Abstract
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. To test whether maternal polygenic risk scores (PRSs) for neurodevelopmental disorders were associated with early-life exposures previously linked to the disorders. 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. 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. 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). 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. 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.
Highlights
The attention-deficit/hyperactivity disorder (ADHD) polygenic risk score (PRS) was associated with multiple prenatal factors, including infections, 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)
Sensitivity analyses revealed consistent results. 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
Maternal ADHD PRS was associated with younger maternal age at delivery (β coefficient, −0.42; 95% CI, 0.530.31)
Summary
Avon Longitudinal Study of Parents and Children Study Data The ongoing prospective Avon Longitudinal Study of Parents and Children (ALSPAC) initially recruited 14 541 pregnant women living in Avon, United Kingdom, with expected delivery dates from April 1991 to December 1992 and with 13 988 children alive at year 1. The resulting data set included 7921 unrelated mothers and 7975 unrelated children of European ancestry. Detailed procedures for quality control have been published previously.[42] Detailed information on the health and lifestyles of mothers and children was collected from regular clinical visits and self-administrated questionnaires. A detailed description of the cohort has been published previously.[43,44] The study website contains a fully searchable data dictionary and variable search tool.[45] Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the local research ethics committees.[46] All participants provided written informed consent. ALSPAC data collection began September 6, 1990, and is ongoing. Data were analyzed for the current study from April 1 to September 1, 2018
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