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Smoking during pregnancy and ADHD risk: A genetically informed, multiple-rater approach.

ABSTRACT: Maternal smoking during pregnancy (SDP) is a significant public health concern with adverse consequences to the health and well-being of the developing child, including behavioral outcomes such as Attention-Deficit Hyperactivity Disorder (ADHD). There is substantial interest in understanding the nature of this reported association, particularly in light of more recent genetically informed studies that suggest that the SDP-ADHD link is less clear than once thought. In a sample of families (N?=?173) specifically selected for sibling pairs discordant for prenatal smoking exposure, we use a sibling-comparison approach that controls for shared genetic and familial influences to assess the effects of SDP on ADHD symptom dimensions. ADHD was measured by both parent and teacher report on the Conners report forms and the Child Behavior Checklist/Teacher Report Form (CBCL/TRF). Results for the CBCL/TRF Total ADHD score are consistent with prior genetically informed approaches and suggest that previously reported associations between SDP and ADHD are largely due to familial confounding rather than causal teratogenic effects. However, results from the Conners parent report suggest a potentially causal effect of SDP on hyperactive/impulsive and, to a lesser extent, total ADHD symptoms; SDP results in increased parent-reported hyperactive/impulsive and total ADHD symptoms even after accounting for genetic and familial confounding factors. This suggests that the Conners assessment (parent-report) may provide a sensitive measure for use in studies examining child specific SDP effects on continuous and dimensional aspects of ADHD. © 2016 Wiley Periodicals, Inc.

SUBMITTER: Knopik VS

PROVIDER: S-EPMC4958030 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Smoking during pregnancy and ADHD risk: A genetically informed, multiple-rater approach.

Knopik Valerie S VS Marceau Kristine K Bidwell L Cinnamon LC Palmer Rohan H C RH Smith Taylor F TF Todorov Alexandre A Evans Allison Schettini AS Heath Andrew C AC

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 20160122 7

Maternal smoking during pregnancy (SDP) is a significant public health concern with adverse consequences to the health and well-being of the developing child, including behavioral outcomes such as Attention-Deficit Hyperactivity Disorder (ADHD). There is substantial interest in understanding the nature of this reported association, particularly in light of more recent genetically informed studies that suggest that the SDP-ADHD link is less clear than once thought. In a sample of families (N = 17 ...[more]

PMID: 26799787

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Project description:INTRODUCTION:Maternal smoking during pregnancy (SDP) is associated with disruptive behavior. However, there is debate whether the SDP-disruptive behavior association is a potentially causal pathway or rather a spurious effect confounded by shared genetic and environmental factors. AIMS AND METHODS:The Missouri Mothers and Their Children Study is a sibling comparison study that includes families (n = 173) selected for sibling pairs (aged 7-16 years) discordant for SDP. Critically, the sibling comparison design is used to disentangle the effects of SDP from familial confounds on disruptive behavior. An SDP severity score was created for each child using a combination of SDP indicators (timing, duration, and amount of SDP). Multiple informants (parents and teachers) reported on disruptive behavior (i.e., DSM-IV semi-structured interview, the Child Behavior Checklist, and Teacher Report Form). RESULTS:The variability in disruptive behavior was primarily a function of within-family differences (66%-100%). Consistent with prior genetically informed approaches, the SDP-disruptive behavior association was primarily explained by familial confounds (genetic and environmental). However, when using a multi-rater approach (parents and teachers), results suggest a potentially causal effect of SDP on disruptive behavior (b = 0.09, SE = 0.04, p = 0.03). The potentially causal effect of SDP remained significant in sensitivity analyses. DISCUSSION:These findings suggest that familial confounding likely plays a complex role in the SDP-disruptive behavior association when examining both parent and teacher reports of behavior. Importantly, the current study highlights the importance of multiple raters, reflecting a more comprehensive measure of complex behaviors (e.g., disruptive behavior) to examine the teratogenic effects of SDP. IMPLICATIONS:Our study provides additional evidence that controlling for genetic and family factors is essential when examining the effect of SDP on later behavioral problems, as it explains a portion of the association between SDP and later behavioral problems. However, we found a significant association between SDP and disruptive behavior when using a multi-rater approach that capitalizes on both parent and teacher report, suggesting that parent and teacher ratings capture a unique perspective that is important to consider when examining SDP-behavior associations.

Project description:BackgroundAttention deficit/hyperactivity disorder (ADHD) is a highly prevalent childhood disorder. Maternal smoking during pregnancy is a replicated environmental risk factor for this disorder. It is also a robust modifier of gene methylation during the prenatal developmental period. In this study, we sought to identify loci differentially methylated by maternal smoking during pregnancy and relate their methylation levels to various behavioural and physical outcomes relevant to ADHD.MethodsWe extracted DNA from blood samples from children diagnosed with ADHD and deeply phenotyped. Genome-wide DNA methylation was assessed using Infinium MethylationEPIC BeadChip. Maternal smoking during pregnancy was self-declared and assessed retrospectively.ResultsOur sample included 231 children with ADHD. Statistically significant differences in DNA methylation between children exposed or not to maternal smoking during pregnancy were detected in 3457 CpGs. We kept 30 CpGs with at least 5% of methylation difference between the 2 groups for further analysis. Six genes were associated with varied phenotypes of clinical relevance to ADHD. The levels of DNA methylation in RUNX1 were positively correlated with the CBCL scores, and DNA methylation in MYO1G correlated positively with the score at the Conners rating scale. Methylation level in a CpG located in GFI1 correlated with birthweight, a risk factor for ADHD. Differentially methylated regions were also identified and confirmed the association of RUNX1 methylation levels with the CBCL score.LimitationsThe study has several limitations, including the retrospective recall with self-report of maternal smoking during pregnancy as well as the grouping of individuals of varying age and developmental stage and of both males and females. In addition, the correlation design prevents the building of causation models.ConclusionThis study provides evidence for the association between the level of methylation at specific loci and quantitative dimensions highly relevant for ADHD as well as birth weight, a measure that has already been associated with increased risk for ADHD. Our results provide further support to public health educational initiatives to stop maternal smoking during pregnancy.

Project description:INTRODUCTION:Pharmacogenomic studies have used genetic variants to identify smokers likely to respond to pharmacological treatments for smoking cessation. METHODS:We performed a systematic review and meta-analysis of primary and secondary analyses of trials of smoking cessation pharmacotherapies. Eligible were trials with data on a priori selected single nucleotide polymorphisms, replicated non-single nucleotide polymorphisms, and/or the nicotine metabolite ratio. We estimated the genotype × treatment interaction as the ratio of risk ratios (RRR) for treatment effects across genotype groups. RESULTS:We identified 18 trials (N = 9017 participants), including 40 active (bupropion, nicotine replacement therapy [NRT], varenicline, or combination therapies) versus placebo comparisons and 16 active versus active comparisons. There was statistical evidence of heterogeneity across rs16969968 genotypes in CHRNA5 with regard to both 6-month abstinence and end-of-treatment abstinence in non-Hispanic black smokers and end-of-treatment abstinence in non-Hispanic white smokers. There was also heterogeneity across rs1051730 genotypes in CHRNA3 with regard to end-of-treatment abstinence in non-Hispanic white smokers. There was no clear statistical evidence for other genotype-by-treatment combinations. Compared with placebo, NRT was more effective among non-Hispanic black smokers with rs16969968-GG with regard to both 6-month abstinence (RRR for GG vs. GA or AA, 3.51; 95% confidence interval [CI] = 1.19 to 10.30) and end-of-treatment abstinence (RRR for GG vs. GA or AA, 5.84; 95% CI = 1.89 to 18.10). Among non-Hispanic white smokers, NRT effectiveness relative to placebo was comparable across rs1051730 and rs169969960 genotypes. CONCLUSIONS:We did not identify widespread differential effects of smoking cessation pharmacotherapies based on genotype. The quality of the evidence is generally moderate. IMPLICATIONS:Although we identified some evidence of genotype × treatment interactions, the vast majority of analyses did not provide evidence of differential treatment response by genotype. Where we find some evidence, these results should be considered preliminary and interpreted with caution because of the small number of contributing trials per genotype comparison, the wide confidence intervals, and the moderate quality of evidence. Prospective trials and individual-patient data meta-analyses accounting for heterogeneity of treatment effects through modeling are needed to assess the clinical utility of genetically informed biomarkers to guide pharmacotherapy choice for smoking cessation.

Project description:ObjectiveDespite strong pharmacological evidence implicating the norepinephrine transporter in ADHD, genetic studies have yielded largely insignificant results. We tested the association between 30 tag SNPs within the SLC6A2 gene and ADHD, with stratification based on maternal smoking during pregnancy, an environmental factor strongly associated with ADHD.MethodsChildren (6-12 years old) diagnosed with ADHD according to DSM-IV criteria were comprehensively evaluated with regard to several behavioral and cognitive dimensions of ADHD as well as response to a fixed dose of methylphenidate (MPH) using a double-blind placebo controlled crossover trial. Family-based association tests (FBAT), including categorical and quantitative trait analyses, were conducted in 377 nuclear families.ResultsA highly significant association was observed with rs36021 (and linked SNPs) in the group where mothers smoked during pregnancy. Association was noted with categorical DSM-IV ADHD diagnosis (Z=3.74, P=0.0002), behavioral assessments by parents (CBCL, P=0.00008), as well as restless-impulsive subscale scores on Conners'-teachers (P=0.006) and parents (P=0.006). In this subgroup, significant association was also observed with cognitive deficits, more specifically sustained attention, spatial working memory, planning, and response inhibition. The risk allele was associated with significant improvement of behavior as measured by research staff (Z=3.28, P=0.001), parents (Z=2.62, P=0.009), as well as evaluation in the simulated academic environment (Z=3.58, P=0.0003).ConclusionsBy using maternal smoking during pregnancy to index a putatively more homogeneous group of ADHD, highly significant associations were observed between tag SNPs within SLC6A2 and ADHD diagnosis, behavioral and cognitive measures relevant to ADHD and response to MPH. This comprehensive phenotype/genotype analysis may help to further understand this complex disorder and improve its treatment. Clinical trial registration information - Clinical and Pharmacogenetic Study of Attention Deficit with Hyperactivity Disorder (ADHD); www.clinicaltrials.gov; NCT00483106.

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Smoking during pregnancy and ADHD risk: A genetically informed, multiple-rater approach.

Publications

Smoking during pregnancy and ADHD risk: A genetically informed, multiple-rater approach.

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