Association of Maternal Neurodevelopmental Risk Alleles With Early-Life Exposures.

Key PointsQuestionAre maternal polygenic risk scores for neurodevelopmental disorders associated with early-life exposures? FindingsIn this population-based cohort study of 7921 mothers, polygenic risk score for attention-deficit/hyperactivity disorder was associated with a range of early-life exposures linked to neurodevelopmental disorders in offspring. Polygenic risk scores for autism spectrum disorder and schizophrenia showed little evidence association with of early-life exposures. MeaningThe findings suggest that mothers at high genetic risk for attention-deficit/hyperactivity disorder may also be at increased risk for some adverse pregnancy exposures, and future studies should triangulate evidence from different causally informative approaches. This population-based cohort study assesses whether maternal polygenic risk scores for neurodevelopmental disorders are associated with early-life exposures previously linked to the disorders in women with available genotype data. ImportanceEarly-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. ObjectiveTo test whether maternal polygenic risk scores (PRSs) for neurodevelopmental disorders were associated with early-life exposures previously linked to the disorders. Design, Setting, and ParticipantsIn 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. ExposuresMaternal 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 MeasuresOutcomes 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). ResultsMaternal 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 (beta coefficient, -0.06; 95% CI, -0.11 to -0.02), and higher blood levels of cadmium (beta 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 RelevanceThese 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.