Set (CCQ) at age six and age 12 and on problem behavior at ages six and seven. Early maternal regulation quality predicted later ego-resiliency and aggressiveness. In addition, significant gene-environment interactions revealed that children with the 7+ DRD4 tandem repeat polymorphism and poor maternal regulation quality in infancy showed lower scores in ego-resiliency and higher scores in ego-undercontrol and CCQ aggressiveness. In contrast, children who had experienced effective maternal regulation in infancy showed a comparable level in personality traits and problem behavior as the DRD4 7- group independent of the levels of maternal regulatory behavior. Similarly, longitudinal caregiving × DRD4 interactions were found for behavior problems in middle childhood, especially for oppositional-aggression, inattentive-hyperactivity, and social competence. Early caregiving effects were only found for maternal regulation quality, but not for maternal responsiveness. Effective early maternal regulation in infancy can moderate the negative effect of DRD4 7+ on children’s self-regulation in middle childhood and adolescence. However, maternal responsiveness has no comparable effects. It seems relevant to consider several dimensions of early caregiving and to also measure the environment in more detail in gene-environment studies.

Association of exposure to prenatal perfluoroalkyl substances and estrogen receptor 1 polymorphisms with the second to fourth digit ratio in school-aged children: The Hokkaido study

Per- and Polyfluoroalkyl substances (PFAS) have endocrine-disrupting effects. The ratio of the lengths of the second and fourth digits (2D:4D) is a noninvasive retrospective index of prenatal exposure to sex hormones, and estrogen receptor 1 (ESR1) polymorphisms may contribute to 2D:4D determination. We investigated whether ESR1 polymorphisms modify the effects of prenatal PFAS exposure on 2D:4D. Participants (n = 1024) with complete data in a prospective birth cohort study (the Hokkaido Study) were included, and maternal plasma in the third trimester was used to examine PFAS concentrations. 2D:4D was determined from photocopies of palms of children using Vernier calipers. ESR1 polymorphisms (rs2234693, rs9340799, and rs2077647) were genotyped by TaqMan polymerase chain reaction. PFAS and 2D:4D association with ESR1 polymorphisms was assessed by multiple linear regression adjusted for potential confounding factors. A 10-fold increase in maternal perfluorooctanoic acid (PFOA) concentration was associated with a 1.54% [95% confidence interval (CI): 0.40, 2.68] increase in mean 2D:4D in children with an AA genotype at rs9340799 and a 2.24% (95% CI: 0.57, 3.92) increase in children with an AA genotype at rs2077647. A 10-fold increase in perfluorododecanoic acid (PFDoDA) was associated with a significant increase in 2D:4D in children with the AA genotype [rs9340799, 1.18% (95% CI: 0.02, 2.34); and rs2077647, 1.67% (95% CI: 0.05, 3.28)]. These associations were apparent among males. A significant gene-environment interaction between PFOA or PFDoDA and ESR1 polymorphism was detected. These findings suggest that ESR1 polymorphisms modify the effects of prenatal exposure to PFAS on sex differentiation.

Genetic predispositions moderate the effectiveness of tobacco excise taxes.

BackgroundTobacco consumption is one of the leading causes of preventable death. In this study, we analyze whether someone’s genetic predisposition to smoking moderates the response to tobacco excise taxes.MethodsWe interact polygenic scores for smoking behavior with state-level tobacco excise taxes in longitudinal data (1992-2016) from the US Health and Retirement Study (N = 12,058).ResultsSomeone’s genetic propensity to smoking moderates the effect of tobacco excise taxes on smoking behavior along the extensive margin (smoking vs. not smoking) and the intensive margin (the amount of tobacco consumed). In our analysis sample, we do not find a significant gene-environment interaction effect on smoking cessation.ConclusionsWhen tobacco excise taxes are relatively high, those with a high genetic predisposition to smoking are less likely (i) to smoke, and (ii) to smoke heavily. While tobacco excise taxes have been effective in reducing smoking, the gene-environment interaction effects we observe in our sample suggest that policy makers could benefit from taking into account the moderating role of genes in the design of future tobacco control policies.

Genetic susceptibility in air pollution-induced airway inflammation in elderly women

BACKGROUND AND AIM: Evidence is supporting that air pollutants can activate inflammatory responses which increase oxidative stress and further affect respiratory health. So far, epidemiological studies on this pathway have mainly disregarded genetic effects. Thus, we aim to investigate the role of genetic susceptibility in air pollution-induced airway inflammation. METHODS: We used data from 445 women (68–79 years) enrolled in the ongoing cohort study on the influence of air pollution on lung function, inflammation and aging (SALIA) between baseline (years 1984–94) and first follow-up (years 2007–10). Biomarkers of airway inflammation were determined at follow-up in induced-sputum samples (levels of leukotriene (LT)B4, tumour necrosis factor-α (TNF-α), the total number of cells and nitric oxide derivatives). Out of 272 lung function-related single nucleotide polymorphisms, we calculated biomarker-specific weighted genetic risk scores (GRS) using internal weights from elastic net regression. Interactions between GRS and chronic NO2, NOx, PM2.5, PM10, PMcoarse, and PM2.5 absorbance exposure (the centred means of cumulative exposure to each air pollutant over observation time) on inflammation were investigated by adjusted linear regression models. RESULTS:Our results confirm that higher exposure to each air pollutant increase airway inflammation (TNF-α) and additionally, higher exposure to PMcoarse increases LTB4 level. Furthermore, we observed significant gene-environment interaction effects for TNF-α (adj. GRSxNOx: p-value=0.036, adj. GRSxPM2.5: p-value=0.021, adj. GRSxPMcoarse: p-value=0.001) and for LTB4 (adj. GRSxPMcoarse: p-value=0.001). Women with high GRS compared to low GRS had an increased risk of air pollution-induced higher TNF-α level as well as higher LTB4 level. CONCLUSIONS:Genetic susceptibility may play a role in the pathway of chronic air pollution exposure to airway inflammation responses. KEYWORDS: Air pollution, Epigenomics, Female, Long-term exposure, Respiratory outcomes, Risk assessment

Psychosocial experiences modulate asthma-associated genes through gene-environment interactions.

Social interactions and the overall psychosocial environment have a demonstrated impact on health, particularly for people living in disadvantaged urban areas. Here, we investigated the effect of psychosocial experiences on gene expression in peripheral blood immune cells of children with asthma in Metro Detroit. Using RNA-sequencing and a new machine learning approach, we identified transcriptional signatures of 19 variables including psychosocial factors, blood cell composition, and asthma symptoms. Importantly, we found 169 genes associated with asthma or allergic disease that are regulated by psychosocial factors and 344 significant gene-environment interactions for gene expression levels. These results demonstrate that immune gene expression mediates the link between negative psychosocial experiences and asthma risk.

Familial risk for endometriosis and its interaction with smoking, age at menarche and body mass index: a population-based cohort study among siblings.

To quantify familial risk of endometriosis among full siblings and examine interactions between family history and smoking, age at menarche or body mass index (BMI). Population-based nationwide cohort study. Using data from the Korean National Health Insurance and Screening Programme databases on kinship, healthcare utilisation, lifestyle and anthropometrics, we identified 2109288 women with full siblings and their environmental risk factors from 2002 to 2018. Familial risks were estimated using Cox proportional-hazards models, represented as incidence risk ratios (IRR) with 95% CI. Interaction between family history and smoking, age at menarche or BMI were assessed on an additive scale. IRR of endometriosis among women with and without affected siblings. From 19195 women with affected siblings, 1126 developed endometriosis with an incidence of 35.45/10000 person-years. Familial risk of endometriosis with versus without affected siblings was increased to IRR 2.75 (95% CI 2.25-3.36), and the highest risk was with affected twins (IRR 6.98; 95% CI 4.19-11.62). Women with both a family history and either smoking, early menarche or low BMI had a significantly higher risk of endometriosis compared with the general population and can be regarded as a high-risk group, the IRRs were 4.28 (95% CI 2.43-7.55), 3.47 (95% CI 2.82-4.26) and 3.09 (95% CI 2.68-3.56), respectively. Substantial effect modification of the associations was noted by smoking and early menarche, as their combined risk with family history exceeded the sum of their individual risks, which was also statistically significant. Genetic factors are the primary contributor to the familial aggregation of endometriosis. Significant gene-environment interaction exists between family history and smoking or early menarche. Significant gene-environment interaction exists between family history of endometriosis and smoking or early menarche.

Effects of the association between APOE rs405509 polymorphisms and gene-environment interactions on hand grip strength among middle-aged and elderly people in a rural population in southern China

BackgroundHand grip strength is a complex phenotype. The current study aimed to identify the effects of the association between APOE rs405509 polymorphisms and gene-environment interactions on hand grip strength among middle-aged and elderly people in a rural population in Gongcheng, southern China.MethodsAPOE rs405509 polymorphisms in 1724 participants (695 men and 1029 women, aged 45–97 years old) were genotyped using the Sequenom MassARRAY platform. Statistical analysis was conducted using SPSS 21.0 and Plink 1.90.ResultsThe APOE rs405509 G allele was associated with lower hand grip strength in all participants (β = −1.04, P value <0.001), and the correlation seemed to be even stronger among women. A significant gene-environment interaction was observed between APOE rs405509 and smoking, especially in men. The hand grip strength of male smokers carrying the GG genotype was significantly higher than that of nonsmokers (P value = 0.004).ConclusionsAPOE rs405509 polymorphisms might be genetic factors that affect hand grip strength in a rural population in Gongcheng, southern China. The APOE rs405509-smoking interaction has an impact on hand grip strength.

Post-traumatic Stress Symptoms and Serotonin Transporter (5-HTTLPR) Polymorphism in Breast Cancer Patients.

Introduction: Post-traumatic Symptoms (PTSS) and Post-traumatic Stress Disorder (PTSD) have been reported to affect a quite significant proportion of cancer patients. No study has examined the relationship between serotonin transporter gene-linked polymorphic region (5-HTTLPR) and cancer, including Gene-Environment interactions between this polymorphism and specific causes of distress, such as cancer related problems (CRP) or life stressful events (SLE).Methods: One hundred and forty five breast cancer outpatients participated in the study and were assessed using the Impact of Event Scale (IES), the Problem List (PL) developed by the National Comprehensive Cancer Network (NCCN) Distress Management Guidelines and the Paykel's Life Events Interview to evaluate the exposure to SLE during the year before the cancer diagnosis. Each patient was genotyped for 5-HTTLPR polymorphism by analyzing genomic DNA obtained from whole blood cells. Gene-Environment interactions were tested through moderation analysis.Results: Twenty-six patients (17.7%) were classified as PTSS cases using the IES. Genotype and phenotype distributions did not differ across individuals with/without PTSS (genotype: χ2 = 1.5; df = 2; p = 0.3; phenotype χ2 = 0.9; df = 1; p = 0.2). For both the genotype and phenotype model, using CRP as a predictor showed significant gene-environment interactions with IES total score (p = 0.020 and p = 0.004, respectively), with individuals carrying the l/l allele showing a greater probability of experiencing PTSS. No interaction was found in relationship to SLE (p = 0.750).Conclusion: This study showed a significant GEI between CRP and PTSS in breast cancer patients, with carriers of the l/l allele showing indicators consistent with greater sensitivity to stress.

Prenatal exposure to criteria air pollutants and associations with congenital anomalies: A Lebanese national study

Maternal exposure to air pollution has been associated with a higher birth defect (BD) risk. Previous studies suffer from inaccurate exposure assessment methods, confounding individual-level variations, and classical analytical modelling. This study aimed to examine the association between maternal exposure to criteria air pollutants and BD risk. A total of 553 cases and 10,214 controls were identified from private and public databases. Two subgroups were then formed: one for a matched case-control design, and another for Feature Selection (FS) analysis. Exposure assessment was based on the mean air pollutant-specific levels in the mother’s residential area during the specific BD gestational time window of risk (GTWR) and other time intervals. Multivariate regression models outcomes consistently showed a significant protective effect for folic acid intake and highlighted parental consanguinity as a strong BD risk factor. After adjusting for these putative risk factors and other covariates, results show that maternal exposure to PM2.5 during the first trimester is significantly associated with a higher overall BD risk (OR:1.05, 95%CI:1.01–1.09), and with a higher risk of genitourinary defects (GUD) (OR:1.06, 95%CI:1.01–1.11) and neural tube defects (NTD) (OR:1.10, 95%CI:1.03–1.17) during specific GTWRs. Maternal exposure to NO2 during GTWR exhibited a significant protective effect for NTD (OR:0.94, 95%CI:0.90–0.99), while all other examined associations were not statistically significant. Additionally, maternal exposure to SO2 during GTWR showed a significant association with a higher GUD risk (OR:1.17, 95%CI:1.08–1.26). When limiting selection to designated monitor coverage radiuses, PM2.5 maintained significance with BD risk and showed a significant gene-environment interaction for GUD (p = 0.018), while NO2 protective effect expanded to other subtypes. On the other hand, FS analysis confirmed maternal exposure to PM2.5 and NO2 as important features for GUD, CHD, and NTD. Our findings, set the basis for building a novel BD risk prediction model.

Interaction of FKBP5 variant rs3800373 and city living alters the neural stress response in the anterior cingulate cortex

Psychosocial stress effects of urban living are associated with substantially increased risk for schizophrenia, mood and anxiety disorders, by altering stress-induced activity in the amygdala and pregenual anterior cingulate cortex (ACC). Genetic factors are likely to modulate the impact of city living on stress processing. Growing evidence suggests a key role of FKBP5, a co-chaperone regulating the glucocorticoid receptor sensitivity, in the etiology of stress-related disorders. Here we investigated the interaction of city living and genetic variation in FKBP5 (rs3800373) on neural activity in stress-sensitive brain systems. Functional magnetic resonance imaging was performed in 31 healthy young adults using the Montreal Imaging Stress Task. Subjects were divided into groups depending on the number of inhabitants of their current residency. There was a significant main effect of city living on neural activity in the amygdala-hippocampus complex, replicating prior findings. Moreover, we found an interaction between rs3800373 and city living modulating responses in the bilateral subgenual ACC and right pregenual ACC. Specifically, only city dwellers carrying the FKBP5 minor risk allele showed increased stress responses in the subgenual and pregenual ACC when compared to those living in small towns. A significant gene-environment interaction on neural stress responses in the amygdala or hippocampus was only found in FKBP5 major allele carriers. These results point to a potential role of the FKBP5 rs3800373 minor risk allele in predisposing those who live in bigger cities to changes of functional responsivity in the pre- and subgenual ACC, thereby increasing the risk for developing stress-related mental disorders.

Identifying environmental risk factors and gene-environment interactions in holoprosencephaly.

Holoprosencephaly is the most common malformation of the forebrain (1 in 250 embryos) with severe consequences for fetal and child development. This study evaluates nongenetic factors associated with holoprosencephaly risk, severity, and gene-environment interactions. For this retrospective case control study, we developed an online questionnaire focusing on exposures to common and rare toxins/toxicants before and during pregnancy, nutritional factors, maternal health history, and demographic factors. Patients with holoprosencephaly were primarily ascertained from our ongoing genetic and clinical studies of holoprosencephaly. Controls included children with Williams-Beuren syndrome (WBS) ascertained through online advertisements in a WBD support group and fliers. Difference in odds of exposures between cases and controls as well as within cases with varying holoprosencephaly severity were studied. Cases included children born with holoprosencephaly (n = 92) and the control group consisted of children with WBS (n = 56). Pregnancy associated risk associated with holoprosencephaly included maternal pregestational diabetes (9.2% of cases and 0 controls, p = .02), higher alcohol consumption (adjusted odds ratio [aOR], 1.73; 95% CI, 0.88-15.71), and exposure to consumer products such as aerosols or sprays including hair sprays (aOR, 2.46; 95% CI, 0.89-7.19). Significant gene-environment interactions were identified including for consumption of cheese (p < .05) and espresso drinks (p = .03). The study identifies modifiable risk factors and gene-environment interactions that should be considered in future prevention of holoprosencephaly. Studies with larger HPE cohorts will be needed to confirm these findings.

The effects of polygenic risk for psychiatric disorders and smoking behaviour on psychotic experiences in UK Biobank

While psychotic experiences are core symptoms of mental health disorders like schizophrenia, they are also reported by 5–10% of the population. Both smoking behaviour and genetic risk for psychiatric disorders have been associated with psychotic experiences, but the interplay between these factors remains poorly understood. We tested whether smoking status, maternal smoking around birth, and number of packs smoked/year were associated with lifetime occurrence of three psychotic experiences phenotypes: delusions (n = 2067), hallucinations (n = 6689), and any psychotic experience (delusions or hallucinations; n = 7803) in 157,366 UK Biobank participants. We next calculated polygenic risk scores for schizophrenia (PRSSCZ), bipolar disorder (PRSBP), major depression (PRSDEP) and attention deficit hyperactivity disorder (PRSADHD) in 144,818 UK Biobank participants of European ancestry to assess whether association between smoking and psychotic experiences was attenuated after adjustment of diagnosis of psychiatric disorders and the PRSs. Finally, we investigated whether smoking exacerbates the effects of genetic predisposition on the psychotic phenotypes in gene-environment interaction models. Smoking status, maternal smoking, and number of packs smoked/year were associated with psychotic experiences (p < 1.77 × 10−5). Except for packs smoked/year, effects were attenuated but remained significant after adjustment for diagnosis of psychiatric disorders and PRSs (p < 1.99 × 10−3). Gene-environment interaction models showed the effects of PRSDEP and PRSADHD (but not PRSSCZ or PRSBP) on delusions (but not hallucinations) were significantly greater in current smokers compared to never smokers (p < 0.002). There were no significant gene-environment interactions for maternal smoking nor for number of packs smoked/year. Our results suggest that both genetic risk of psychiatric disorders and smoking status may have independent and synergistic effects on specific types of psychotic experiences.

The role of TPH2 variant rs4570625 in shaping infant attention to social signals

TPH2, the rate-limiting enzyme in the synthesis of serotonin, has been connected to several psychiatric outcomes. Its allelic variant, rs4570625, has been found to relate to individual differences in cognitive and emotion regulation during infancy with T-carriers of rs4570625 showing a relatively heightened attention bias for fearful faces. A significant gene-environment interaction was also reported with the T-carriers of mothers with depressive symptoms showing the highest fear bias.We investigated these associations in a sample of 8-month old infants (N = 330), whose mothers were prescreened for low/high levels of prenatal depressive and/or anxiety symptoms. Attention disengagement from emotional faces (neutral, happy, fearful, and phase-scrambled control faces) to distractors was assessed with eye tracking and an overlap paradigm. Maternal depressive symptoms were assessed at several time points during pregnancy and postpartum. The mean levels of symptoms at six months postpartum and the trajectories of symptoms from early pregnancy until six months postpartum were used in the analyses (N = 274).No main effect of the rs4570625 genotype on attention disengagement was found. The difference in fear bias between the genotypes was significant but in an opposite direction compared to a previous study. The results regarding the interaction of the genotype and maternal depression were not in accordance with the previous studies.These results show inconsistencies in the effects of the rs4570625 genotype on attention biases in separate samples of infants from the same population with only slight differences in age.