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.
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 (pFDR<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 (pFDR<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 (R2 = 0.77, p = 0.09) than the CpGs sampled from random genomic regions; age was actually found to be significantly less so (R2 = 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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
CEP78 is a centrosomal protein implicated in ciliogenesis and ciliary length control, and mutations in the
CEP78
gene cause retinal cone-rod dystrophy associated with hearing loss. However, the ...mechanism by which CEP78 affects cilia formation is unknown. Based on a recently discovered disease-causing
CEP78
p.L150S mutation, we identified the disease-relevant interactome of CEP78. We confirmed that CEP78 interacts with the EDD1-DYRK2-DDB1
VPRBP
E3 ubiquitin ligase complex, which is involved in CP110 ubiquitination and degradation, and identified a novel interaction between CEP78 and CEP350 that is weakened by the CEP78
L150S
mutation. We show that CEP350 promotes centrosomal recruitment and stability of CEP78, which in turn leads to centrosomal recruitment of EDD1. Consistently, cells lacking CEP78 display significantly increased cellular and centrosomal levels of CP110, and depletion of CP110 in CEP78-deficient cells restored ciliation frequency to normal. We propose that CEP78 functions downstream of CEP350 to promote ciliogenesis by negatively regulating CP110 levels via an EDD1-dependent mechanism.
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 17.sup.th 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 (beta) = 0.13 (CI = 0.12, 0.15), and at 5 years: beta = 0.11 (CI = 0.09, 0.14). However, paternal anxiety was also associated with behaviour problems at 1.5 years: beta = 0.03 (CI = 0.01-0.03) and at 5 years beta = 0.03 (CI = 0.02, 0.03). These associations were attenuated in the sibling comparison analyses: beta = -0.02 (CI = -0.02-0.05) at 1.5 years and beta = -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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To estimate the prevalence of overweight, obesity, and thinness among Norwegian 13-year-olds and the changes from childhood (age 8 years) to adolescence (age 13 years); and to explore associations ...with sex, region, and population density from childhood to adolescence.
We used longitudinal, anthropometric data collected by school health nurses conducted in Norway. Weight status was classified according to the International Obesity Task Force cut-offs for overweight, obesity, and thinness, and according to mean body mass index (kg/m2).
The Norwegian Youth Growth Study, consisting of a nationally representative sample of Norwegian 13-year-olds (n = 1852; 50.7% girls), which is a part of The Norwegian Growth Cohort.
Among 13-year-old Norwegians, the prevalence of overweight (including obesity), obesity, and thinness was 15.8%, 2.5%, and 7.3%, respectively. There was little evidence that these had changed from 8 to 13 years. From 8 to 13 years, the odds of obesity was highest in the Northern region of Norway compared to the South-East (odds ratio (OR): 3.78 (95% confidence interval (CI): 1.13, 12.65; p = 0.036) and in rural areas (OR: 4.76 (95% CI: 1.52, 14.90; p = 0.027). Over the same age period, girls had a trend towards a higher odds of thinness compared to boys (OR: 1.65 (95% CI: 0.98, 2.78; p = 0.057).
In Norway, the prevalence of overweight, obesity, and thinness among 13-year-olds seem to be established by age 8 years. The prevalence of obesity was higher in the North and in rural areas. The results indicate the continued need for early prevention and treatment, and targeted interventions to certain areas.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Epilepsy affects 0.5% to 1% of children and is the most frequent chronic neurologic condition in childhood. Incidence rates appear to be declining in high-income countries. The validity of epilepsy ...diagnoses from different data sources varies, and contemporary population-based incidence studies are needed.
The study was based on the Norwegian Mother and Child Cohort Study. Potential epilepsy cases were identified through registry linkages and parental questionnaires. Cases were validated through medical record reviews and telephone interviews of parents.
The study population included 112 744 children aged 3 to 13 years (mean 7.4 years) at end of registry follow-up (December 31, 2012). Of these, 896 had registry recordings and/or questionnaire reports of epilepsy. After validation, 587 (66%) met the criteria for an epilepsy diagnosis. The incidence rate of epilepsy was 144 per 100 000 person-years in the first year of life and 58 per 100 000 for ages 1 to 10 years. The cumulative incidence of epilepsy was 0.66% at age 10 years, with 0.62% having active epilepsy. The 309 children (34%) with erroneous reports of epilepsy from the registry and/or the questionnaires had mostly been evaluated for nonepileptic paroxysmal events, or they had undergone electroencephalography examinations because of other developmental or neurocognitive difficulties.
Approximately 1 out of 150 children is diagnosed with epilepsy during the first 10 years of life, with the highest incidence rate observed during infancy. Validation of epilepsy diagnoses in administrative data and cohort studies is crucial because reported diagnoses may not meet diagnostic criteria for epilepsy.
This is an update of the Norwegian Mother and Child Cohort Study (MoBa) cohort profile which was published in 2006. Pregnant women attending a routine ultrasound examination were initially invited. ...The first child was born in October 1999 and the last in July 2009. The participation rate was 41%. The cohort includes more than 114 000 children, 95 000 mothers and 75 000 fathers. About 1900 pairs of twins have been born. There are approximately 16 400 women who participate with more than one pregnancy. Blood samples were obtained from both parents during pregnancy and from mothers and children (umbilical cord) after birth. Samples of DNA, RNA, whole blood, plasma and urine are stored in a biobank. During pregnancy, the mother responded to three questionnaires and the father to one. After birth, questionnaires were sent out when the child was 6 months, 18 months and 3 years old. Several sub-projects have selected participants for in-depth clinical assessment and exposure measures. The purpose of this update is to explain and describe new additions to the data collection, including questionnaires at 5, 7, 8 and 13 years as well as linkages to health registries, and to point to some findings and new areas of research. Further information can be found at www.fhi.no/moba-en. Researchers interested in collaboration and access to the data can complete an electronic application available on the MoBa website above.
Abstract
The SARS-CoV-2 Omicron variant has more than 15 mutations in the receptor binding domain of the Spike protein enabling increased transmissibility and viral escape from antibodies in ...vaccinated individuals. It is unclear how vaccine immunity protects against Omicron infection. Here we show that vaccinated participants at a super-spreader event have robust recall response of humoral and pre-existing cellular immunity induced by the vaccines, and an emergent de novo T cell response to non-Spike antigens. Individuals with Omicron SARS-CoV-2 breakthrough infections have significantly increased activated SARS-CoV-2 wild type Spike-specific cytotoxic T cells, activated follicular helper (T
FH
) cells, functional T cell responses, boosted humoral responses, and rapid release of Spike and RBD-specific IgG
+
B cell plasmablasts and memory B cells into circulation. Omicron breakthrough infection affords significantly increased de novo memory T cell responses to non-Spike viral antigens. Concerted T and B cell responses may provide durable and broad immunity.
Abstract
STUDY QUESTION
Is the use of ART, a proxy for infertility, associated with epigenetic age acceleration?
SUMMARY ANSWER
The epigenetic age acceleration measured by Dunedin Pace of Aging ...methylation (DunedinPoAm) differed significantly between non-ART and ART mothers.
WHAT IS KNOWN ALREADY
Among mothers who used ART, epigenetic age acceleration may be associated with low oocyte yield and poor ovarian response. However, the difference in epigenetic age acceleration between non-ART and ART mothers (or even fathers) has not been examined.
STUDY DESIGN, SIZE, DURATION
The Norwegian Mother, Father and Child Cohort Study (MoBa) recruited pregnant women and their partners across Norway at around 18 gestational weeks between 1999 and 2008. Approximately 95 000 mothers, 75 000 fathers and 114 000 children were included. Peripheral blood samples were taken from mothers and fathers at ultrasound appointments or from mothers at childbirth, and umbilical cord blood samples were collected from the newborns at birth.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Among the MoBa participants, we selected 1000 couples who conceived by coitus and 894 couples who conceived by IVF (n = 525) or ICSI (n = 369). We measured their DNA methylation (DNAm) levels using the Illumina MethylationEPIC array and calculated epigenetic age acceleration. A linear mixed model was used to examine the differences in five different epigenetic age accelerations between non-ART and ART parents.
MAIN RESULTS AND THE ROLE OF CHANCE
We found a significant difference in the epigenetic age acceleration calculated by DunedinPoAm between IVF and non-ART mothers (0.021 years, P-value = 2.89E−06) after adjustment for potential confounders. Further, we detected elevated DunedinPoAm in mothers with tubal factor infertility (0.030 years, P-value = 1.34E−05), ovulation factor (0.023 years, P-value = 0.0018) and unexplained infertility (0.023 years, P-value = 1.39E−04) compared with non-ART mothers. No differences in epigenetic age accelerations between non-ART and ICSI fathers were found. DunedinPoAm also showed stronger associations with smoking, education and parity than the other four epigenetic age accelerations.
LIMITATIONS, REASONS FOR CAUTION
We were not able to determine the directionality of the causal pathway between the epigenetic age accelerations and infertility. Since parents’ peripheral blood samples were collected after conception, we cannot rule out the possibility that the epigenetic profile of ART mothers was influenced by the ART treatment. Hence, the results should be interpreted with caution, and our results might not be generalizable to non-pregnant women.
WIDER IMPLICATIONS OF THE FINDINGS
A plausible biological mechanism behind the reported association is that IVF mothers could be closer to menopause than non-ART mothers. The pace of decline of the ovarian reserve that eventually leads to menopause varies between females yet, in general, accelerates after the age of 30, and some studies show an increased risk of infertility in females with low ovarian reserve.
STUDY FUNDING/COMPETING INTEREST(S)
This study was partly funded by the Research Council of Norway (Women’s fertility, project no. 320656) and through its Centres of Excellence Funding Scheme (project no. 262700). M.C.M. has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement number 947684). The authors declare no conflict of interest.
TRIAL REGISTRATION NUMBER
N/A.
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