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- Kupers, LK, et al.
(författare)
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Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 1893-
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Tidskriftsartikel (refereegranskat)abstract
- Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from −183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10−7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10−74) and BMI in pregnancy (3/914, p = 1.13x10−3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.
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| 2. |
- Czamara, D, et al.
(författare)
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Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2548-
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Tidskriftsartikel (refereegranskat)abstract
- Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk.
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- Sikdar, S, et al.
(författare)
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Comparison of smoking-related DNA methylation between newborns from prenatal exposure and adults from personal smoking
- 2019
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Ingår i: Epigenomics. - : Future Medicine Ltd. - 1750-192X .- 1750-1911. ; 11:13, s. 1487-1500
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Cigarette smoking influences DNA methylation genome wide, in newborns from pregnancy exposure and in adults from personal smoking. Whether a unique methylation signature exists for in utero exposure in newborns is unknown. Materials & methods: We separately meta-analyzed newborn blood DNA methylation (assessed using Illumina450k Beadchip), in relation to sustained maternal smoking during pregnancy (9 cohorts, 5648 newborns, 897 exposed) and adult blood methylation and personal smoking (16 cohorts, 15907 participants, 2433 current smokers). Results & conclusion: Comparing meta-analyses, we identified numerous signatures specific to newborns along with many shared between newborns and adults. Unique smoking-associated genes in newborns were enriched in xenobiotic metabolism pathways. Our findings may provide insights into specific health impacts of prenatal exposure on offspring.
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- Halfdanarson, O, et al.
(författare)
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Antipsychotic use in pregnancy and risk of attention/deficit-hyperactivity disorder and autism spectrum disorder: a Nordic cohort study
- 2022
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Ingår i: Evidence-based mental health. - : BMJ. - 1468-960X .- 1362-0347. ; 25:2, s. 54-62
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Tidskriftsartikel (refereegranskat)abstract
- Antipsychotics are increasingly used among women of childbearing age and during pregnancy.ObjectiveTo determine whether children exposed to antipsychotics in utero are at increased risk of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD), accounting for maternal diagnoses of bipolar, psychotic and other psychiatric disorders.DesignPopulation-based cohort study, including a sibling analysis.SettingNationwide data on all pregnant women and their live-born singletons in Denmark (1997-2017), Finland (1996-2016), Iceland (2004-2017), Norway (2004-2017), and Sweden (2006-2016).Participants4 324 086 children were eligible for inclusion to the study cohort.InterventionAntipsychotic exposure in utero, assessed by pregnancy trimester, type of antipsychotic, and varying patterns of use.Main outcome measuresNon-mutually exclusive diagnoses of ADHD and ASD. We used Cox proportional hazard models to calculate hazard ratios (HRs) controlling for maternal psychiatric disorders and other potential confounding factors.FindingsAmong 4 324 086 singleton births, 15 466 (0.4%) were exposed to antipsychotics in utero. During a median follow-up of 10 years, we identified 72 257 children with ADHD and 38 674 children with ASD. Unadjusted HRs were raised for both outcomes but shifted substantially towards the null after adjustment; 1.10 (95%CI 1.00 to 1.27) for ADHD and 1.12 (0.97 to 1.29) for ASD. Adjusted HRs remained consistent by trimester of exposure and type of antipsychotic. Comparing in utero exposure with pre-pregnancy use yielded HRs of 0.74 (0.62 to 0.87) for ADHD and 0.88 (0.70 to 1.10) for ASD. Sibling analyses yielded HRs of 1.14 (0.79 to 1.64) for ADHD and 1.34 (0.75 to 2.39) for ASD.DiscussionOur findings suggest little or no increased risk of child ADHD or ASD after in utero exposure to antipsychotics.Clinical implicationsResults regarding child neurodevelopment are reassuring for women who need antipsychotics during pregnancy.
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- Magnus, MC, et al.
(författare)
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Fetal death after the introduction of COVID-19 mitigation measures in Sweden, Denmark and Norway: a registry-based study
- 2022
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1, s. 20625-
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Tidskriftsartikel (refereegranskat)abstract
- It remains unclear whether the rate of fetal death has changed during the COVID-19 pandemic. We assessed the impact of COVID-19 mitigation measures on fetal death in Sweden (449,347 births), Denmark (290,857 pregnancies) and Norway (261,057 pregnancies) using robust population-based registry data. We used Cox regression to assess the impact of the implementation of pandemic mitigation measures on March 12th, 2020, on miscarriage (fetal loss before gestational week 22) and stillbirth (fetal loss after gestational week 22). A total of 11% of 551,914 pregnancies in Denmark and Norway ended in miscarriage, while the proportion of stillbirths among 937,174 births across the three countries was 0.3%. There was no difference in the risk of fetal death during the year following pandemic mitigation measures. For miscarriage, the combined hazard ratio (HR) for Norway and Denmark was 1.01 (95% CI 0.98, 1.03), and for stillbirth, the combined HR for all three countries was 0.99 (95% CI 0.89, 1.09). We observed a slightly decreased risk of miscarriage during the first 4 months, with an HR of 0.94 (95% CI 0.90, 0.99) after lockdown. In conclusion, the risk of fetal death did not change after the implementation of COVID-19 pandemic mitigation measures in the three Scandinavian countries.
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- Marinovich, ML, et al.
(författare)
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Developing evidence-based recommendations for optimal interpregnancy intervals in high-income countries: protocol for an international cohort study
- 2019
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 9:1, s. e027941-
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Tidskriftsartikel (refereegranskat)abstract
- Short interpregnancy interval (IPI) has been linked to adverse pregnancy outcomes. WHO recommends waiting at least 2 years after a live birth and 6 months after miscarriage or induced termination before conception of another pregnancy. The evidence underpinning these recommendations largely relies on data from low/middle-income countries. Furthermore, recent epidemiological investigations have suggested that these studies may overestimate the effects of IPI due to residual confounding. Future investigations of IPI effects in high-income countries drawing from large, population-based data sources are needed to inform IPI recommendations. We aim to assess the impact of IPIs on maternal and child health outcomes in high-income countries.Methods and analysisThis international longitudinal retrospective cohort study will include more than 18 million pregnancies, making it the largest study to investigate IPI in high-income countries. Population-based data from Australia, Finland, Norway and USA will be used. Birth records in each country will be used to identify consecutive pregnancies. Exact dates of birth and clinical best estimates of gestational length will be used to estimate IPI. Administrative birth and health data sources with >99% coverage in each country will be used to identify maternal sociodemographics, pregnancy complications, details of labour and delivery, birth and child health information. We will use matched and unmatched regression models to investigate the impact of IPI on maternal and infant outcomes, and conduct meta-analysis to pool results across countries.Ethics and disseminationEthics boards at participating sites approved this research (approval was not required in Finland). Findings will be published in peer-reviewed journals and presented at international conferences, and will inform recommendations for optimal IPI in high-income countries. Findings will provide important information for women and families planning future pregnancies and for clinicians providing prenatal care and giving guidance on family planning.
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- Ortqvist, AK, et al.
(författare)
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The association between maternal characteristics and SARS-CoV-2 in pregnancy: a population-based registry study in Sweden and Norway
- 2022
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1, s. 8355-
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Tidskriftsartikel (refereegranskat)abstract
- The objectives of the current study were to identify risk factors for SARS-CoV-2 positivity, and to address how different testing strategies, choice of comparison group, and population background characteristics may influence observed associations. National registries data for 107,627 pregnant women in Sweden and 81,195 in Norway, were used to identify risk factors for SARS-CoV-2, separately for women under non-universal testing (testing by indication) and universal testing (testing of all pregnant women in contact with a delivery ward). We also investigated underlying characteristics associated with testing for SARS-CoV-2. Overall, 2.1% of pregnant women in Sweden and 1.1% in Norway were test-positive during the pandemic’s first 18 months. We show that the choice of test strategy for SARS-CoV-2 provided different associations with risk factors for the disease; for instance, women who were overweight, obese or had gestational diabetes had increased odds of being test-positive under non-universal testing, but not under universal testing. Nevertheless, a consistent pattern of association between being born in the Middle East and Africa and test-positivity was found independent of test strategy and in both countries. These women were also less likely to get tested. Our results are useful to consider for surveillance and clinical recommendations for pregnant women during the current and future pandemics.
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| 35. |
- van der Meer, D, et al.
(författare)
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Brain scans from 21,297 individuals reveal the genetic architecture of hippocampal subfield volumes
- 2020
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Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 25:11, s. 3053-3065
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Tidskriftsartikel (refereegranskat)abstract
- The hippocampus is a heterogeneous structure, comprising histologically distinguishable subfields. These subfields are differentially involved in memory consolidation, spatial navigation and pattern separation, complex functions often impaired in individuals with brain disorders characterized by reduced hippocampal volume, including Alzheimer’s disease (AD) and schizophrenia. Given the structural and functional heterogeneity of the hippocampal formation, we sought to characterize the subfields’ genetic architecture. T1-weighted brain scans (n = 21,297, 16 cohorts) were processed with the hippocampal subfields algorithm in FreeSurfer v6.0. We ran a genome-wide association analysis on each subfield, co-varying for whole hippocampal volume. We further calculated the single-nucleotide polymorphism (SNP)-based heritability of 12 subfields, as well as their genetic correlation with each other, with other structural brain features and with AD and schizophrenia. All outcome measures were corrected for age, sex and intracranial volume. We found 15 unique genome-wide significant loci across six subfields, of which eight had not been previously linked to the hippocampus. Top SNPs were mapped to genes associated with neuronal differentiation, locomotor behaviour, schizophrenia and AD. The volumes of all the subfields were estimated to be heritable (h2 from 0.14 to 0.27, all p < 1 × 10–16) and clustered together based on their genetic correlations compared with other structural brain features. There was also evidence of genetic overlap of subicular subfield volumes with schizophrenia. We conclude that hippocampal subfields have partly distinct genetic determinants associated with specific biological processes and traits. Taking into account this specificity may increase our understanding of hippocampal neurobiology and associated pathologies.
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