Long-term prenatal exposure to paracetamol is associated with DNA methylation differences in children diagnosed with ADHD

Gervin, Kristina; Nordeng, Hedvig; Ystrøm, Eivind; Reichborn‐Kjennerud, Ted; Lyle, Robert

doi:10.1186/s13148-017-0376-9

Cited by 59 publications

(103 citation statements)

References 60 publications

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“…This latter duration was of interest based on previous studies that characterised 20-30 days of acetaminophen use as "long-term" exposure. 5,8,13 Any acetaminophen use and longer durations of use were both higher among those with tobacco use in pregnancy, self-reported depression or anxiety, and antidepressant use. Although headaches or migraines accounted for the largest proportion of reported indications, higher doses per exposure day were observed in those indicating use for arthritis, sleep, fever, or cold/flu.…”

Section: Principal Findingsmentioning

confidence: 99%

“…1 It has been previously reported that between 40% and 65% of pregnant women use acetaminophen, [1][2][3][4][5][6][7] with estimates of 3%-20% of women reporting use in all three trimesters. 3,8 An emerging set of studies have signalled modest, yet concerning associations between acetaminophen and select pregnancy and childhood adverse outcomes, including preeclampsia, 9,10 preterm birth, 9 asthma (review and meta-analysis 11 ), and neurodevelopmental disorders [3][4][5][6][7][8][12][13][14] (review and meta-analysis 15 ). However, interpretation of these findings as causally related to prenatal acetaminophen exposure has been problematic.…”

Section: Backg Rou N Dmentioning

confidence: 99%

See 1 more Smart Citation

Acetaminophen use in pregnancy: Examining prevalence, timing, and indication of use in a prospective birth cohort

Bandoli

Palmsten

Chambers

2019

Paediatric Perinatal Epid

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Background: Previous studies of prenatal acetaminophen use have not addressed what indications and maternal co-factors describe acetaminophen use.Objective: The objective of this study was to describe these parameters in a wellcharacterised, prospective birth cohort.Methods: Data were drawn from the MotherToBaby study of pregnant women enrolled from 2004 to 2018. Daily acetaminophen diaries were calculated for all exposed women with complete dose and duration information. Descriptive statistics were used to assess maternal characteristics associated with acetaminophen use.Prevalence by 2-year interval was described, and linear regression was used to test for trend. Indication of use and dose per indication were summarised.Results: Of 2441 subjects, 1515 (62%) reported use of acetaminophen. Over the 15-year period, there was a decline in use of 2.5% for each 2-year period (test for trend = 0.001) with 58% reporting acetaminophen use in 2017-2018. Among women with acetaminophen use in pregnancy (n = 1515), 58% reported <10 days of use, 13% reported 10-19 days of use, 9% reported 20-44 days of use, and 9% reported 45 or more days of use. Twelve per cent had undefined duration of use. Increasing duration of exposure was associated with tobacco use, obesity, self-reported depression or anxiety, and antidepressant use. The most frequently reported indication was headache, however, indication varied by duration of use, with more women reporting use for sleep or pain/injury in the categories with the longest duration of use. Median dose per exposed day was highest among those reporting use for sleep, and higher doses were more frequently reported for arthritis, injury, and pain. Conclusion:Acetaminophen is used by the majority of pregnant women, and some continue to use for many weeks in pregnancy. Given the heterogeneity in duration of use, indication, and dose, studies that estimate the risk of adverse outcomes associated with acetaminophen must carefully consider these factors. K E Y W O R D Sacetaminophen, indications for use, pregnancy, prevalence

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Section: Principal Findingsmentioning

confidence: 99%

Section: Backg Rou N Dmentioning

confidence: 99%

Acetaminophen use in pregnancy: Examining prevalence, timing, and indication of use in a prospective birth cohort

Bandoli

Palmsten

Chambers

2019

Paediatric Perinatal Epid

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“…DNA methylation studies relevant to ADHD or ADHD symptoms to date are limited. They include five candidate gene studies on relatively small samples [22][23][24][25][26] , and four studies targeting specific environmental exposures, such as malnutrition, in relation to ADHD symptoms, by using candidate and epigenome-wide association study (EWAS) approaches [27][28][29][30] . Three prior EWAS studies are relevant.…”

Section: Introductionmentioning

confidence: 99%

Large epigenome-wide association study of childhood ADHD identifies peripheral DNA methylation associated with disease and polygenic risk burden

et al. 2020

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Epigenetic variation in peripheral tissues is being widely studied as a molecular biomarker of complex disease and disease-related exposures. To date, few studies have examined differences in DNA methylation associated with attention-deficit hyperactivity disorder (ADHD). In this study, we profiled genetic and methylomic variation across the genome in saliva samples from children (age 7-12 years) with clinically established ADHD (N = 391) and nonpsychiatric controls (N = 213). We tested for differentially methylated positions (DMPs) associated with both ADHD diagnosis and ADHD polygenic risk score, by using linear regression models including smoking, medication effects, and other potential confounders in our statistical models. Our results support previously reported associations between ADHD and DNA methylation levels at sites annotated to VIPR2, and identify several novel disease-associated DMPs (p < 1e-5), although none of them were genome-wide significant. The two top-ranked, ADHD-associated DMPs (cg17478313 annotated to SLC7A8 and cg21609804 annotated to MARK2) are also significantly associated with nearby SNPs (p = 1.2e-46 and p = 2.07e-59), providing evidence that disease-associated DMPs are under genetic control. We also report a genome-wide significant association between ADHD polygenic risk and variable DNA methylation at a site annotated to the promoter of GART and SON (p = 6.71E-8). Finally, we show that ADHD-associated SNPs colocalize with SNPs associated with methylation levels in saliva. This is the first large-scale study of DNA methylation in children with ADHD. Our results represent novel epigenetic biomarkers for ADHD that may be useful for patient stratification, reinforce the importance of genetic effects on DNA methylation, and provide plausible molecular mechanisms for ADHD risk variants.

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“…DNA methylation (DNAm) is involved in the regulation of genes and is essential for normal development. Human epigenome-wide association studies (EWAS) are widely used to investigate the association between DNAm variation and prenatal environmental factors, and understanding the developmental origin of phenotypes and diseases[1-3]. These studies are often performed in umbilical cord blood (UCB), which is collected from the umbilical cord after birth.…”

Section: Introductionmentioning

confidence: 99%

Systematic evaluation and validation of reference and library selection methods for deconvolution of cord blood DNA methylation data

Gervin

Salas

Bakulski

et al. 2019

Preprint

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40 Background: Umbilical cord blood (UCB) is commonly used in epigenome-wide association 41 studies of prenatal exposures. Accounting for cell type composition is critical in such studies as it 42 reduces confounding due to the cell specificity of DNA methylation (DNAm). In the absence of cell 43 sorting information, statistical methods can be applied to deconvolve heterogeneous cell mixtures. 44 Among these methods, reference-based approaches leverage age appropriate cell-specific DNA-45 methylation profiles to estimate cellular composition. In UCB, four reference datasets comprising 46 DNAm signatures profiled in purified cell populations have been published using the Illumina 450K 47 and 850K EPIC arrays. These datasets are biologically and technically different, and currently there 48is no consensus on how to best apply them. Here, we systematically evaluate and compare these 49 datasets and provide recommendations for reference-based UCB deconvolution. Results: We first 50 evaluated the four reference datasets to ascertain both the purity of the samples and the potential 51

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Long-term prenatal exposure to paracetamol is associated with DNA methylation differences in children diagnosed with ADHD

Cited by 59 publications

References 60 publications

Acetaminophen use in pregnancy: Examining prevalence, timing, and indication of use in a prospective birth cohort

Acetaminophen use in pregnancy: Examining prevalence, timing, and indication of use in a prospective birth cohort

Large epigenome-wide association study of childhood ADHD identifies peripheral DNA methylation associated with disease and polygenic risk burden

Systematic evaluation and validation of reference and library selection methods for deconvolution of cord blood DNA methylation data

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