IMPORTANCE Early-life exposures, such as prenatal maternal lifestyle, illnesses, nutritional deficiencies, toxin levels, and adverse birth events, have long been considered potential risk factors for neurodevelopmental disorders in offspring. However, maternal genetic factors could be confounding the association between early-life exposures and neurodevelopmental outcomes in offspring, which makes inferring a causal relationship problematic. OBJECTIVE To test whether maternal polygenic risk scores (PRSs) for neurodevelopmental disorders were associated with early-life exposures previously linked to the disorders. DESIGN, SETTING, AND PARTICIPANTS In this UK population-based cohort study, 7921 mothers with genotype data from the Avon Longitudinal Study of Parents and Children (ALSPAC) underwent testing for association of maternal PRS for attention-deficit/hyperactivity disorder (ADHD PRS), autism spectrum disorder (ASD PRS), and schizophrenia (SCZ PRS) with 32 early-life exposures. ALSPAC data collection began September 6, 1990, and is ongoing. Data were analyzed for the current study from April 1 to September 1, 2018. EXPOSURES Maternal ADHD PRS, ASD PRS, and SCZ PRS were calculated using discovery effect size estimates from the largest available genome-wide association study and a significance threshold of P < .05. MAIN OUTCOMES AND MEASURES Outcomes measured included questionnaire data on maternal lifestyle and behavior (eg, smoking, alcohol consumption, body mass index, and maternal age), maternal use of nutritional supplements and medications in pregnancy (eg, acetaminophen, iron, zinc, folic acid, and vitamins), maternal illnesses (eg, diabetes, hypertension, rheumatism, psoriasis, and depression), and perinatal factors (eg, birth weight, preterm birth, and cesarean delivery). RESULTS Maternal PRSs were available from 7921 mothers (mean [SD] age, 28.5 [4.8] years). The ADHD PRS was associated with multiple prenatal factors, including infections (odds ratio [OR], 1.11; 95% CI, 1.04-1.18), use of acetaminophen during late pregnancy (OR, 1.11; 95% CI, 1.04-1.18), lower blood levels of mercury (β coefficient, −0.06; 95% CI, −0.11 to −0.02), and higher blood levels of cadmium (β coefficient, 0.07; 95% CI, 0.05-0.09). Little evidence of associations between ASD PRS or SCZ PRS and prenatal factors or of association between any of the PRSs and adverse birth events was found. Sensitivity analyses revealed consistent results. CONCLUSIONS AND RELEVANCE These findings suggest that maternal risk alleles for neurodevelopmental disorders, primarily ADHD, are associated with some pregnancy-related exposures. These findings highlight the need to carefully account for potential genetic confounding and triangulate evidence from different approaches when assessing the effects of prenatal exposures on neurodevelopmental disorders in offspring.

Background Attention-deficit hyperactivity disorder (ADHD) is associated with later depression and there is considerable genetic overlap between them. This study investigated if ADHD and ADHD genetic liability are causally related to depression using two different methods. Methods First, a longitudinal population cohort design was used to assess the association between childhood ADHD (age 7 years) and recurrent depression in young-adulthood (age 18–25 years) in N = 8310 individuals in the Avon Longitudinal Study of Parents and Children (ALSPAC). Second, two-sample Mendelian randomization (MR) analyses examined relationships between genetic liability for ADHD and depression utilising published Genome-Wide Association Study (GWAS) data. Results Childhood ADHD was associated with an increased risk of recurrent depression in young-adulthood (OR 1.35, 95% CI 1.05–1.73). MR analyses suggested a causal effect of ADHD genetic liability on major depression (OR 1.21, 95% CI 1.12–1.31). MR findings using a broader definition of depression differed, showing a weak influence on depression (OR 1.07, 95% CI 1.02–1.13). Conclusions Our findings suggest that ADHD increases the risk of depression later in life and are consistent with a causal effect of ADHD genetic liability on subsequent major depression. However, findings were different for more broadly defined depression.

Psychiatric disorders are highly heritable and associated with a wide variety of social adversity and physical health problems. Using genetic liability (rather than phenotypic measures of disease) as a proxy for psychiatric disease risk can be a useful alternative for research questions that would traditionally require large cohort studies with long-term follow up. Here we conducted a hypothesis-free phenome-wide association study in about 330,000 participants from the UK Biobank to examine associations of polygenic risk scores (PRS) for five psychiatric disorders (major depression (MDD), bipolar disorder (BP), schizophrenia (SCZ), attention-deficit/ hyperactivity disorder (ADHD) and autism spectrum disorder (ASD)) with 23,004 outcomes in UK Biobank, using the open-source PHESANT software package. There was evidence after multiple testing (p<2.55x10-06) for associations of PRSs with 294 outcomes, most of them attributed to associations of PRS MDD (n = 167) and PRS SCZ (n = 157) with mental health factors. Among others, we found strong evidence of association of higher PRS ADHD with 1.1 months younger age at first sexual intercourse [95% confidence interval [CI]:-1.25,-0.92] and a history of physical maltreatment; PRS ASD with 0.01% lower erythrocyte distribution width [95%CI:-0.013,-0.007]; PRS SCZ with 0.95 lower odds of playing computer games [95%CI:0.95,0.96]; PRS MDD with a 0.12 points higher neuroticism score [95%CI:0.111,0.135] and PRS BP with 1.03 higher odds of having a university degree [95%CI:1.02,1.03]. We were able to show that genetic liabilities for five major psychiatric disorders associate with long-term aspects of adult life, including socio-demographic factors, mental and physical health. This is evident even in individuals from the general population who do not necessarily present with a psychiatric disorder diagnosis.

BackgroundExposure to endocrine-disrupting chemicals can alter normal physiology and increase susceptibility to non-communicable diseases like obesity. Especially the prenatal and early postnatal period is highly vulnerable to adverse effects by environmental exposure, promoting developmental reprogramming by epigenetic alterations. To obtain a deeper insight into the role of prenatal bisphenol A (BPA) exposure in children’s overweight development, we combine epidemiological data with experimental models and BPA-dependent DNA methylation changes.MethodsBPA concentrations were measured in maternal urine samples of the LINA mother-child-study obtained during pregnancy (n = 552), and BPA-associated changes in cord blood DNA methylation were analyzed by Illumina Infinium HumanMethylation450 BeadChip arrays (n = 472). Methylation changes were verified by targeted MassARRAY analyses, assessed for their functional translation by qPCR and correlated with children’s body mass index (BMI) z scores at the age of 1 and 6 years. Further, female BALB/c mice were exposed to BPA from 1 week before mating until delivery, and weight development of their pups was monitored (n ≥ 8/group). Additionally, human adipose-derived mesenchymal stem cells were treated with BPA during the adipocyte differentiation period and assessed for exposure-related epigenetic, transcriptional and morphological changes (n = 4).ResultsIn prenatally BPA-exposed children two CpG sites with deviating cord blood DNA-methylation profiles were identified, among them a hypo-methylated CpG in the promoter of the obesity-associated mesoderm-specific transcript (MEST). A mediator analysis suggested that prenatal BPA exposure was connected to cord blood MEST promoter methylation and MEST expression as well as BMI z scores in early infancy. This effect could be confirmed in mice in which prenatal BPA exposure altered Mest promoter methylation and transcription with a concomitant increase in the body weight of the juvenile offspring. An experimental model of in vitro differentiated human mesenchymal stem cells also revealed an epigenetically induced MEST expression and enhanced adipogenesis following BPA exposure.ConclusionsOur study provides evidence that MEST mediates the impact of prenatal BPA exposure on long-term body weight development in offspring by triggering adipocyte differentiation.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0478-z) contains supplementary material, which is available to authorized users.