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Introduction Neurodevelopmental disorders involve atypical brain development affecting domains such as language, motor skills, social communication, attention, activity regulation, and learning. This group of disorders includes attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) and is sometimes broadened to encompass schizophrenia (SCZ) because its onset is often preceded by neurodevelopmental impairments. Neurodevelopmental disorders are highly heritable (60%-90%), although they are associated with a combination of multiple genetic, environmental, and stochastic factors.

ctrum disorder (ASD) and is sometimes broadened to encompass schizophrenia (SCZ) because its onset is often preceded by neurodevelopmental impairments. Neurodevelopmental disorders are highly heritable (60%-90%), although they are associated with a combination of multiple genetic, environmental, and stochastic factors. Prenatal and perinatal exposures to adversities have long been considered to be possible risk factors for neurodevelopmental disorders and are biologically plausible as causal risks because they occur during a sensitive time in neurodevelopment. Prenatal factors linked with neurodevelopmental disorders include smoking, alcohol intake, nutritional deficiencies (eg, vitamin D), poor nutrition, nonuse of nutritional supplements (eg, folic acid), medication use (eg, acetaminophen [paracetamol], antidepressants), prepregnancy body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared), age at delivery, metabolic disorders (eg, diabetes, preeclampsia), immune-related conditions (eg, infection, autoimmune diseases), depression, stressful life events, and toxin levels (eg, mercury, lead). Adverse perinatal factors (eg, low birth weight, prematurity, cesarean delivery) have been shown to be associated with all 3 neurodevelopmental disorders. However, with some exceptions, most of these studies were observational and are therefore not appropriate for assessing causality.

toxin levels (eg, mercury, lead). Adverse perinatal factors (eg, low birth weight, prematurity, cesarean delivery) have been shown to be associated with all 3 neurodevelopmental disorders. However, with some exceptions, most of these studies were observational and are therefore not appropriate for assessing causality. Confounding by sometimes unknown lifestyle, socioeconomic, or genetic factors can lead to apparent associations between early-life factors and neurodevelopmental outcomes that are not causal. Potential genetic confounding is particularly important for factors such as maternal smoking, which is known to be associated with maternal genotype. Other factors such as birth weight are associated with maternal and fetal genotypes. If genetic factors are independently associated with neurodevelopmental disorders and early-life exposures (horizontal pleiotropy), then associations could arise for noncausal reasons. For example, of 12 studies using different causally informative designs, such as discordant sibling pairs, maternal vs paternal exposures, an assisted conception cohort, and children of twins, 11 showed that maternal smoking in pregnancy does not appear to have a causal effect on ADHD, although it has an effect on lowering birth weight. However, such designs have not been able to address the full range of prenatal and perinatal risks.

paternal exposures, an assisted conception cohort, and children of twins, 11 showed that maternal smoking in pregnancy does not appear to have a causal effect on ADHD, although it has an effect on lowering birth weight. However, such designs have not been able to address the full range of prenatal and perinatal risks. Genome-wide association studies (GWAS) suggest that genetic liability to neurodevelopmental disorders is in part conferred by a large number of common (present in >1% of the population) single-nucleotide polymorphisms (SNPs). These SNPs can be used to generate composite measures called polygenic risk scores (PRSs), which have been shown to be associated with a range of phenotypes in the general population for neurodevelopmental disorders. In this study, we used a large population-based pregnancy cohort from the United Kingdom to investigate whether PRSs for ADHD (ADHD PRS), ASD (ASD PRS), and schizophrenia (SCZ PRS) are associated with early-life exposures linked to these disorders.

phenotypes in the general population for neurodevelopmental disorders. In this study, we used a large population-based pregnancy cohort from the United Kingdom to investigate whether PRSs for ADHD (ADHD PRS), ASD (ASD PRS), and schizophrenia (SCZ PRS) are associated with early-life exposures linked to these disorders. Methods 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. Of those, 10 015 mothers and 9912 children underwent genotyping using 2 platforms (Human660W-quad and Human Hap550-quad [Illumina], respectively). After standard quality control, the resulting data set included 7921 unrelated mothers and 7975 unrelated children of European ancestry. Detailed procedures for quality control have been published previously. 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. The study website contains a fully searchable data dictionary and variable search tool. Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the local research ethics committees. 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.

. Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the local research ethics committees. 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. Polygenic Risk Score Polygenic risk scores were calculated using PRSice, version 1.25 (Statistical Genetics Unit, King’s College London) and PLINK, version 1.9, as the weighted mean number of disorder risk alleles in approximate linkage equilibrium (R2 < 0.1 within 1000-kilobase distance), as described previously. Risk alleles for ADHD and ASD were defined as those identified in the most recent combined Psychiatric Genomics Consortium and Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) analysis of case-control GWAS at a significance threshold of P < .05 to maximize phenotypic variance. Risk alleles for schizophrenia were identified by the Psychiatric Genomics Consortium meta-analysis. For sensitivity analysis, PRSs were derived using various P values. The number of SNPs included for each threshold and correlations among PRSs are provided in eTables 1 and 2 in the Supplement.

mize phenotypic variance. Risk alleles for schizophrenia were identified by the Psychiatric Genomics Consortium meta-analysis. For sensitivity analysis, PRSs were derived using various P values. The number of SNPs included for each threshold and correlations among PRSs are provided in eTables 1 and 2 in the Supplement. Outcome Measures Prenatal Factors Related to Maternal Lifestyle Maternal smoking and alcohol consumption were assessed by self-report during the first and third trimesters; the participants were asked whether they had smoked or consumed alcohol in the past 3 months. The 2 measurements were used to classify smoking and alcohol consumption during pregnancy as any time vs never. Binge drinking was defined as having consumed the equivalent of more than 4 drinks per day at least once during the past 4 weeks. Maternal BMI was derived from self-reported prepregnancy height and weight. Maternal age was obtained at recruitment. Maternal Use of Nutritional Supplements and Medications in Pregnancy The use of antidepressants and the intake of iron, zinc, folic acid, or vitamin supplements were categorized as never vs ever based on maternal report in the first and third trimesters. Use of acetaminophen was maternally reported for the first (week 18) and the second (week 32) halves of pregnancy.

ations in Pregnancy The use of antidepressants and the intake of iron, zinc, folic acid, or vitamin supplements were categorized as never vs ever based on maternal report in the first and third trimesters. Use of acetaminophen was maternally reported for the first (week 18) and the second (week 32) halves of pregnancy. Maternal Illnesses and Conditions Stressful life events scores were calculated based on maternal report of whether participants had experienced 18 different stressful life events during the first and third trimesters of their pregnancy. Severe depression, diabetes, hypertension, rheumatism, and psoriasis were categorized as ever vs never experienced. In addition, mothers were asked if they experienced preeclampsia, infections, or bleeding during pregnancy. Biomarkers of Nutritional Status and Toxin Exposure in Pregnancy Blood levels of vitamin D (25-hydroxyvitamin D), selenium, mercury, cadmium, and lead were measured in maternal blood samples during pregnancy, as described elsewhere. All of these measures were log-transformed. Perinatal Factors and Conditions Adverse birth events included low birth weight, preterm delivery, cesarean delivery, hypoxia, and Apgar scores at 1 and 5 minutes after birth, and were obtained from obstetric records. Low birth weight was defined as less than 2500 g; preterm delivery, born before 37 weeks’ gestation. The Apgar score was dichotomized as healthy when 7 or greater and adverse when less than 7. Mothers were asked if they initiated breastfeeding their child in the first month after birth.

obtained from obstetric records. Low birth weight was defined as less than 2500 g; preterm delivery, born before 37 weeks’ gestation. The Apgar score was dichotomized as healthy when 7 or greater and adverse when less than 7. Mothers were asked if they initiated breastfeeding their child in the first month after birth. Statistical Analysis Data were analyzed from April 1 to September 1, 2018. Associations of early-life exposures with maternal ADHD PRS, ASD PRS, or SCZ PRS were assessed using general linear models for continuous outcomes and general linear models with logit-link function and Poisson distribution for binary outcomes in Stata software, version 15.1 (StataCorp). Ten population stratification principal components derived from unrelated individuals using the Eigenstrat method were included as covariates in all analyses. In addition, the perinatal factors were tested for association with child ADHD PRS, ASD PRS, and SCZ PRS after adjusting for sex and 10 principal components because perinatal factors can be associated with maternal or child genetic risk. Effect estimates are presented per 1-SD increase in PRS.

variates in all analyses. In addition, the perinatal factors were tested for association with child ADHD PRS, ASD PRS, and SCZ PRS after adjusting for sex and 10 principal components because perinatal factors can be associated with maternal or child genetic risk. Effect estimates are presented per 1-SD increase in PRS. To correct for multiple testing of 32 early-life exposures, the number of independent tests was determined based on the number of principal components that explained 80% of covariance between the early-life exposures in a principal component analysis (eMethods and eTable 3 in the Supplement). We concluded that 21 independent tests were performed, leading to a multiple testing–corrected P < .0024 (.05/21), which is slightly less conservative than the Bonferroni-corrected P < .0016 (.05/32) (assuming that all tests are independent). As a sensitivity analysis, we performed an inverse probability weighting on missing maternal genetic data (eMethods in the Supplement) because ADHD PRS and SCZ PRS were associated with attrition in the ALSPAC core study. A comparison between the study samples with (n = 7486) and without (n = 6307) genetic data suggests that the groups differ in some of the analyzed factors (eMethods and eTable 4 in the Supplement).

ic data (eMethods in the Supplement) because ADHD PRS and SCZ PRS were associated with attrition in the ALSPAC core study. A comparison between the study samples with (n = 7486) and without (n = 6307) genetic data suggests that the groups differ in some of the analyzed factors (eMethods and eTable 4 in the Supplement). Results Associations Between PRSs and Early-Life Exposures Factors Associated With Maternal Lifestyle Descriptive characteristics of the sample are presented in Table 1. Mean (SD) age of mothers of the ALSPAC study sample was 28.5 (4.8) years; mean (SD) BMI, 22.9 (3.8). Maternal PRSs for neurodevelopmental disorders showed evidence of associations with smoking (ADHD PRS and SCZ PRS), use of acetaminophen (ADHD PRS), prepregnancy BMI (ADHD PRS and SCZ PRS), and age at delivery (ADHD PRS) (Table 2). A 1-SD increase in maternal ADHD PRS was associated with a 27% increase of smoking during pregnancy (odds ratio [OR], 1.27; 95% CI, 1.19-1.35); a 1-SD increase in maternal SCZ PRS, with an 11% increase of smoking during pregnancy (OR, 1.11; 95% CI, 1.04-1.18). Maternal ADHD PRS was associated with younger maternal age at delivery (β coefficient, −0.42; 95% CI, 0.53-0.31) (similar results were found for associations between PRSs and categorically defined age groups in eTable 5 in the Supplement). Association with maternal prepregnancy BMI occurred in opposite directions for ADHD PRS (β coefficient, 0.27; 95% CI, 0.18-0.36) and SCZ PRS (β coefficient, −0.16; 95% CI, −0.26 to −0.07). Examining associations at different times, we found evidence of an association between ADHD PRS and use of acetaminophen during the second half of pregnancy, such that a 1-SD increase in ADHD PRS was associated with an 11% increase in the odds of taking acetaminophen (OR, 1.11; 95% CI, 1.04-1.18).

CI, −0.26 to −0.07). Examining associations at different times, we found evidence of an association between ADHD PRS and use of acetaminophen during the second half of pregnancy, such that a 1-SD increase in ADHD PRS was associated with an 11% increase in the odds of taking acetaminophen (OR, 1.11; 95% CI, 1.04-1.18). Table 1. Sample Description Exposure Total No. of Participants Participants With Exposure Smoking, No. (%) During first trimester 7330 1620 (22.1) During third trimester 6787 1157 (17.0) Alcohol consumption, No. (%) During first trimester 7276 4051 (55.7) During third trimester 4355 1526 (35.0) Binge drinking during first trimester, No. (%) 7263 1181 (16.3) Any nutritional supplements in pregnancy, No. (%) Iron 7270 1541 (21.2) Zinc 7270 92 (1.3) Folic acid 7263 688 (9.5) Vitamins 7253 1190 (16.4) Acetaminophen, No. (%) Early pregnancy 7142 3838 (53.7) Late pregnancy 6748 2888 (42.8) Any antidepressants in pregnancy, No. (%) 7153 58 (0.8) Maternal illnesses and conditions Prepregnancy BMI, mean (SD) [range] 6516 22.9 (3.8) [12.5-51.2] Age at delivery, mean (SD) [range], y 7486 28.5 (4.8) [15-44] Ever had diabetes, No. (%) 6913 71 (1.0) Gestational diabetes, No. (%) 7412 68 (0.9) Ever had hypertension, No. (%) 6806 984 (14.5) Gestational hypertension, No. (%) 7252 1058 (14.6) Preeclampsia, No. (%) 7412 160 (2.2) Any vaginal bleeding in pregnancy, No. (%) 6759 1198 (17.7) Any infection in pregnancy, No. (%) 6683 1476 (22.1) Ever had rheumatism, No. (%) 6817 295 (4.3) Ever had psoriasis, No. (%) 6793 256 (3.8) Ever had severe depression, No. (%) 6847 539 (7.9) Stressful life event score, mean (SD) [range] First trimester 6841 3.6 (2.6) [0-18] Third trimester 6695 3.5 (2.4) [0-26] Pregnancy blood levels, mean (SD), [range] Vitamin D, pg/mL 4793 67.6 (32.1) [8.6-248.1] Selenium, μg/L 2625 112.4 (24.0) [17.0-319.4] Hemoglobin, g/dL 2535 2.1 (1.1) [0.3-11.5] Cadmium, μg/L 2624 0.5 (0.6) [0.1-4.6] Lead, μg/dL 2624 3.6 (1.5) [0.2-19.1] Cesarean delivery, No. (%) 6660 674 (10.1) Low birth weight (<2500 g), No. (%) 7387 328 (4.4) Preterm delivery (<37 wk), No. (%) 7486 399 (5.3) Hypoxia, No. (%) 4405 1301 (29.5) Low Apgar score, No. (%) At 1 min 4387 539 (12.3) At 5 min 4383 49 (1.1) Breastfeeding at 1 mo, No. (%) 6490 5053 (77.9) Abbreviation: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared).

8 (4.4) Preterm delivery (<37 wk), No. (%) 7486 399 (5.3) Hypoxia, No. (%) 4405 1301 (29.5) Low Apgar score, No. (%) At 1 min 4387 539 (12.3) At 5 min 4383 49 (1.1) Breastfeeding at 1 mo, No. (%) 6490 5053 (77.9) Abbreviation: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared). SI conversion factors: To convert cadmium to nanomoles per liter, multiply by 8.896; hemoglobin to grams per liter, multiply by 10.0; lead to micromoles per liter, multiply by 0.0483; selenium to micromoles per liter, multiply by 0.0127; vitamin D to picomoles per liter, multiply by 2.496.

8 (4.4) Preterm delivery (<37 wk), No. (%) 7486 399 (5.3) Hypoxia, No. (%) 4405 1301 (29.5) Low Apgar score, No. (%) At 1 min 4387 539 (12.3) At 5 min 4383 49 (1.1) Breastfeeding at 1 mo, No. (%) 6490 5053 (77.9) Abbreviation: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared). SI conversion factors: To convert cadmium to nanomoles per liter, multiply by 8.896; hemoglobin to grams per liter, multiply by 10.0; lead to micromoles per liter, multiply by 0.0483; selenium to micromoles per liter, multiply by 0.0127; vitamin D to picomoles per liter, multiply by 2.496. Table 2. Associations of Maternal PRSs for ADHD, ASD, and Schizophrenia With Lifestyle-Related Prenatal Exposures Variable ADHD PRS ASD PRS SCZ PRS OR or β Coefficient (95% CI)a P Value OR or β Coefficient (95% CI)a P Value OR or β Coefficient (95% CI)a P Value Smoking, OR During first trimester 1.25 (1.17 to 1.33) 1 × 10−11 1.04 (0.98 to 1.11) .18 1.14 (1.04 to 1.18) .001 During third trimester 1.27 (1.18 to 1.36) 6 × 10−11 1.06 (0.99 to 1.14) .09 1.06 (0.99 to 1.14) .08 Alcohol consumption, OR During first trimester 0.99 (0.92 to 1.06) .76 1.00 (0.94 to 1.08) .91 1.01 (0.94 to 1.08) .85 During third trimester 0.91 (0.84 to 0.98) .02 1.05 (0.97 to 1.13) .22 1.05 (0.97 to 1.13) .26 Binge drinking during first trimester 1.11 (1.03 to 1.18) .004 1.05 (0.98 to 1.13) .15 1.08 (1.01 to 1.16) .02 Taking supplements during pregnancy, OR Iron 0.97 (0.91 to 1.03) .31 1.00 (0.94 to 1.06) .92 1.09 (1.02 to 1.16) .01 Zinc 0.91 (0.74 to 1.13) .40 0.98 (0.79 to 1.20) .82 1.22 (0.99 to 1.50) .06 Folic acid 0.96 (0.89 to 1.05) .36 1.06 (0.98 to 1.15) .17 1.11 (1.03 to 1.21) .01 Vitamins 0.94 (0.88 to 1.01) .09 0.99 (0.92 to 1.06) .73 1.10 (1.03 to 1.18) .005 Use of acetaminophen, OR In early pregnancy 1.09 (1.02 to 1.17) .01 1.00 (0.94 to 1.08) .93 0.97 (0.90 to 1.03) .32 In late pregnancy 1.11 (1.04 to 1.18) .002 0.99 (0.93 to 1.05) .68 1.02 (0.95 to 1.08) .62 Use of antidepressants, OR 1.06 (0.82 to 1.38) .64 1.05 (0.81 to 1.36) .70 1.02 (0.78 to 1.32) .90 Prepregnancy BMI, β coefficient 0.27 (0.18 to 0.36) 8 × 10−9 −0.02 (−0.11 to 0.07) .70 −0.16 (−0.26 to −0.07) .001 Age at delivery, β coefficient −0.42 (−0.53 to −0.31) 2 × 10−14 0.09 (−0.01 to 0.20) .095 0.05 (−0.06 to 0.16) .35 Abbreviations: ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); OR, odds ratio; PRS, polygenic risk score; SCZ, schizophrenia.

o −0.31) 2 × 10−14 0.09 (−0.01 to 0.20) .095 0.05 (−0.06 to 0.16) .35 Abbreviations: ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); OR, odds ratio; PRS, polygenic risk score; SCZ, schizophrenia. a Odds ratios were calculated for binary outcomes; β coefficients, for continuous outcomes. Maternal Illnesses and Conditions We found evidence of associations between all 3 maternal PRSs and a higher risk of experiencing severe depression (OR range, 1.12 [95% CI, 1.02-1.23] to 1.21 [95% CI, 1.11-1.33]) and an increased stressful life events score in the first trimester of pregnancy (β coefficient range, 0.11 [95% CI, 0.05-0.17] to 0.13 [95% CI, 0.07-0.19]) (Table 3). In addition, ADHD PRS showed evidence of an association with infection during pregnancy (OR, 1.11; 95% CI, 1.04-1.18). Little evidence was found for associations with other illnesses or conditions.

in the first trimester of pregnancy (β coefficient range, 0.11 [95% CI, 0.05-0.17] to 0.13 [95% CI, 0.07-0.19]) (Table 3). In addition, ADHD PRS showed evidence of an association with infection during pregnancy (OR, 1.11; 95% CI, 1.04-1.18). Little evidence was found for associations with other illnesses or conditions. Table 3. Associations of Maternal PRSs for ADHD, ASD, and Schizophrenia With Maternal Illnesses and Conditions Variable ADHD PRS ASD PRS SCZ PRS OR or β Coefficient (95% CI)a P Value OR or β Coefficient (95% CI)a P Value OR or β Coefficient (95% CI)a P Value Ever had diabetes, OR 1.30 (1.03 to 1.65) .03 1.13 (0.89 to 1.43) .31 1.01 (0.79 to 1.28) .97 Gestational diabetes, OR 1.32 (1.03 to 1.67) .03 1.04 (0.82 to 1.32) .75 0.89 (0.70 to 1.13) .33 Ever had hypertension, OR 1.06 (0.98 to 1.14) .13 1.01 (0.94 to 1.09) .74 1.07 (0.99 to 1.15) .08 Gestational hypertension, OR 0.96 (0.90 to 1.03) .27 0.99 (0.92 to 1.06) .746 1.05 (0.97 to 1.12) .21 Preeclampsia, OR 1.09 (0.93 to 1.28) .30 1.18 (1.01 to 1.39) .04 1.08 (0.92 to 1.26) .37 Vaginal bleeding in pregnancy, OR 1.03 (0.96 to 1.10) .47 1.01 (0.94 to 1.08) .80 1.08 (1.00 to 1.15) .04 Any infection in pregnancy, OR 1.11 (1.04 to 1.18) .002 1.06 (0.99 to 1.13) .09 1.03 (0.97 to 1.10) .33 Ever had rheumatism, OR 1.05 (0.93 to 1.19) .40 1.16 (1.03 to 1.31) .02 1.03 (0.91 to 1.16) .63 Ever had psoriasis, OR 1.00 (0.88 to 1.13) .97 1.04 (0.92 to 1.18) .53 1.04 (0.91 to 1.18) .55 Ever had severe depression, OR 1.21 (1.11 to 1.33) 4 × 10−5 1.12 (1.02 to 1.23) .01 1.21 (1.11 to 1.33) 5 × 10−5 Stressful life event score, β coefficient First trimester 0.13 (0.07 to 0.19) 4 × 10−5 0.11 (0.05 to 0.17) 3 × 10−4 0.12 (0.06 to 0.18) 2 × 10−4 Third trimester 0.08 (0.02 to 0.14) .008 0.09 (0.004 to 0.03) .004 0.05 (−0.01 to 0.11) .09 Abbreviations: ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; OR, odds ratio; PRS, polygenic risk score; SCZ, schizophrenia.

.19) 4 × 10−5 0.11 (0.05 to 0.17) 3 × 10−4 0.12 (0.06 to 0.18) 2 × 10−4 Third trimester 0.08 (0.02 to 0.14) .008 0.09 (0.004 to 0.03) .004 0.05 (−0.01 to 0.11) .09 Abbreviations: ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; OR, odds ratio; PRS, polygenic risk score; SCZ, schizophrenia. a Odds ratios were calculated for binary outcomes; β coefficients, for continuous outcomes. Biomarkers of Nutritional Status and Toxin Exposure in Pregnancy Maternal ADHD PRS showed evidence of association with lower selenium levels (β coefficient, −0.01; 95% CI, −0.02 to 0.005) and higher cadmium levels (β coefficient, 0.07; 95% CI, 0.05-0.0009). In addition, ADHD PRS showed evidence of associations with lower mercury levels (β coefficient, −0.06; 95% CI, −0.11 to −0.02), but little evidence of association with vitamin D or lead (Table 4). Little evidence was found for associations between maternal ASD PRS and SCZ PRS and any of the biomarkers.

I, 0.05-0.0009). In addition, ADHD PRS showed evidence of associations with lower mercury levels (β coefficient, −0.06; 95% CI, −0.11 to −0.02), but little evidence of association with vitamin D or lead (Table 4). Little evidence was found for associations between maternal ASD PRS and SCZ PRS and any of the biomarkers. Table 4. Associations of Maternal PRSs for ADHD, ASD, and Schizophrenia With Maternal Blood Biomarkers of Nutritional Status and Toxins in Pregnancy Biomarker ADHD PRS ASD PRS SCZ PRS β Coefficient (95% CI) P Value β Coefficient (95% CI) P Value β Coefficient (95% CI) P Value Vitamin Da 0.01 (−0.003 to 0.02) .99 −0.01 (−0.02 to 0.01) .24 0.01 (−0.003 to 0.02) .12 Selenium −0.01 (−0.02 to 0.00) .001 0.001 (−0.01 to 0.01) .84 0.004 (−0.004 to 0.01) .30 Mercury −0.06 (−0.11 to −0.02) .003 0.02 (−0.02 to 0.06) .42 0.03 (−0.02 to 0.07) .24 Cadmium 0.07 (0.05 to 0.09) 1 × 10−9 0.01 (−0.01 to 0.03 .52 0.03 (0.004 to 0.05) .02 Lead −0.03 (−0.08 to 0.03) .36 0.03 (−0.03 to 0.08) .36 −0.01 (−0.07 to 0.04) .63 Abbreviations: ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; PRS, polygenic risk score; SCZ, schizophrenia. a Indicates log transformed. Perinatal Factors and Conditions We found little evidence of an association between maternal neurodevelopmental risk scores and birth events, including low birth weight, preterm delivery, cesarean delivery, and hypoxia (Table 5). Furthermore, there was no strong evidence of associations between these outcomes and child neurodevelopmental PRSs (Table 5).

found little evidence of an association between maternal neurodevelopmental risk scores and birth events, including low birth weight, preterm delivery, cesarean delivery, and hypoxia (Table 5). Furthermore, there was no strong evidence of associations between these outcomes and child neurodevelopmental PRSs (Table 5). Table 5. Associations of Maternal and Child PRSs for ADHD, ASD, and Schizophrenia With Perinatal Exposures and Conditions Exposure No. of Participants ADHD PRS ASD PRS SCZ PRS No Yes Total OR (95% CI) P Value OR (95% CI) P Value OR (95% CI) P Value Associations With Maternal PRSs Cesarean delivery 5986 674 6660 0.99 (0.91-1.08) .80 1.03 (0.95-1.12) .47 0.95 (0.87-1.03) .20 Low birth weight, <2500 g 7059 328 7387 1.08 (0.97-1.21) .18 1.00 (0.90-1.13) .94 1.02 (0.62-1.68) .94 Preterm delivery, <37 wk 7087 399 7486 0.99 (0.89-1.10) .85 0.96 (0.87-1.07) .49 0.96 (0.87-1.07) .46 Hypoxia 3104 1301 4405 1.05 (0.97-1.14) .20 1.04 (0.97-1.13) .28 1.02 (0.95-1.11) .56 Low Apgar score At 1 min 3848 539 4387 1.11 (1.01-1.23) .03 1.02 (0.93-1.13) .65 1.00 (0.91-1.11) .95 At 5 min 4334 49 4383 1.05 (0.79-1.39) .74 1.04 (0.79-1.38) .78 0.77 (0.57-1.03) .07 Breastfeeding at 1 mo 1437 5053 6490 0.88 (0.78-0.99) .04 1.05 (0.92-1.19) .47 1.02 (0.90-1.16) .75 Associations With Child PRSs Cesarean delivery 6126 686 6812 0.98 (0.90-1.07) .62 0.97 (0.89-1.05) .45 1.00 (0.92-1.08) .92 Low birth weight, 2500 g 7118 298 7416 1.06 (0.94-1.19) .36 0.97 (0.86-1.09) .63 0.96 (0.85-1.09) .54 Preterm delivery, <37 wk 7134 374 7508 1.03 (0.92-1.15) .62 0.94 (0.85-1.05) .30 0.95 (0.85-1.06) .37 Hypoxia 3147 1256 4403 0.97 (0.90-1.05) .52 0.99 (0.91-1.07) .74 0.98 (0.91-1.06) .66 Low Apgar score At 1 min 3886 511 4397 1.01 (1.00-1.01) .27 1.00 (0.99-1.01) .69 1.00 (0.99-1.01) .45 At 5 min 4348 47 4395 1.00 (1.00-1.01) .13 1.00 (1.00-1.00) .44 1.00 (1.00-1.00) .56 Breastfeeding at 1 mo 1351 5701 7052 0.89 (0.78-1.02) .10 1.06 (0.93-1.22) .39 1.04 (0.91-1.19) .60 Abbreviations: ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; OR, odds ratio; PRS, polygenic risk score; SCZ, schizophrenia.

1.00 (1.00-1.01) .13 1.00 (1.00-1.00) .44 1.00 (1.00-1.00) .56 Breastfeeding at 1 mo 1351 5701 7052 0.89 (0.78-1.02) .10 1.06 (0.93-1.22) .39 1.04 (0.91-1.19) .60 Abbreviations: ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; OR, odds ratio; PRS, polygenic risk score; SCZ, schizophrenia. Sensitivity Analyses Sensitivity analysis revealed consistent results across different P value thresholds for all 3 PRSs, as shown in eFigures 1 to 6 in the Supplement. To account for attrition, we performed inverse probability weighting on availability of genetic data and reran our main analysis with the derived weights, which revealed a similar pattern of results (eTables 6 and 7 in the Supplement). In addition, we evaluated the observational association of the investigated early-life exposures with ADHD and ASD symptoms in children in the ALSPAC population (eMethods and eTable 8 in the Supplement). We found evidence of an association of smoking (relative risk [RR], 1.70; 95% CI, 1.37-2.10) and use of acetaminophen (RR, 1.45; 95% CI, 1.18-1.78) during pregnancy, ever having depression (RR, 1.64; 95% CI, 1.20-2.25), and an increased stressful life events score (RR, 1.15; 95% CI, 1.10-1.20) with an increased risk of ADHD, as described previously for this cohort.

(relative risk [RR], 1.70; 95% CI, 1.37-2.10) and use of acetaminophen (RR, 1.45; 95% CI, 1.18-1.78) during pregnancy, ever having depression (RR, 1.64; 95% CI, 1.20-2.25), and an increased stressful life events score (RR, 1.15; 95% CI, 1.10-1.20) with an increased risk of ADHD, as described previously for this cohort. Discussion The present study examines the association between neurodevelopmental disorder PRSs and early-life exposures associated with those disorders. We found that maternal risk alleles for neurodevelopmental disorders, primarily ADHD, were associated with some prenatal factors. These findings are in line with those of studies showing substantial associations between genetic factors and environmental experiences and highlight the need to account for genetic confounding in studies of pregnancy-related exposures and neurodevelopmental disorders. Only maternal stressful life events during pregnancy and lifetime depression showed consistent associations with PRS for all 3 neurodevelopmental disorders. These associations are in line with previous findings suggesting that some stressful life events are heritable and that stressful life events, depression, and neurodevelopmental disorders share genetic risk factors. Apart from horizontal pleiotropy, a potential explanation for the PRS associations with stressful life events is that maternal traits of neurodevelopmental disorders could be associated with stressful situations, making mothers at high genetic risk for ADHD more likely to encounter stressful events.

netic risk factors. Apart from horizontal pleiotropy, a potential explanation for the PRS associations with stressful life events is that maternal traits of neurodevelopmental disorders could be associated with stressful situations, making mothers at high genetic risk for ADHD more likely to encounter stressful events. Maternal ADHD PRS showed associations with a variety of prenatal factors. Consistent with previous studies, we found that genetic liability for ADHD was associated with higher BMI, younger maternal age at delivery, and smoking. To our knowledge, this study was the first to report that genetic liability to ADHD may also be associated with infections, acetaminophen use, and blood levels of toxins in pregnant mothers. Acetaminophen exposure in pregnancy is of considerable current interest because studies have raised concern about its safety owing to the observed association with offspring ADHD. Our results suggest that mothers with higher ADHD PRS may also be more likely to use acetaminophen in pregnancy. Whether the association between ADHD and acetaminophen use holds after adjusting for shared genetic factors and represents a causal relationship should be assessed in a causally informative mendelian randomization framework and with other genetically informative designs that test and account for horizontal pleiotropy.

Whether the association between ADHD and acetaminophen use holds after adjusting for shared genetic factors and represents a causal relationship should be assessed in a causally informative mendelian randomization framework and with other genetically informative designs that test and account for horizontal pleiotropy. The association between ADHD PRS and lower biomarker levels of selenium and mercury may seem counterintuitive. However, because fish is a major source of these heavy metals in the general population and ADHD is associated with low fish consumption, a possible explanation could be that mothers with higher ADHD PRS consumed less fish.

n between ADHD PRS and lower biomarker levels of selenium and mercury may seem counterintuitive. However, because fish is a major source of these heavy metals in the general population and ADHD is associated with low fish consumption, a possible explanation could be that mothers with higher ADHD PRS consumed less fish. In contrast to ADHD PRS, we found little evidence of associations between ASD PRS or SCZ PRS and early-life factors (except for SCZ PRS with lower BMI and more smoking, consistent with previous studies). It is possible that ADHD risk alleles have especially widespread pleiotropic or causal effects on lifestyle and risk-taking behavior during pregnancy. In addition, the differential pattern of associations could be driven in part by genetic overlap between the 3 disorders and educational attainment. Although ADHD has shown genetic overlap with lower educational attainment, genetic overlap with higher educational attainment has been found for ASD and less strongly for schizophrenia. Educational attainment has been shown to be associated with health-conscious behavior and pregnancy-related exposures. The differential associations with educational attainment might also explain why many of the coefficients for ASD PRS and SCZ PRS were in the opposite direction from ADHD PRS (eg, age at childbirth, selenium levels, folic acid intake, and breastfeeding). Future studies could use a multipolygenic score model to assess the extent to which associations between neurodevelopmental disorder risk alleles and prenatal factors may be explained by education-associated alleles.

direction from ADHD PRS (eg, age at childbirth, selenium levels, folic acid intake, and breastfeeding). Future studies could use a multipolygenic score model to assess the extent to which associations between neurodevelopmental disorder risk alleles and prenatal factors may be explained by education-associated alleles. Our results have implications for supporting pregnant women with neurodevelopmental problems such as ADHD, given that maternal neurodevelopmental risk alleles were associated with exposure to adverse conditions (eg, stress) and risky behaviors (eg, smoking) in pregnancy. The associations between ADHD PRS and prenatal exposures were generally of small magnitude, and additional types of investigations are needed to assess whether the associations are of clinical importance. Nevertheless, our findings add to the increasing evidence that the observational associations between many prenatal factors and neurodevelopmental disorders in offspring may be at least partially genetically confounded. However, the presence of genetic confounding does not exclude a causal effect. Genetic effects may even be mediated through an environmental exposure. For example, in the present study, we found that maternal ADHD PRS was associated with higher levels of the heavy metal cadmium, for which smoking is a common source. Although maternal genetic liability for ADHD predisposes mothers to smoke during pregnancy, prenatal cadmium exposure due to smoking could still be associated with an increased risk for ADHD in offspring. However, this increased risk has been shown to be unlikely by triangulation of evidence from studies comparing smoking during pregnancy between mothers and fathers and between genetically related and unrelated mothers (in vitro fertilization cohort). Disentangling complex questions of whether prenatal factors causally influence risk of neurodevelopmental disorders in offspring will likely require such triangulation of evidence from multiple approaches that rely on different assumptions and have unrelated sources of potential biases, including genetically informed methods.

ngling complex questions of whether prenatal factors causally influence risk of neurodevelopmental disorders in offspring will likely require such triangulation of evidence from multiple approaches that rely on different assumptions and have unrelated sources of potential biases, including genetically informed methods. Limitations ALSPAC did not assess diagnosis of maternal ADHD or ASD, and only 7 mothers reported a diagnosis of SCZ; therefore, we were not able to evaluate the estimation of our generated PRSs or test for the association of observed maternal neurodevelopmental traits with early-life exposures in ALSPAC. Nevertheless, previous studies of children in the ALSPAC population have found robust associations between ADHD PRS and ADHD symptoms, associations between ASD PRS and ASD symptoms, and associations between SCZ PRS and negative symptoms of SCZ. Polygenic risk scores have been demonstrated to be useful instruments for polygenic traits commonly used to investigate the genetic architecture of many disorders. However, PRSs currently explain only a small amount of variance in heritability of neurodevelopmental disorders. Our power to detect associations with exposures may have been low for ASD because its SNP heritability is lower than that for ADHD and SCZ.

nly used to investigate the genetic architecture of many disorders. However, PRSs currently explain only a small amount of variance in heritability of neurodevelopmental disorders. Our power to detect associations with exposures may have been low for ASD because its SNP heritability is lower than that for ADHD and SCZ. Given that ADHD PRS (as well as SCZ PRS) is associated with study attrition, we performed inverse probability weighting sensitivity analyses accounting for the probability of having genetic data available. The weighted analyses showed similar results. Nevertheless, given that not all selection-associated factors could be included in the weighting, bias may remain. Furthermore, sample sizes were small for some early-life exposures, and the nested studies for heavy metal detection in pregnancy might be limited by selection bias. Although we have accounted for multiple testing, we must acknowledge that some of our findings might still occur by chance. Our study relied on self-reported smoking and alcohol consumption. These exposures may be underreported, especially during pregnancy, when smoking and alcohol consumption is considered socially undesirable, but results were consistent when comparing self-reported smoking and alcohol consumption before pregnancy (eTable 9 in the Supplement). We also did not have information about maternal use of medication to treat symptoms of ADHD, ASD, or schizophrenia and therefore cannot exclude the possibility that potential intake of medication for maternal mental health has led to spurious associations. However, excluding all mothers who reported they had taken medication for neuropsychiatric problems (ie, depression, anxiety, migraine, or sleeping problems) did not change our results (eTable 10 in the Supplement). We encourage replication of our findings in well-powered data sets.

th has led to spurious associations. However, excluding all mothers who reported they had taken medication for neuropsychiatric problems (ie, depression, anxiety, migraine, or sleeping problems) did not change our results (eTable 10 in the Supplement). We encourage replication of our findings in well-powered data sets. Conclusions Our findings suggest that several early-life factors linked to neurodevelopmental disorders are associated with maternal genetic liabilities to these disorders, primarily ADHD. Therefore, to draw conclusions about causality, future studies need to account for potential genetic confounding and triangulate evidence from different causally informative approaches. In addition, mothers with high genetic liability to ADHD may be at increased risk for many adverse pregnancy factors. Supplement. eMethods. Calculation of Polygenic Risk Scores and Analyses eTable 1. Number of SNPs Used to Calculate the Polygenic Risk Scores (PRS) for ADHD, ASD, and Schizophrenia eTable 2. Correlation (r) of Polygenic Risk Scores (PRS) for ADHD, ASD, and Schizophrenia eTable 3. Principal Component Analysis of Outcomes to Determine the Number of Independent Tests eTable 4. Comparison of Study Sample With and Without Available Genetics Data eTable 5. Association of Maternal Polygenic Risk Scores (PRS) for ADHD, ASD, and Schizophrenia (P < .05) With Maternal Age at Delivery eTable 6. Association of Maternal Polygenic Risk Scores (PRS) (P < .05) With Prenatal Exposures Linked to Offspring Neurodevelopmental Disorders

eTable 4. Comparison of Study Sample With and Without Available Genetics Data eTable 5. Association of Maternal Polygenic Risk Scores (PRS) for ADHD, ASD, and Schizophrenia (P < .05) With Maternal Age at Delivery eTable 6. Association of Maternal Polygenic Risk Scores (PRS) (P < .05) With Prenatal Exposures Linked to Offspring Neurodevelopmental Disorders eTable 7. Association of Maternal Polygenic Risk Scores (PRS) (P < .05) With Perinatal Exposures and Conditions Linked to Offspring Neurodevelopmental Disorders eTable 8. Association of Early Life Exposure With Observed ADHD and ASD Symptoms in ALSPAC eTable 9. Association of Maternal Polygenic Risk Scores (P < .05) With Maternal Alcohol Consumption, Smoking Behavior, and Stressful Life Events at Different Time Intervals During and Before Pregnancy eTable 10. Association of Maternal Polygenic Risk Scores (PRS) (P < .05) With Prenatal Exposures Linked to Offspring Neurodevelopmental Disorders, Excluding Mothers Who Have Reported Taking Medication for Anxiety, Depression, Migraine, Sleeping Problem, or Other eFigure 1. Association of Maternal Polygenic Risk Scores for ADHD at Different P Value Thresholds With Prenatal and Perinatal Exposures Linked to Offspring Neurodevelopmental Disorders With Continuous Outcomes eFigure 2. Association of Maternal Polygenic Risk Scores for ADHD at Different P Value Thresholds With Prenatal and Perinatal Exposures Linked to Offspring Neurodevelopmental Disorders With Binary Outcomes

eFigure 1. Association of Maternal Polygenic Risk Scores for ADHD at Different P Value Thresholds With Prenatal and Perinatal Exposures Linked to Offspring Neurodevelopmental Disorders With Continuous Outcomes eFigure 2. Association of Maternal Polygenic Risk Scores for ADHD at Different P Value Thresholds With Prenatal and Perinatal Exposures Linked to Offspring Neurodevelopmental Disorders With Binary Outcomes eFigure 3. Association of Maternal Polygenic Risk Scores for Autism at Different P Value Thresholds With Prenatal and Perinatal Exposures Linked to Offspring Neurodevelopmental Disorders With Continuous Outcomes eFigure 4. Association of Maternal Polygenic Risk Scores for Autism at Different P Value Thresholds With Prenatal and Perinatal Exposures Linked to Offspring Neurodevelopmental Disorders With Binary Outcomes eFigure 5. Association of Maternal Polygenic Risk Scores for Schizophrenia at Different P Value Thresholds With Prenatal and Perinatal Exposures Linked to Offspring Neurodevelopmental Disorders With Continuous Outcomes eFigure 6. Association of Maternal Polygenic Risk Scores for Schizophrenia at Different P Value Thresholds With Prenatal and Perinatal Exposures Linked to Offspring Neurodevelopmental Disorders With Binary Outcomes Click here for additional data file.