Placental efflux transporters and antiseizure or antidepressant medication use impact birth weight in MoBa cohort.

Low birth weight raises neonatal risks and lifelong health issues and is linked to maternal medication use during pregnancy. We examined data from the Norwegian Mother, Father, and Child Cohort Study and the Medical Birth Registry of Norway, including 69,828 offspring with genotype data and 81,189 with maternal genotype data. We identified genetic risk variants in placental efflux transporters, calculated genetic scores based on alleles related to transporter activity, and assessed their interaction with prenatal use of antiseizure or antidepressant medication on offspring birth weight. Our study uncovered possible genetic variants in both offspring (rs3740066) and mothers (rs10248420; rs2235015) in placental efflux transporters (MRP2-ABCC2 and MDR1-ABCB1) that modulated the association between prenatal exposure to antiseizure medication and low birth weight in the offspring. Antidepressant exposure was associated with low birth weight, but there were no gene-drug interactions. The interplay between MRP2-ABCC2 and MDR1-ABCB1 variants and antiseizure medication may impact neonatal birth weight.

Urban environment in pregnancy and postpartum depression: An individual participant data meta-analysis of 12 European birth cohorts.

BACKGROUND: Urban environmental exposures associate with adult depression, but it is unclear whether they are associated to postpartum depression (PPD). OBJECTIVES: We investigated associations between urban environment exposures during pregnancy and PPD. METHODS: We included women with singleton deliveries to liveborn children from 12 European birth cohorts (N with minimum one exposure = 30,772, analysis N range 17,686-30,716 depending on exposure; representing 26-46 % of the 66,825 eligible women). We estimated maternal exposure during pregnancy to ambient air pollution with nitrogen dioxide (NO2) and particulate matter (PM2.5 and PM10), road traffic noise (Lden), natural spaces (Normalised Difference Vegetation Index; NDVI, proximity to major green or blue spaces) and built environment (population density, facility richness and walkability). Maternal PPD was assessed 3-18 months after birth using self-completed questionnaires. We used adjusted logistic regression models to estimate cohort-specific associations between each exposure and PPD and combined results via meta-analysis using DataSHIELD. RESULTS: Of the 30,772 women included, 3,078 (10 %) reported having PPD. Exposure to PM10 was associated with slightly increased odds of PPD (adjusted odd ratios (OR) of 1.08 [95 % Confidence Intervals (CI): 0.99, 1.17] per inter quartile range increment of PM10) whilst associations for exposure to NO2 and PM2.5 were close to null. Exposure to high levels of road traffic noise (≥65 dB vs. < 65 dB) was associated with an OR of 1.12 [CI: 0.95, 1.32]. Associations between green spaces and PPD were close to null; whilst proximity to major blue spaces was associated with increased risk of PPD (OR 1.12, 95 %CI: 1.00, 1.26). All associations between built environment and PPD were close to null. Multiple exposure models showed similar results. DISCUSSION: The study findings suggest that exposure to PM10, road traffic noise and blue spaces in pregnancy may increase PPD risk, however future studies should explore this causally.

Tracing the adaptive evolution of SARS-CoV-2 during vaccine roll-out in Norway.

Vaccination against SARS-CoV-2 has greatly mitigated the impact of the COVID-19 pandemic. However, concerns have been raised about the degree to which vaccination might drive the emergence and selection of immune escape mutations that will hamper the efficacy of the vaccines. In this study, we investigate whether vaccination impacted the micro-scale adaptive evolution of SARS-CoV-2 in the Oslo region of Norway, during the first nine months of 2021, a period in which the population went from near-zero to almost 90 per cent vaccine coverage in the population over 50 years old. Weekly aggregated data stratified by age on vaccine uptake and number of SARS-CoV-2 cases in the area were obtained from the National Immunization Registry and the Norwegian Surveillance System for Communicable Diseases, respectively. A total of 6,438 virus sequences (7.5 per cent of the registered cases) along with metadata were available. We used a causal-driven approach to investigate the relationship between vaccination progress and changes in the frequency of 362 mutations present in at least ten samples, conditioned on the emergence of new lineages, time, and population vaccination coverage. After validating our approach, we identified 21 positive and 12 negative connections between vaccination progress and mutation prevalence, and most of them were outside the Spike protein. We observed a tendency for the mutations that we identified as positively connected with vaccination to decrease as the vaccinated population increased. After modelling the fitness of different competing mutations in a population, we found that our observations could be explained by a clonal interference phenomenon in which high fitness mutations would be outcompeted by the emergence or introduction of other high-fitness mutations.

Comprehensive evaluation of smoking exposures and their interactions on DNA methylation.

BACKGROUND: Smoking impacts DNA methylation, but data are lacking on smoking-related differential methylation by sex or dietary intake, recent smoking cessation (<1 year), persistence of differential methylation from in utero smoking exposure, and effects of environmental tobacco smoke (ETS). METHODS: We meta-analysed data from up to 15,014 adults across 5 cohorts with DNA methylation measured in blood using Illumina's EPIC array for current smoking (2560 exposed), quit < 1 year (500 exposed), in utero (286 exposed), and ETS exposure (676 exposed). We also evaluated the interaction of current smoking with sex or diet (fibre, folate, and vitamin C). FINDINGS: Using false discovery rate (FDR < 0.05), 65,857 CpGs were differentially methylated in relation to current smoking, 4025 with recent quitting, 594 with in utero exposure, and 6 with ETS. Most current smoking CpGs attenuated within a year of quitting. CpGs related to in utero exposure in adults were enriched for those previously observed in newborns. Differential methylation by current smoking at 4-71 CpGs may be modified by sex or dietary intake. Nearly half (35-50%) of differentially methylated CpGs on the 450 K array were associated with blood gene expression. Current smoking and in utero smoking CpGs implicated 3049 and 1067 druggable targets, including chemotherapy drugs. INTERPRETATION: Many smoking-related methylation sites were identified with Illumina's EPIC array. Most signals revert to levels observed in never smokers within a year of cessation. Many in utero smoking CpGs persist into adulthood. Smoking-related druggable targets may provide insights into cancer treatment response and shared mechanisms across smoking-related diseases. FUNDING: Intramural Research Program of the National Institutes of Health, Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, Chief Scientist Office of the Scottish Government Health Directorates and the Scottish Funding Council, Medical Research Council UK and the Wellcome Trust.

Impaired glucose tolerance and cardiovascular risk factors in relation to infertility: a Mendelian randomization analysis in the Norwegian Mother, Father, and Child Cohort Study.

STUDY QUESTION: Are impaired glucose tolerance (as measured by fasting glucose, glycated hemoglobin, and fasting insulin) and cardiovascular disease risk (as measured by low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, systolic blood pressure, and diastolic blood pressure) causally related to infertility? SUMMARY ANSWER: Genetic instruments suggest that higher fasting insulin may increase infertility in women. WHAT IS KNOWN ALREADY: Observational evidence suggests a shared etiology between impaired glucose tolerance, cardiovascular risk, and fertility problems. STUDY DESIGN, SIZE, DURATION: This study included two-sample Mendelian randomization (MR) analyses, in which we used genome-wide association summary data that were publicly available for the biomarkers of impaired glucose tolerance and cardiovascular disease, and sex-specific genome-wide association studies (GWASs) of infertility conducted in the Norwegian Mother, Father, and Child Cohort Study. PARTICIPANTS/MATERIALS, SETTING, METHODS: There were 68 882 women (average age 30, involved in 81 682 pregnancies) and 47 474 of their male partners (average age 33, 55 744 pregnancies) who had available genotype data and who provided self-reported information on time-to-pregnancy and use of ARTs. Of couples, 12% were infertile (having tried to conceive for ≥12 months or used ARTs to conceive). We applied the inverse variance weighted method with random effects to pool data across variants and a series of sensitivity analyses to explore genetic instrument validity. (We checked the robustness of genetic instruments and the lack of unbalanced horizontal pleiotropy, and we used methods that are robust to population stratification.) Findings were corrected for multiple comparisons by the Bonferroni method (eight exposures: P-value < 0.00625). MAIN RESULTS AND THE ROLE OF CHANCE: In women, increases in genetically determined fasting insulin levels were associated with greater odds of infertility (+1 log(pmol/l): odds ratio 1.60, 95% CI 1.17 to 2.18, P-value = 0.003). The results were robust in the sensitivity analyses exploring the validity of MR assumptions and the role of pleiotropy of other cardiometabolic risk factors. There was also evidence of higher glucose and glycated hemoglobin causing infertility in women, but the findings were imprecise and did not pass our P-value threshold for multiple testing. The results for lipids and blood pressure were close to the null, suggesting that these did not cause infertility. LIMITATIONS, REASONS FOR CAUTION: We did not know if underlying causes of infertility were in the woman, man, or both. Our analyses only involved couples who had conceived. We did not have data on circulating levels of cardiometabolic risk factors, and we opted to conduct an MR analysis using GWAS summary statistics. No sex-specific genetic instruments on cardiometabolic risk factors were available. Our results may be affected by selection and misclassification bias. Finally, the characteristics of our study sample limit the generalizability of our results to populations of non-European ancestry. WIDER IMPLICATIONS OF THE FINDINGS: Treatments for lower fasting insulin levels may reduce the risk of infertility in women. STUDY FUNDING/COMPETING INTEREST(S): The MoBa Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Norwegian Ministry of Education and Research. This work was supported by the European Research Council [grant numbers 947684, 101071773, 293574, 101021566], the Research Council of Norway [grant numbers 262700, 320656, 274611], the South-Eastern Norway Regional Health Authority [grant numbers 2020022, 2021045], and the British Heart Foundation [grant numbers CH/F/20/90003, AA/18/1/34219]. Open Access funding was provided by the Norwegian Institute of Public Health. The funders had no role in the study design; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the article for publication. D.A.L. has received research support from National and International government and charitable bodies, Roche Diagnostics and Medtronic for research unrelated to the current work. O.A.A. has been a consultant to HealthLytix. The rest of the authors declare that no competing interests exist. TRIAL REGISTRATION NUMBER: N/A.

Controlled Synthesis of SnO2 Nanostructures as Alloy Anode via Restricted Potential Toward Building High-Performance Dual-Ion Batteries with Graphite Cathode.

Dual-ion batteries (DIBs) are considered one of the promising energy storage devices in which graphite serves as a bi-functional electrode, i.e., anode and cathode in the aprotic organic solvents. Unlike conventional lithium-ion batteries (LIBs), DIBs reversibly store the cations and anions in the anode and cathodes during redox reactions, respectively. The electrolyte is a source for both cations and anions, so the choice of electrolyte plays a vital role. In the present work, the synthesis of SnO2 nanostructures is reported as a possible alternative for graphite anode, and the Li-storage performance is optimized in half-cell (Li/SnO2 ) assembly with varying amounts of conductive additive (acetylene black) and limited working potential (1 V vs Li). Finally, a DIB using recovered graphite (RG) fabricated from spent LIB as a cathode and SnO2 nanostructures as an anode under balanced loading conditions. Prior to the fabrication, both electrodes are pre-cycled to eliminate irreversibility. An in-situ impedance study has been employed to validate the passivation layer formation during the charge-discharge process. The high-performance SnO2 /RG-based DIB delivered a maximum discharge capacity of 380 mAh g-1 . The electrochemical performance of DIB has been assessed by varying temperature conditions to evaluate their suitability in different climatic conditions.

High-Performance Li-Ion and Na-Ion Capacitors Based on a Spinel Li4Ti5O12 Anode and Carbonaceous Cathodes.

Lithium-ion hybrid capacitors (LICs) have become promising electrochemical energy storage systems that overcome the limitations of lithium-ion batteries and electrical double-layer capacitors. The asymmetric combination of these devices enhances the overall electrochemical performance by delivering simultaneous energy and power capabilities. Lithium titanate (Li4Ti5O12, LTO), a spinel zero-strain material, has been studied extensively as an anode material for LIC applications because of its high-rate capability, negligible volume change, and enhanced cycling performance. Here, the different synthetic methods and modifications of the intercalation-type LTO to enhance the overall electrochemical performance of LICs are mainly focused. Moreover, the cathodic part (i.e., the activated carbon derived from various sources, including natural products, polymers, and inorganic materials) is also dealt with as it contributes substantially to the overall performance of the LIC. Not only do the anode and cathode, but also the electrolytes have a substantial influence on LIC performance. The electrolytes used in LTO-based LICs as well as in flexible and bendable configurations are also mentioned. Overall, the previous work along with other available reports on LTO-based LICs in a simplified way is analyzed.

Synthesis and Characterization of the New Li1+xAl1+xSi1-xO4 (x = 0-0.25) Solid Electrolyte for Lithium-Ion Batteries.

A systematic study was performed to investigate the effect of the sintering temperature, sintering duration, and aluminum doping on the crystalline structure and ionic conductivity of the Li1+xAl1+xSi1-xO4 (LASO; x = 0-0.25) solid electrolyte. There was a strong indication that an increase in the sintering temperature and sintering time increased the ionic conductivity of the electrolyte. In particular, the doping concentration and composition ratio (Li1+xAl1+xSi1-xO4; x = 0-0.25) were found to be crucial factors for achieving high ionic conductivity. The sintering time of 18 h and lithium concentration influenced the lattice parameters of the LASO electrolyte, resulting in a significant improvement in ionic conductivity from 2.11 × 10-6 (for pristine LASO) to 1.07 × 10-5 S cm-1. An increase in the lithium concentration affected the stoichiometry, and it facilitated a smoother Li-ion transfer process since lithium served as an ion-conducting bridge between LASO grains.

Effect of Sodium Phosphate Coating on Cu and Mg-Substituted P2-Na0.67Ni0.33Mn0.67O2 for Improving the Cycling Performance of Sodium-Ion Capacitors.

Sodium-ion capacitors (SICs) bridge the performance gaps between batteries and supercapacitors by providing a high energy and power density in a single configuration. As battery-type active materials, sodium preintercalated layered metal oxides are desirable owing to their unique crystal structure, simple synthesis process, and high working voltage. However, their poor cyclic stability and low kinetics limit their application. Herein, we report increased rate capability and cycle stability achieved by introducing transition metal substitution and surface coating strategies. By substituting a portion of Ni and Mn with Cu and Mg (the sample name was denoted as NMCM), the P2-O2 transition which occurs at high voltages was alleviated. Additionally, a thin and uniform sodium phosphate coating layer suppressed surface side reactions occurring during charge-discharge processes, as observed through ex-situ X-ray photoelectron spectroscopy and ex-situ transmission electron microscopy. Compared to the pristine sample, the capacity improved by 48% at a high current density of 4 A g-1. After 100 cycles, the sodium-phosphate-coated sample (NMCM@P) retained about 90% of its capacity, whereas NMCM had a capacity retention of 63%. When evaluating the longer stability of SIC full cells, NMCM@P exhibited an outstanding stability of 71% after 5000 cycles. This was higher than that of NMCM, which retained only 17% of its initial capacity.

Statistical methods to detect mother-father genetic interaction effects on risk of infertility: A genome-wide approach.

Infertility is a heterogeneous phenotype, and for many couples, the causes of fertility problems remain unknown. One understudied hypothesis is that allelic interactions between the genotypes of the two parents may influence the risk of infertility. Our aim was, therefore, to investigate how allelic interactions can be modeled using parental genotype data linked to 15,789 pregnancies selected from the Norwegian Mother, Father, and Child Cohort Study. The newborns in 1304 of these pregnancies were conceived using assisted reproductive technologies (ART), and the remainder were conceived naturally. Treating the use of ART as a proxy for infertility, different parameterizations were implemented in a genome-wide screen for interaction effects between maternal and paternal alleles at the same locus. Some of the models were more similar in the way they were parameterized, and some produced similar results when implemented on a genome-wide scale. The results showed near-significant interaction effects in genes relevant to the phenotype under study, such as Dynein axonemal heavy chain 17 (DNAH17) with a recognized role in male infertility. More generally, the interaction models presented here are readily adaptable to the study of other phenotypes in which maternal and paternal allelic interactions are likely to be involved.

Stability selection enhances feature selection and enables accurate prediction of gestational age using only five DNA methylation sites.

BACKGROUND: DNA methylation (DNAm) is robustly associated with chronological age in children and adults, and gestational age (GA) in newborns. This property has enabled the development of several epigenetic clocks that can accurately predict chronological age and GA. However, the lack of overlap in predictive CpGs across different epigenetic clocks remains elusive. Our main aim was therefore to identify and characterize CpGs that are stably predictive of GA. RESULTS: We applied a statistical approach called 'stability selection' to DNAm data from 2138 newborns in the Norwegian Mother, Father, and Child Cohort study. Stability selection combines subsampling with variable selection to restrict the number of false discoveries in the set of selected variables. Twenty-four CpGs were identified as being stably predictive of GA. Intriguingly, only up to 10% of the CpGs in previous GA clocks were found to be stably selected. Based on these results, we used generalized additive model regression to develop a new GA clock consisting of only five CpGs, which showed a similar predictive performance as previous GA clocks (R2 = 0.674, median absolute deviation = 4.4 days). These CpGs were in or near genes and regulatory regions involved in immune responses, metabolism, and developmental processes. Furthermore, accounting for nonlinear associations improved prediction performance in preterm newborns. CONCLUSION: We present a methodological framework for feature selection that is broadly applicable to any trait that can be predicted from DNAm data. We demonstrate its utility by identifying CpGs that are highly predictive of GA and present a new and highly performant GA clock based on only five CpGs that is more amenable to a clinical setting.

Neuromodulatory feasibility of a current limiter-based tDCS device: a resting-state electroencephalography study.

Recently, we introduced a current limiter-based novel transcranial direct-current stimulation (tDCS) device that does not generate significant tDCS-induced electrical artifacts, thereby facilitating simultaneous electroencephalography (EEG) measurement during tDCS application. In this study, we investigated the neuromodulatory effect of the tDCS device using resting-state EEG data measured during tDCS application in terms of EEG power spectral densities (PSD) and brain network indices (clustering coefficient and path length). Resting-state EEG data were recorded from 10 healthy subjects during both eyes-open (EO) and eyes-closed (EC) states for each of five different conditions (baseline, sham, post-sham, tDCS, and post-tDCS). In the tDCS condition, tDCS was applied for 12 min with a current intensity of 1.5 mA, whereas tDCS was applied only for the first 30 s in the sham condition. EEG PSD and brain network indices were computed for the alpha frequency band most closely associated with resting-state EEG. Both alpha PSD and network indices were found to significantly increase during and after tDCS application compared to those of the baseline condition in the EO state, but not in the EC state owing to the ceiling effect. Our results demonstrate the neuromodulatory effect of the tDCS device that does not generate significant tDCS-induced electrical artifacts, thereby allowing simultaneous measurement of electrical brain activity. We expect our novel tDCS device to be practically useful in exploring the impact of tDCS on neuromodulation more precisely using ongoing EEG data simultaneously measured during tDCS application.

Interphase stabilized electrospun SnO2 fibers as alloy anode via restricted cycling for Li-ion capacitors with high energy and wide temperature operation.

The second-generation supercapacitor comprises the hybridized energy storage mechanism of Lithium-ion batteries and electrical double-layer capacitors, i.e, Lithium-ion capacitors (LICs). The electrospun SnO2 nanofibers are synthesized by a simple electrospinning technique and are directly used as anode material for LICs with activated carbon (AC) as a cathode. However, before the assembly, the battery-type electrode SnO2 is electrochemically pre-lithiated (LixSn + Li2O), and AC loading is balanced with respect to its half-cell performance. First, the SnO2 is tested in the half-cell assembly with a limited potential window of 0.005 to 1 V vs. Li to avoid the conversion reaction of Sn0 to SnOx. Also, the limited potential window allows only the reversible alloy/de-alloying process. Finally, the assembled LIC, AC/(LixSn + Li2O), displayed a maximum energy density of 185.88 Wh kg-1 with ultra-long cyclic durability of over 20,000 cycles. Further, the LIC is also exposed to various temperature conditions (-10, 0, 25, & 50 °C) to study the feasibility of using them in different environmental conditions.

The X-factor in ART: does the use of assisted reproductive technologies influence DNA methylation on the X chromosome?

BACKGROUND: Assisted reproductive technologies (ART) may perturb DNA methylation (DNAm) in early embryonic development. Although a handful of epigenome-wide association studies of ART have been published, none have investigated CpGs on the X chromosome. To bridge this knowledge gap, we leveraged one of the largest collections of mother-father-newborn trios of ART and non-ART (natural) conceptions to date to investigate sex-specific DNAm differences on the X chromosome. The discovery cohort consisted of 982 ART and 963 non-ART trios from the Norwegian Mother, Father, and Child Cohort Study (MoBa). To verify our results from the MoBa cohort, we used an external cohort of 149 ART and 58 non-ART neonates from the Australian 'Clinical review of the Health of adults conceived following Assisted Reproductive Technologies' (CHART) study. The Illumina EPIC array was used to measure DNAm in both datasets. In the MoBa cohort, we performed a set of X-chromosome-wide association studies ('XWASs' hereafter) to search for sex-specific DNAm differences between ART and non-ART newborns. We tested several models to investigate the influence of various confounders, including parental DNAm. We also searched for differentially methylated regions (DMRs) and regions of co-methylation flanking the most significant CpGs. Additionally, we ran an analogous model to our main model on the external CHART dataset. RESULTS: In the MoBa cohort, we found more differentially methylated CpGs and DMRs in girls than boys. Most of the associations persisted after controlling for parental DNAm and other confounders. Many of the significant CpGs and DMRs were in gene-promoter regions, and several of the genes linked to these CpGs are expressed in tissues relevant for both ART and sex (testis, placenta, and fallopian tube). We found no support for parental DNAm-dependent features as an explanation for the observed associations in the newborns. The most significant CpG in the boys-only analysis was in UBE2DNL, which is expressed in testes but with unknown function. The most significant CpGs in the girls-only analysis were in EIF2S3 and AMOT. These three loci also displayed differential DNAm in the CHART cohort. CONCLUSIONS: Genes that co-localized with the significant CpGs and DMRs associated with ART are implicated in several key biological processes (e.g., neurodevelopment) and disorders (e.g., intellectual disability and autism). These connections are particularly compelling in light of previous findings indicating that neurodevelopmental outcomes differ in ART-conceived children compared to those naturally conceived.

Nucleated red blood cells explain most of the association between DNA methylation and gestational age.

Determining if specific cell type(s) are responsible for an association between DNA methylation (DNAm) and a given phenotype is important for understanding the biological mechanisms underlying the association. Our EWAS of gestational age (GA) in 953 newborns from the Norwegian MoBa study identified 13,660 CpGs significantly associated with GA (pBonferroni<0.05) after adjustment for cell type composition. When the CellDMC algorithm was applied to explore cell-type specific effects, 2,330 CpGs were significantly associated with GA, mostly in nucleated red blood cells [nRBCs; n = 2,030 (87%)]. Similar patterns were found in another dataset based on a different array and when applying an alternative algorithm to CellDMC called Tensor Composition Analysis (TCA). Our findings point to nRBCs as the main cell type driving the DNAm-GA association, implicating an epigenetic signature of erythropoiesis as a likely mechanism. They also explain the poor correlation observed between epigenetic age clocks for newborns and those for adults.

Highly promoted solvent-co-intercalation process in pencil graphite anode and Na3V2(PO4)3 cathode in full-cell Na-ion battery.

The electrochemical performance of graphite recovered from 6H-pencil with the highest content of SiO2 is evaluated in both Na-ion half and full-cell assemblies. The concept of sodium co-intercalation into graphite is exploited by fabricating cells with electrolytes based on tetraethylene glycol dimethyl ether (G4) and diethylene glycol dimethyl ether (G2). The capacity at high current rates is maximum when the G2-based electrolyte is used, both in half and full cells, while the capacity retention after high current rates is better in a G4-based system. Upon calculating the capacity contribution, the G2-based system shows prominent capacitance-based charge storage, whereas the G4-based system has a higher contribution from the Faradaic mechanism. The former also shows a faster diffusion mechanism. While G2 based system has higher capacity retention in half-cell, G4 based system has higher capacity retention in full-cell. When G2 is used as the electrolyte solvent, the irreversibility during cycling is high, affecting cell performance. The full cells with G4 and G2 electrolytes show maximum energy/power densities of 33 Wh kg-1/2.7 kW kg-1 and 23 Wh kg-1/1.4 kW kg-1, respectively. Our study shows that the charge storage mechanism can be varied by tuning the electrolyte solvent. This study is the first to explore pencil graphite for sodium-ion storage.

An examination of mediation by DNA methylation on birthweight differences induced by assisted reproductive technologies.

BACKGROUND: Children born after assisted reproductive technologies (ART) differ in birthweight from those naturally conceived. It has been hypothesized that this might be explained by epigenetic mechanisms. We examined whether cord blood DNA methylation mediated the birthweight difference between 890 newborns conceived by ART (764 by fresh embryo transfer and 126 frozen thawed embryo transfer) and 983 naturally conceived newborns from the Norwegian Mother, Father, and Child Cohort Study (MoBa). DNA methylation was measured by the Illumina Infinium MethylationEPIC array. We conducted mediation analyses to assess whether differentially methylated CpGs mediated the differences in birthweight observed between: (1) fresh embryo transfer and natural conception and (2) frozen and fresh embryo transfer. RESULTS: We observed a difference in birthweight between fresh embryo transfer and naturally conceived offspring of - 120 g. 44% (95% confidence interval [CI] 26% to 81%) of this difference in birthweight between fresh embryo transfer and naturally conceived offspring was explained by differences in methylation levels at four CpGs near LOXL1, CDH20, and DRC1. DNA methylation differences at two CpGs near PTGS1 and RASGRP4 jointly mediated 22% (95% CI 8.1% to 50.3%) of the birthweight differences between fresh and frozen embryo transfer. CONCLUSION: Our findings suggest that DNA methylation is an important mechanism in explaining birthweight differences according to the mode of conception. Further research should examine how gene regulation at these loci influences fetal growth.

Maternal and paternal anxiety during pregnancy: Comparing the effects on behavioral problems in offspring.

Prenatal maternal anxiety has been associated with both short and long-term mental health problems in the child. The current study aims to examine the association between maternal and paternal prenatal anxiety and behaviour problems in the child at 1.5 and 5 years, using three different approaches; (1) adjusting for covariates, (2) using fathers' anxiety during pregnancy as a negative control, and (3) using a sibling-comparison design, controlling for unmeasured family factors. We used data from the Norwegian Mother, Father and Child Cohort Study (MoBa) is used. MoBa is a cohort consisting of about 114 000 pregnancies (about 34000 siblings) recruited from 1999 to 2008. Self-reported measures on maternal anxiety were obtained twice in pregnancy and 6 months after birth, while paternal anxiety was reported prenatally at 17th weeks of gestation. Maternal reports on child behaviour problems were obtained at 1.5 and 5 years of age. Results suggests that prenatal exposure to maternal anxiety was associated with behaviour problems at 1.5 years: adjusted beta (ß) = 0.13 (CI = 0.12, 0.15), and at 5 years: ß = 0.11 (CI = 0.09, 0.14). However, paternal anxiety was also associated with behaviour problems at 1.5 years: ß = 0.03 (CI = 0.01-0.03) and at 5 years ß = 0.03 (CI = 0.02, 0.03). These associations were attenuated in the sibling comparison analyses: ß = -0.02 (CI = -0.02-0.05) at 1.5 years and ß = -0.05 (CI = -0.10, 0.02) at 5 years. In conclusions, the sibling analyses are not consistent with a direct effect of prenatal maternal anxiety on child behaviour problems. It is more likely that genetic or shared family environment explain this association.

EWAS of post-COVID-19 patients shows methylation differences in the immune-response associated gene, IFI44L, three months after COVID-19 infection.

Although substantial progress has been made in managing COVID-19, it is still difficult to predict a patient's prognosis. We explored the epigenetic signatures of COVID-19 in peripheral blood using data from an ongoing prospective observational study of COVID-19 called the Norwegian Corona Cohort Study. A series of EWASs were performed to compare the DNA methylation profiles between COVID-19 cases and controls three months post-infection. We also investigated differences associated with severity and long-COVID. Three CpGs-cg22399236, cg03607951, and cg09829636-were significantly hypomethylated (FDR < 0.05) in COVID-19 positive individuals. cg03607951 is located in IFI44L which is involved in innate response to viral infection and several systemic autoimmune diseases. cg09829636 is located in ANKRD9, a gene implicated in a wide variety of cellular processes, including the degradation of IMPDH2. The link between ANKRD9 and IMPDH2 is striking given that IMPDHs are considered therapeutic targets for COVID-19. Furthermore, gene ontology analyses revealed pathways involved in response to viruses. The lack of significant differences associated with severity and long-COVID may be real or reflect limitations in sample size. Our findings support the involvement of interferon responsive genes in the pathophysiology of COVID-19 and indicate a possible link to systemic autoimmune diseases.