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Male sex and advanced age are associated with severe symptoms of COVID-19. Sex and age also exhibit substantial associations with genome-wide DNA methylation (DNAm) differences in humans. Using a random sample of Illumina EPIC-based genome-wide methylomes from peripheral whole blood of 1,976 parents, participating in The Norwegian Mother, Father and Child Cohort Study (MoBa), we explored whether DNAm in genes linked to SARS-CoV-2 host cell entry and to severe COVID-19 were associated with sex and age. This was carried out by testing 1,572 DNAm sites (CpGs) located near 45 genes for associations with age and sex. We found that DNAm in 281 and 231 of 1,572 CpGs were associated (p FDR <0.01) with sex and aging, respectively. CpGs linked to SARS-CoV-2 host cell entry genes were all associated with age and sex, except for the ACE2 receptor gene (located on the X-chromosome), which was only associated with sex (p FDR <0.01). Furthermore, we examined whether 1,487 autosomal CpGs associated with host-cell entry and severe COVID-19 were more or less associated with sex and age than what would be expected from the same number of randomly sampled genome-wide CpGs. We found that the CpGs associated with host-cell entry and severe COVID-19 were not more or less associated with sex (R 2 = 0.77, p = 0.09) than the CpGs sampled from random genomic regions; age was actually found to be significantly less so (R 2 = 0.36, p = 0.04). Hence, while we found wide-spread associations between sex and age at CpGs linked to genes implicated with SARS-CoV-2 host cell entry and severe COVID-19, the effect from the sum of these CpGs was not stronger than that from randomly sampled CpGs; for age it was significantly less so. These findings could suggest that advanced age and male sex may not be unsurmountable barriers for the SARS-CoV-2 virus to evolve increased infectiousness.

Assisted reproductive technology (ART) may affect fetal development through epigenetic mechanisms as the timing of ART procedures coincides with the extensive epigenetic remodeling occurring between fertilization and embryo implantation. However, it is unknown to what extent ART procedures alter the fetal epigenome. Underlying parental characteristics and subfertility may also play a role. Here we identify differences in cord blood DNA methylation, measured using the Illumina EPIC platform, between 962 ART conceived and 983 naturally conceived singleton newborns. We show that ART conceived newborns display widespread differences in DNA methylation, and overall less methylation across the genome. There were 607 genome-wide differentially methylated CpGs. We find differences in 176 known genes, including genes related to growth, neurodevelopment, and other health outcomes that have been associated with ART. Both fresh and frozen embryo transfer show DNA methylation differences. Associations persist after controlling for parents’ DNA methylation, and are not explained by parental subfertility. Timing of assisted reproduction technology (ART) procedures coincides with extensive epigenetic remodeling early after conception. Here the authors identify 176 DNA methylation differences in cord blood of newborns conceived with ART. including genes related to growth, neurodevelopment, and cancer.

Insomnia is common and associated with adverse pregnancy and perinatal outcomes in observational studies. However, those associations could be vulnerable to residual confounding or reverse causality. Our aim was to estimate the association of insomnia with stillbirth, miscarriage, gestational diabetes (GD), hypertensive disorders of pregnancy (HDP), perinatal depression, preterm birth (PTB), and low/high offspring birthweight (LBW/HBW). We used 2-sample mendelian randomization (MR) with 81 single-nucleotide polymorphisms (SNPs) instrumenting for a lifelong predisposition to insomnia. Our outcomes included ever experiencing stillbirth, ever experiencing miscarriage, GD, HDP, perinatal depression, PTB (gestational age <37 completed weeks), LBW (<2,500 grams), and HBW (>4,500 grams). We used data from women of European descent (N = 356,069, mean ages at delivery 25.5 to 30.0 years) from UK Biobank (UKB), FinnGen, Avon Longitudinal Study of Parents and Children (ALSPAC), Born in Bradford (BiB), and the Norwegian Mother, Father and Child Cohort (MoBa). Main MR analyses used inverse variance weighting (IVW), with weighted median and MR-Egger as sensitivity analyses. We compared MR estimates with multivariable regression of insomnia in pregnancy on outcomes in ALSPAC (N = 11,745). IVW showed evidence of an association of genetic susceptibility to insomnia with miscarriage (odds ratio (OR): 1.60, 95% confidence interval (CI): 1.18, 2.17, p = 0.002), perinatal depression (OR 3.56, 95% CI: 1.49, 8.54, p = 0.004), and LBW (OR 3.17, 95% CI: 1.69, 5.96, p < 0.001). IVW results did not support associations of insomnia with stillbirth, GD, HDP, PTB, and HBW, with wide CIs including the null. Associations of genetic susceptibility to insomnia with miscarriage, perinatal depression, and LBW were not observed in weighted median or MR-Egger analyses. Results from these sensitivity analyses were directionally consistent with IVW results for all outcomes, with the exception of GD, perinatal depression, and PTB in MR-Egger. Multivariable regression showed associations of insomnia at 18 weeks of gestation with perinatal depression (OR 2.96, 95% CI: 2.42, 3.63, p < 0.001), but not with LBW (OR 0.92, 95% CI: 0.69, 1.24, p = 0.60). Multivariable regression with miscarriage and stillbirth was not possible due to small numbers in index pregnancies. Key limitations are potential horizontal pleiotropy (particularly for perinatal depression) and low statistical power in MR, and residual confounding in multivariable regression. In this study, we observed some evidence in support of a possible causal relationship between genetically predicted insomnia and miscarriage, perinatal depression, and LBW. Our study also found observational evidence in support of an association between insomnia in pregnancy and perinatal depression, with no clear multivariable evidence of an association with LBW. Our findings highlight the importance of healthy sleep in women of reproductive age, though replication in larger studies, including with genetic instruments specific to insomnia in pregnancy are important.

Maternal smoking during pregnancy, especially when sustained, leads to numerous adverse health outcomes in offspring. Pregnant women disproportionately underreport smoking and smokers tend to have lower follow-up rates to repeat questionnaires. Missing, incomplete, or inaccurate data on presence and duration of smoking in pregnancy impairs identification of novel health effects and limits adjustment for smoking in studies of other pregnancy exposures. An objective biomarker in newborns of maternal smoking during pregnancy would be valuable. We developed a biomarker of sustained maternal smoking in pregnancy using common DNA methylation platforms. Using a dimension reduction method, we developed and tested a numeric score in newborns to reflect sustained maternal smoking in pregnancy from data on cotinine, a short-term smoking biomarker measured mid-pregnancy, and Illumina450K cord blood DNA methylation from newborns in the Norwegian Mother and Child Cohort Study (MoBa). This score reliably predicted smoking status in the training set ( = 1,057; accuracy = 96%, sensitivity = 80%, specificity = 98%). Sensitivity (58%) was predictably lower in the much smaller test set ( = 221), but accuracy (91%) and specificity (97%) remained high. Reduced birth weight, a well-known effect of maternal smoking, was as strongly related to the score as to cotinine. A three-site score had lower, but acceptable, performance (accuracy = 82%, accuracy = 83%). Our smoking methylation score represents a promising novel biomarker of sustained maternal smoking during pregnancy easily calculated with Illumina450K or IlluminaEPIC data. It may help identify novel health impacts and improve adjustment for smoking when studying other risk factors with more subtle effects.

Generating prediction models from high dimensional data often result in large models with many predictors. Causal inference for such models can therefore be difficult or even impossible in practice. The stand-alone software package MinLinMo emphasizes small linear prediction models over highest possible predictability with a particular focus on including variables correlated with the outcome, minimal memory usage and speed. MinLinMo is demonstrated on large epigenetic datasets with prediction models for chronological age, gestational age, and birth weight comprising, respectively, 15, 14 and 10 predictors. The parsimonious MinLinMo models perform comparably to established prediction models requiring hundreds of predictors.

Associations between influenza infection and sleep disorders are poorly studied. We investigated if pandemic influenza infection or vaccination with Pandemrix in 2009/2010 was associated with narcolepsy or hypersomnia in children and young adults. We followed the Norwegian population under age 30 from January 2008 through December 2012 by linking national health registry data. Narcolepsy diagnoses were validated using hospital records. Risks of narcolepsy or hypersomnia were estimated as adjusted hazard ratios (HRs) in Cox regression models with influenza infection and vaccination as time-dependent exposures. Among the 1,638,526 persons under age 30 in Norway in 2009, 3.6% received a physician diagnosis of influenza during the pandemic, while 41.9% were vaccinated against pandemic influenza. Between October 1st 2009 and December 31st 2012, 72 persons had onset of narcolepsy and 305 were diagnosed with hypersomnia. The risk of a sleep disorder was associated with infection during the first six months, adjusted HR 3.31 with 95% confidence interval [CI], 1.01–10.79 for narcolepsy and adjusted HR 3.13 (95% CI, 1.12–8.76) for hypersomnia. The risk of narcolepsy was strongly associated with vaccination during the first six months adjusted HR 17.21 (95% CI, 6.28–47.14), while the adjusted HR for hypersomnia was 1.54 (95% CI, 0.81–2.93). The study confirms an increased HR of narcolepsy following pandemic vaccination. Slightly increased HRs of narcolepsy and hypersomnia are also seen after influenza infection. However, the role of infection should be viewed with caution due to underreporting of influenza.

Aims: For everyone with a positive test for SARS-CoV-2 in Norway, we studied whether age, sex, comorbidity, continent of birth and nursing home residency were risk factors for hospitalization, invasive mechanical ventilation treatment and death. Methods: Data for everyone who had tested positive for SARS-CoV-2 in Norway by end of June 2020 (N = 8569) were linked at the individual level to hospitalization, receipt of invasive mechanical ventilation treatment and death measured to end of July 2020. Underlying comorbidity was proxied by hospital-based in- or outpatient treatment during the two months before the SARS-CoV-2 test. Multivariable generalized linear models were used to assess risk ratios (RRs). Results: Risk of hospitalization was particularly high for elderly (for those aged 90 and above: RR 9.5; 95% confidence interval (CI) 7.1–12.7; comparison group aged below 50), Norwegian residents born in Asia, Africa or Latin-America (RR 2.1; 95% CI 1.9–2.4; comparison group born in Norway), patients with underlying comorbidity (RR 1.6; 95% CI 1.4–1.8) and men (RR 1.3; 95% CI 1.2–1.5). Men and residents born in Africa, Asia and Latin-America were also at higher risk of receiving ventilation treatment and dying, but the mortality risk was especially high for the elderly (for those aged 90 and above: RR 607.9; 95% CI 145.5–2540.1; comparison group aged below 50) and residents in nursing homes (RR 4.2; 95% CI 3.1–5.7). Conclusions: High age was the most important predictor of severe disease and death if infected with SARS-CoV-2, and nursing home residents were at particularly high risk of death.

Folate is vital for fetal development. Periconceptional folic acid supplementation and food fortification are recommended to prevent neural tube defects. Mechanisms whereby periconceptional folate influences normal development and disease are poorly understood: epigenetics may be involved. We examine the association between maternal plasma folate during pregnancy and epigenome-wide DNA methylation using Illumina’s HumanMethyl450 Beadchip in 1,988 newborns from two European cohorts. Here we report the combined covariate-adjusted results using meta-analysis and employ pathway and gene expression analyses. Four-hundred forty-three CpGs (320 genes) are significantly associated with maternal plasma folate levels during pregnancy (false discovery rate 5%); 48 are significant after Bonferroni correction. Most genes are not known for folate biology, including APC2 , GRM8 , SLC16A12 , OPCML , PRPH , LHX1 , KLK4 and PRSS21. Some relate to birth defects other than neural tube defects, neurological functions or varied aspects of embryonic development. These findings may inform how maternal folate impacts the developing epigenome and health outcomes in offspring. Folic acid is routinely recommended for women trying to conceive to ensure proper fetal development. Here, the authors perform a large epigenomics study to examine which fetal epigenetic changes are associated with varied maternal plasma folate levels.

A few studies indicate that women with prolonged time-to-pregnancy (TTP) have an increased risk of cardiovascular disease (CVD). This has not been studied in men. We evaluated CVD risk by self-reported TTP among parous women (n = 64,064) and men (n = 50,533) participating in the Norwegian Mother, Father and Child Cohort Study. TTP was categorized as 0–3 (reference), 4–12 and > 12 months. CVD diagnosed between 2008 and 2017 were available from the national patient and general practitioner databases. Risk of CVD by TTP was estimated using Cox regression adjusting for baseline age, education, BMI, smoking, diabetes, and number of offspring in both sexes, and history of endometriosis, ovarian cysts, preterm birth and pre-eclampsia for women. Mean age was 33 for women and 35 for men at baseline (years). The rate of any CVD was 24 per 1000 person years among women and 22 per 1000 person years among men. Longer TTP was associated with increased rate of CVD among women, with adjusted hazard ratios (HRs) of 1.07 (95% CI: 1.03, 1.09) for TTP 4–12 months and 1.14 (1.08, 1.20) for TTP > 12 months. Among men, respective HRs for CVD were 1.06 (1.00, 1.10) for TTP 4–12 months and 1.07 (1.01, 1.14) for TTP > 12 months. We observed sex-differences in the relationship with CVD sub-types but none were statistically significant. In conclusion, both men and women with a prolonged TTP had a small increased risk of CVD, clinical significance of which is unclear. Further studies are necessary to investigate in detail what underlying causes of prolonged TTP might be reflected in the increased risk of CVD. Longer follow-up is required to confirm these preliminary findings.

Introduction Women's reproductive lifespan has increased over the past two decades. Simultaneously, female reproductive behavior has changed, with increasing age at first birth. Early menarche has been associated with adverse health outcomes, but research investigating the association between maternal age at childbirth and daughter's age at menarche is, so far, inconclusive. Whether the interval between menarche and childbirth or between childbirth and menopause among mothers is associated with age at menarche in daughters is not known. Material and Methods We conducted a cohort study with retrospectively collected data including mothers and daughters participating in the Norwegian Mother, Father and Child Cohort Study. Within this cohort, we identified two study populations. First, we included 14 576 mother‐daughter pairs with complete information on maternal age at menarche and childbirth and the daughter's age at menarche. Second, we included 1350 mother‐daughter pairs with complete information on maternal age at childbirth and natural menopause, and daughter's age at menarche. We calculated odds ratios (OR) with 95% confidence intervals (CIs) in a discrete survival analysis for daughters' age at menarche by time intervals from menarche to childbirth or from childbirth to menopause in mothers. We adjusted for relevant covariates. Results We found 5% lower yearly odds (partially adjusted OR 0.95 (CI 0.90–0.99)) of reaching menarche among daughters born by mothers <16 years after menarche compared to the reference category born 16–20 years following menarche. After additionally adjusting for maternal birth year, the effect estimate was further reduced (fully adjusted OR 0.79 (CI 0.74–0.84)). Among daughters born by mothers >20 years after menarche, the likelihood of early menarche was higher (fully adjusted OR 1.19 (CI 1.13–1.27)) compared to the reference category. Regarding the childbirth‐menopause interval, our findings did not reach statistical significance in either of our models. Conclusions Daughters born to mothers with a shorter time interval (<16 years) between menarche and childbirth have a lower likelihood of experiencing early menarche compared to the reference category (16–20 years), and daughters born to mothers with a longer time interval from menarche to childbirth (>20 years) have a higher likelihood of reaching early menarche. Using data from the Norwegian MoBa study, we found that mothers who give birth shortly after their own menarche have daughters with a lower likelihood of early menarche.