Genome-wide characterization of circulating metabolic biomarkers.

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1-7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8-11. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases.

The role of the annexin A protein family at the maternal-fetal interface.

Successful pregnancy requires the tolerance of the maternal immune system for the semi-allogeneic embryo, as well as a synchrony between the receptive endometrium and the competent embryo. The annexin family belongs to calcium-regulated phospholipid-binding protein, which functions as a membrane skeleton to stabilize the lipid bilayer and participate in various biological processes in humans. There is an abundance of the annexin family at the maternal-fetal interface, and it exerts a crucial role in embryo implantation and the subsequent development of the placenta. Altered expression of the annexin family and dysfunction of annexin proteins or polymorphisms of the ANXA gene are involved in a range of pregnancy complications. In this review, we summarize the current knowledge of the annexin A protein family at the maternal-fetal interface and its association with female reproductive disorders, suggesting the use of ANXA as the potential therapeutic target in the clinical diagnosis and treatment of pregnancy complications.

Genetic Factors Associated With Adverse Pregnancy Outcomes in Chronic Pancreatitis.

INTRODUCTION: The effects of genetic factors on pregnancy outcomes in chronic pancreatitis (CP) patients remain unclear. We evaluated the impacts of clinical features and mutations in main CP-susceptibility genes ( SPINK1 , PRSS1 , CTRC , and CFTR ) on pregnancy outcomes in Chinese CP patients. METHODS: This was a prospective cohort study with 14-year follow-up. The sample comprised female CP patients with documented pregnancy and known genetic backgrounds. Adverse pregnancy outcomes were compared between patients with and without gene mutations. Univariate and multivariate analyses were performed to determine the impact factors for adverse pregnancy outcomes. RESULTS: Totally, 160 female CP patients with a pregnancy history were enrolled; 59.4% of patients carried pathogenic mutations in CP-susceptibility genes. Adverse pregnancy outcomes occurred in 38 patients (23.8%); the prevalence of adverse outcomes was significantly higher in those harboring gene mutations than those without (30.5% vs 13.8%, P = 0.015). Notably, the rates of preterm delivery (12.6% vs 3.1%, P = 0.036) and abortion (17.9% vs 4.6%, P = 0.013) were remarkably higher in patients with gene mutations (especially SPINK1 mutations) than those without. In multivariate analyses, both CP-susceptibility gene mutations (odds ratio, 2.52; P = 0.033) and SPINK1 mutations (odds ratio, 2.60; P = 0.037) significantly increased the risk of adverse pregnancy outcomes. Acute pain attack during pregnancy was another risk factor for adverse pregnancy outcomes. DISCUSSION: Pathogenic mutations in CP-susceptibility genes, especially SPINK1 , were independently related to adverse pregnancy outcomes in CP patients. Significant attention should be paid to pregnant females harboring CP-susceptibility gene mutations (ClinicalTrials.gov: NCT06055595).

Reassuring pregnancy outcomes in women with mild COL4A3-5-related disease (Alport syndrome) and genetic type of disease can aid personalized counseling.

Individualized pre-pregnancy counseling and antenatal care for women with chronic kidney disease (CKD) require disease-specific data. Here, we investigated pregnancy outcomes and long-term kidney function in women with COL4A3-5 related disease (Alport Syndrome, (AS)) in a large multicenter cohort. The ALPART-network (mAternaL and fetal PregnAncy outcomes of women with AlpoRT syndrome), an international collaboration of 17 centers, retrospectively investigated COL4A3-5 related disease pregnancies after the 20th week. Outcomes were stratified per inheritance pattern (X-Linked AS (XLAS)), Autosomal Dominant AS (ADAS), or Autosomal Recessive AS (ARAS)). The influence of pregnancy on estimated glomerular filtration rate (eGFR)-slope was assessed in 192 pregnancies encompassing 116 women (121 with XLAS, 47 with ADAS, and 12 with ARAS). Median eGFR pre-pregnancy was over 90ml/min/1.73m2. Neonatal outcomes were favorable: 100% live births, median gestational age 39.0 weeks and mean birth weight 3135 grams. Gestational hypertension occurred during 23% of pregnancies (reference: 'general' CKD G1-G2 pregnancies incidence is 4-20%) and preeclampsia in 20%. The mean eGFR declined after pregnancy but remained within normal range (over 90ml/min/1.73m2). Pregnancy did not significantly affect eGFR-slope (pre-pregnancy ß=-1.030, post-pregnancy ß=-1.349). ARAS-pregnancies demonstrated less favorable outcomes (early preterm birth incidence 3/11 (27%)). ARAS was a significant independent predictor for lower birth weight and shorter duration of pregnancy, next to the classic predictors (pre-pregnancy kidney function, proteinuria, and chronic hypertension) though missing proteinuria values and the small ARAS-sample hindered analysis. This is the largest study to date on AS and pregnancy with reassuring results for mild AS, though inheritance patterns could be considered in counseling next to classic risk factors. Thus, our findings support personalized reproductive care and highlight the importance of investigating kidney disease-specific pregnancy outcomes.

Two pregnancies of an ornithine carbamoyltransferase deficiency disease carrier and review of the literature.

Introduction: Background: the underlying cause of the deficiency of ornithine carbamoyltransferase (OTCD) is a gene mutation on the X chromosome. In females, the phenotype is highly variable, ranging from asymptomatic to neurologic compromise secondary to hyperammonemia and it can be prompted by numerous triggers, including pregnancy. Objective: the objective of this article is to report a case of two pregnancies of an OTCD-carrier, and to review the literature describing OTCD and pregnancy, parturition and postpartum. Methods: an extensive search in PubMed in December 2021 was conducted using different search terms. After screening all abstracts, 23 papers that corresponded to our inclusion criteria were identified. Results: the article focuses on the management of OTCD during pregnancy, parturition, and the postpartum period in terms of clinical presentation, ammonia levels and treatment. Conclusions: females with OTCD can certainly plan a pregnancy, but they need a careful management during delivery and particularly during the immediate postpartum period. If possible, a multidisciplinary team of physicians, dietitians, obstetrician-gynecologist, neonatologists, pharmacists, etc. with expertise in this field should participate in the care of women with OTCD and their children during this period and in their adult life.

Introducción: Antecedentes: la causa subyacente de la deficiencia de ornitina transcarbamilasa (OTC) es una mutación genética en el cromosoma X. En las mujeres, el fenotipo es muy variable, desde asintomático hasta presentar un compromiso neurológico secundario a hiperamonemia, y puede ser provocado por numerosos factores desencadenantes, incluido el embarazo. Objetivo: el objetivo de este artículo es reportar un caso de dos embarazos de una portadora de OTC, y revisar la literatura que describe OTC y embarazo, parto y posparto. Métodos: se realizó una búsqueda exhaustiva en PubMed en diciembre de 2021 utilizando diferentes términos de búsqueda. Después de examinar todos los resúmenes, identificamos 23 artículos que correspondían a nuestros criterios de inclusión. Resultados: el artículo se centra en el manejo de la OTC durante el embarazo, el parto y el posparto en términos de presentación clínica, niveles de amonio y tratamiento. Conclusiones: las mujeres con OTC pueden planificar un embarazo, pero necesitan un manejo cuidadoso durante el parto, y particularmente, durante el posparto inmediato. Si es posible, un equipo multidisciplinar de médicos, dietistas, ginecólogos-obstetras, neonatólogos, farmacéuticos, etc., con experiencia en este campo, debe participar en el cuidado de las mujeres con OTC y sus hijos durante este periodo y en su vida adulta.

Placental accelerated aging in antenatal depression.

BACKGROUND: Antenatal maternal depression is associated with poor pregnancy outcomes and long-term effects on the offspring. Previous studies have identified links between antenatal depression and placental DNA methylation and between placental epigenetic aging and poor pregnancy outcomes, such as preterm labor and preeclampsia. The relationship between antenatal depression and poor pregnancy outcomes may be partly mediated via placental aging. OBJECTIVE: This study aimed to investigate whether antenatal depressive symptoms are associated with placental epigenetic age acceleration, an epigenetic aging clock measure derived from the difference between methylation age and gestational age at delivery. STUDY DESIGN: The study included 301 women who provided placenta samples at delivery as part of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies - Singletons that recruited participants from diverse race and ethnic groups at 12 US clinical sites (2009-2013). Women underwent depression screening using the Edinburgh Postnatal Depression Scale up to 6 times across the 3 trimesters of pregnancy. Depressive symptoms status was determined for each pregnancy trimester using an Edinburgh Postnatal Depression Scale score, in which a score of ≥10 was defined as having depressive symptoms and a score of <10 was defined as not having depressive symptoms. Placental DNA methylation was profiled from placenta samples. Placental epigenetic age was estimated using a methylation-based age estimator (placental "epigenetic clock") that has previously been found to have high placental gestational age prediction accuracy for uncomplicated term pregnancies. Placental age acceleration was defined to be the residual upon regressing the estimated epigenetic age on gestational age at delivery. Associations between an Edinburgh Postnatal Depression Scale score of ≥10 and an Edinburgh Postnatal Depression Scale score of <10 in the first, second, and third trimesters of pregnancy (ie, depressive symptoms vs none in each trimester) and placental age acceleration were tested using multivariable linear regression adjusting for maternal age, parity, race and ethnicity, and employment. RESULTS: There were 31 (10.3%), 48 (16%), and 49 (16.4%) women with depressive symptoms (ie, Edinburgh Postnatal Depression Scale score of ≥10) in the first, second, and third trimesters of pregnancy, respectively. Of these women, 21 (7.2%) had sustained first- and second-trimester depressive symptoms, 19 (7%) had sustained second- and third-trimester depressive symptoms, and 12 (4.8%) had sustained depressive symptoms throughout pregnancy. Women with depressive symptoms in the second trimester of pregnancy had 0.41 weeks higher placental age acceleration than women without depressive symptoms during the second trimester of pregnancy (ß=0.21 weeks [95% confidence interval, -0.17 to 0.58; P=.28] during the first trimester of pregnancy; ß=0.41 weeks [95% confidence interval, 0.10-0.71; P=.009] during the second trimester of pregnancy; ß=0.17 weeks [95% confidence interval, -0.14 to 0.47; P=.29] during the third trimester of pregnancy). Sustained first- and second-trimester depressive symptoms were associated with 0.72 weeks higher placental age acceleration (95% confidence interval, 0.29-1.15; P=.001) than no depressive symptom in the 2 trimesters. The association between second-trimester depressive symptoms and higher placental epigenetic age acceleration strengthened in the analysis of pregnancies with male fetuses (ß=0.53 weeks; 95% confidence interval, 0.06-1.08; P=.03) but was not significant in pregnancies with female fetuses. CONCLUSION: Antenatal depressive symptoms during the second trimester of pregnancy were associated with an average of 0.41 weeks of increased placental age acceleration. Accelerated placental aging may play an important role in the underlying mechanism linking antenatal depression to pregnancy complications related to placental dysfunction.

Single-cell resolution of longitudinal blood transcriptome profiles in rheumatoid arthritis, systemic lupus erythematosus and healthy control pregnancies.

OBJECTIVES: Comparative longitudinal analyses of cellular composition and peripheral blood gene expression in Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and healthy pregnancies. METHODS: In total, 335 whole blood samples from 84 RA, SLE and healthy controls before pregnancy, at each trimester, 6 weeks, 6 months and 12 months post partum were analysed. We combined bulk and single cell RNA analyses for cell-type estimation, validated by flow cytometry, before combining this in a cell-type adjusted analysis for an improved resolution of unrecognised gene expression changes associated with RA and SLE pregnancies. RESULTS: Patients were well regulated throughout pregnancy, and few had pregnancy complications. In SLE, the interferon signature was augmented during pregnancy, and the pregnancy signature was continued post partum. An altered cell type composition strongly influences the profile. In the pregnancy signature, transcripts involved in galactosylation potentially altering the effector functions of autoantibodies became more evident. Several genes in the adjusted RA signature are expressed in mucosal associated invariant T cells. CONCLUSION: We found distinct RA, SLE and pregnancy signatures, and no expression patterns could be attributed to medication or disease activity. Our results support the need for close postpartum follow-up of patients with SLE. Gene expression patterns in RA were closer to healthy controls than to SLE, and primarily became evident after cell-type adjustment. Adjusting for cell abundance unravelled gene expression signatures less associated with variation in cell-composition and highlighted genes with expression profiles associated with changes in specialised cell populations.

The placental vasculature is affected by changes in gene expression and glycogen-rich cells in a diet-induced obesity mouse model.

Maternal obesity is a risk factor for pregnancy complications. Obesity caused by a high-fat diet (HFD) may alter maternal glucose/glycogen metabolism. Here, our objective was to investigate whether the placental vasculature is altered via changes in gene expression and glycogen-rich cells using a preclinical mouse model of diet-induced obesity. We subjected female FVB/N mice to one of three feeding regimens: regular chow (RC) given at preconception and during pregnancy (Control); RC given at preconception and then a HFD during pregnancy (HFD-P); or HFD initiated 4 weeks preconception and during pregnancy (HFD-PreCP). Daily food consumption and weekly maternal weights were recorded. Maternal blood glucose levels were measured at preconception and 4 gestational epochs (E6.5-E9.5, E10.5-E12.5, E13.5-E15.5, E16.5-E19.5). At E8.5-E16.5, total RNA in placentas were isolated for gene expression analyses. Placentas were also collected for HE and periodic acid Schiff's (PAS) staining and glycogen content assays. Dams in the HFD-P and HFD-PreCP groups gained significantly more weight than controls. Pre- and antenatal glucose levels were also significantly higher (15%-30%) in HFD-PreCP dams. Expression of several placental genes were also altered in HFD dams compared with controls. Consumption of the HFD also led to phenotypic and morphologic changes in glycogen trophoblasts (GlyTs) and uterine natural killer (uNK) cells. Alterations in vascularity were also observed in the labyrinth of HFD-PreCP placentas, which correlated with decreased placental efficiency. Overall, we observed that a HFD induces gestational obesity in mice, alters expression of placental genes, affects glucose homeostasis, and alters glycogen-positive GlyTs and uNK cells. All these changes may lead to impaired placental vascular development, and thus heighten the risk for pregnancy complications.

Prenatal serotonin reuptake inhibitor antidepressant exposure, SLC6A4 genetic variations, and cortisol activity in 6-year-old children of depressed mothers: A cohort study.

Prenatal exposure to maternal depression and serotonin reuptake inhibitor (SRI) antidepressants both affect the development of the hypothalamic-pituitary-adrenal (HPA) system, possibly via the neurotransmitter serotonin (5HT). In a community cohort, we investigated the impact of two factors that shape prenatal 5HT signaling (prenatal SRI [pSRI] exposure and child SLC6A4 genotype) on HPA activity at age 6 years. Generalized estimating equation (GEE) models were used to study associations between cortisol reactivity, pSRI exposure, and child SLC6A4 genotype, controlling for maternal depression, child age, and sex (48 pSRI exposed, 74 nonexposed). Salivary cortisol levels were obtained at five time points during a laboratory stress challenge: arrival at the laboratory, following two sequential developmental assessments, and then 20 and 40 min following the onset of a stress-inducing cognitive/social task. Cortisol decreased from arrival across both developmental assessments, and then increased across both time points following the stress challenge in both groups. pSRI-exposed children had lower cortisol levels across all time points. In a separate GEE model, we observed a lower cortisol stress response among children with LG /S alleles compared with children with La/La alleles, and this was particularly evident among children of mothers reporting greater third trimester depressed mood. Our findings suggest that pSRI exposure and a genetic factor associated with modulating 5HT signaling shaped HPA reactivity to a laboratory stress challenge at school age.

Reproductive Carrier Screening Results With Maternal Health Implications During Pregnancy.

OBJECTIVE: To identify conditions on a reproductive carrier screening panel with the potential for carrier manifestations during pregnancy and review the implications for obstetric care. METHODS: This was a retrospective cross-sectional study of consecutive samples from female patients aged 18-55 years submitted to a commercial laboratory for a 274-gene carrier screening panel (January 2020 to September 2022). A literature review was performed to identify genes on the panel with potential for pregnancy complications in carriers. Carrier expression and published recommendations for clinical management were reviewed. RESULTS: We identified 12 genes with potential for carrier manifestations during pregnancy based on reports in the literature: nine with manifestations irrespective of the fetal genetic status ( ABCB11 , COL4A3 , COL4A4 , COL4A5 , DMD , F9 , F11 , GLA , and OTC ) and three ( CPT1A , CYP19A1 , and HADHA ) with manifestations only if the fetus is affected by the condition. Manifestations included cardiomyopathy, hemorrhage, gestational hypertensive disorders, cholestasis of pregnancy, acute fatty liver, hyperammonemic crisis, and maternal virilization. Published recommendations for carrier management were identified for 11 of the 12 genes. Of 91,637 tests performed during the study period, a pathogenic or likely pathogenic variant was identified in 2,139 (2.3%), giving a carrier frequency for any of the 12 genes of 1 in 43 (95% CI 1/41-45) 1,826 (2.0%) of the study population were identified as carriers for one of the nine genes with the potential for carrier manifestations irrespective of an affected or unaffected fetus. CONCLUSION: Approximately 1 in 40 female patients were identified as carriers for a condition with potential for maternal manifestations in pregnancy, including some serious or even life-threatening complications. Obstetric care professionals should be aware of the possibility of pregnancy complications among carriers and the available recommendations for management. FUNDING SOURCE: This study was funded by Natera, Inc.

Heredity of pregnancy-related pelvic girdle pain in Sweden.

INTRODUCTION: Pelvic girdle pain during and after pregnancy is a major public health problem with significant daily problems for affected women and their families. There is now accumulating evidence that pregnancy-related pelvic girdle pain originates from the sacroiliac joints and the pubic symphysis as well as their extra-articular ligaments. However, the heritability of the disease remains to be determined. We hypothesized that there is an increased familial risk of pregnancy-related pelvic girdle pain. MATERIAL AND METHODS: A population-based national database linkage registry study of approximately 9.3 million individuals within 4.2 million families in Sweden with a recruitment period from 1997 to 2018. The Swedish Multi-generation register was used to find female pairs of twins, full siblings, half-siblings and first cousins where both in the pairs had a completed pregnancy. The outcome measure was diagnosis of pregnancy-related pelvic girdle pain (International Classification of Diseases-10 O26.7 [1997-2018]) in the first pregnancy. Data was obtained from the Swedish Hospital Discharge Register, the Swedish Outpatient Care Register, the Swedish Medical Birth Register, the Primary Healthcare Register, and Medical Treatment Register. Cox regression analysis was used to calculate adjusted estimated effect of the exposure variable familial history of pregnancy-related pelvic girdle pain on the outcome variable pregnancy-related pelvic girdle pain at first birth. RESULTS: From the registers, 1 010 064 women pregnant with their first child within 795 654 families were collected. In total, 109 147 women were diagnosed with pregnancy-related pelvic girdle pain. The adjusted hazard ratio for a familial risk of pregnancy-related pelvic girdle pain was 2.09 (95% CI 1.85-2.37) among twins (monozygotic and dizygotic), 1.78 (95% CI 1.74-1.82) in full siblings, 1.16 (95% CI 1.06-1.28) in half-siblings from the mother, 1.09 (95% CI 1.024-1.16) in half-siblings from the father and 1.09 (95% CI 1.07-1.12) in first cousins. CONCLUSIONS: This nationwide observational study showed a familial clustering of pregnancy-related pelvic girdle pain. The hazard ratio for the condition was associated with the degree of relatedness, suggesting that heredity factors contribute to the development of pregnancy-related pelvic girdle pain. There is no causal treatment available for pregnancy-related pelvic girdle pain and further studies are now encouraged to clarify the specific genetic factors that contribute to the disease and for future targeted interventions.

Sperm epigenetics landscape: correlation with embryo quality, reproductive outcomes and offspring's health.

Epigenetics refers to how gene expression and function are modulated without modifying the DNA sequence but through subtle molecular changes or interactions with it. As spermatogenesis progresses, male germ cells suffer plenty of epigenetic modifications, resulting in the definitive epigenome of spermatozoa conditioning its functionality, and this process can be altered by several internal and external factors. The paternal epigenome is crucial for sperm function, fertilization, embryo development, and offspring's health, and altered epigenetic states are associated with male infertility with or without altered semen parameters, embryo quality impairment, and worse ART outcomes together with the future offspring's health risks mainly through intergenerational transmission of epigenetic marks. Identifying epigenetic biomarkers may improve male factor diagnosis and the development of targeted therapies, not only to improve fertility but also to allow an early detection of risk and disease prevention in the progeny. While still there is much research to be done, hopefully in the near future, improvements in high-throughput technologies applied to epigenomes will permit our understanding of the underlying epigenetic mechanisms and the development of diagnostics and therapies leading to improved reproductive outcomes. In this review, we discuss the mechanisms of epigenetics in sperm and how epigenetics behave during spermatogenesis. Additionally, we elaborate on the relationship of sperm epigenetics with sperm parameters and male infertility, and highlight the impact of sperm epigenetic alterations on sperm parameters, embryo quality, ART outcomes, miscarriage rates and offspring's health. Furthermore, we provide insights into the future research of epigenetic alterations in male infertility.

Pregnancy-associated systemic gene expression compared to a pre-pregnancy baseline, among healthy women with term pregnancies.

Background: Pregnancy is known to induce extensive biological changes in the healthy mother. Little is known, however, about what these changes are at the molecular level. We have examined systemic expression changes in protein-coding genes and long non-coding (lnc) RNAs during and after pregnancy, compared to before pregnancy, among healthy women with term pregnancies. Methods: Blood samples were collected from 14 healthy women enrolled in our prospective pregnancy cohort at 7 time-points (before, during and after pregnancy). Total RNA from frozen whole blood was used for RNA sequencing. Following raw read alignment and assembly, gene-level counts were obtained for protein-coding genes and long non-coding RNAs. At each time-point, cell type proportions were estimated using deconvolution. To examine associations between pregnancy status and gene expression over time, Generalized Estimating Equation (GEE) models were fitted, adjusting for age at conception, and with and without adjusting for changes in cell type proportions. Fold-changes in expression at each trimester were examined relative to the pre-pregnancy baseline. Results: Numerous immune-related genes demonstrated pregnancy-associated expression, in a time-dependent manner. The genes that demonstrated the largest changes in expression included several that were neutrophil-related (over-expressed) and numerous immunoglobulin genes (under-expressed). Estimated cell proportions revealed a marked increase in neutrophils, and less so of activated CD4 memory T cells, during pregnancy, while most other cell type proportions decreased or remained unchanged. Adjusting for cell type proportions in our model revealed that although most of the expression changes were due to changes in cell type proportions in the bloodstream, transcriptional regulation was also involved, especially in down-regulating expression of type I interferon inducible genes. Conclusion: Compared to a pre-pregnancy baseline, there were extensive systemic changes in cell type proportions, gene expression and biological pathways associated with different stages of pregnancy and postpartum among healthy women. Some were due to changes in cell type proportions and some due to gene regulation. In addition to providing insight into term pregnancy among healthy women, these findings also provide a "normal" reference for abnormal pregnancies and for autoimmune diseases that improve or worsen during pregnancy, to assess deviations from normal.

Kind of blue - An evaluation of etiologies for prenatal versus postnatal depression symptoms.

BACKGROUND: Prenatal and postnatal depression potentially have severe consequences, but we do not know to what extent they have the same etiological factors. Genetically informative designs yield insight into common etiology between pre- and postnatal depression and inform on potential prevention and intervention efforts. This study evaluates the overlap in genetic and environmental factors in pre- and postnatal depression symptoms. METHODS: We conducted univariate and bivariate modeling, using a quantitative, extended twin study. The sample was a subsample of the MoBa prospective pregnancy cohort study in 6039 pairs of related women. Measurement was conducted at week 30 of pregnancy and 6 months following delivery, using a self-report scale. RESULTS: The heritability of depressive symptoms was 16.2 % (95 % CI = 10.7-22.1) prenatally and 25.7 % (95 % CI = 19.2-32.2) postnatally. The correlation between risk factors for prenatal and postnatal depressive symptoms was at unity (r = 1.00) for genetic effects, and at disunity (r = 0.36) for environmental effects. The genetic effects for postnatal depressive symptoms were 1.7 times larger compared to prenatal depressive symptoms. LIMITATIONS: Although genes for depression become more influential postpartum, only future studies can inform on the mechanisms for such a socio-biological augmentation of effect. CONCLUSION: Genetic risk factors for prenatal and postnatal depressive symptoms are indistinguishable in kind, with greater impact after birth, whereas environmental risk factors for depression symptoms are mostly non-overlapping before and after birth. These findings indicate that interventions could be of different kind before and after birth.

Emerging role of miRNAs, lncRNAs, and circRNAs in pregnancy-associated diseases.

ABSTRACT: Accumulating studies have demonstrated that non-coding RNAs (ncRNAs), functioning as important regulators of transcription and translation, are involved in the establishment and maintenance of pregnancy, especially the maternal immune adaptation process. The endometrial stromal cells (ESCs), trophoblast cells, and decidua immune cells that reside at the maternal-fetal interface are thought to play significant roles in normal pregnancy and pregnancy-associated diseases. Here, we reviewed the up-to-date evidence on how microRNA, long non-coding RNA, and circular RNA regulate ESCs, trophoblast cells, and immune cells and discussed the potential applications of these ncRNAs as diagnostic and therapeutic markers in pregnancy complications.

DNA methylation abnormalities induced by advanced maternal age in villi prime a high-risk state for spontaneous abortion.

BACKGROUND: Advanced maternal age (AMA) has increased in many high-income countries in recent decades. AMA is generally associated with a higher risk of various pregnancy complications, and the underlying molecular mechanisms are largely unknown. In the current study, we profiled the DNA methylome of 24 human chorionic villi samples (CVSs) from early pregnancies in AMA and young maternal age (YMA), 11 CVSs from early spontaneous abortion (SA) cases using reduced representation bisulfite sequencing (RRBS), and the transcriptome of 10 CVSs from AMA and YMA pregnancies with mRNA sequencing(mRNA-seq). Single-cell villous transcriptional atlas presented expression patterns of targeted AMA-/SA-related genes. Trophoblast cellular impairment was investigated through the knockdown of GNE expression in HTR8-S/Vneo cells. RESULTS: AMA-induced local DNA methylation changes, defined as AMA-related differentially methylated regions (DMRs), may be derived from the abnormal expression of genes involved in DNA demethylation, such as GADD45B. These DNA methylation changes were significantly enriched in the processes involved in NOTCH signaling and extracellular matrix organization and were reflected in the transcriptional alterations in the corresponding biological processes and specific genes. Furthermore, the DNA methylation level of special AMA-related DMRs not only significantly changed in AMA but also showed more excessive defects in CVS from spontaneous abortion (SA), including four AMA-related DMRs whose nearby genes overlapped with AMA-related differentially expressed genes (DEGs) (CDK11A, C19orf71, COL5A1, and GNE). The decreased DNA methylation level of DMR near GNE was positively correlated with the downregulated expression of GNE in AMA. Single-cell atlas further revealed comparatively high expression of GNE in the trophoblast lineage, and knockdown of GNE in HTR8-S/Vneo cells significantly impaired cellular proliferation and migration. CONCLUSION: Our study provides valuable resources for investigating AMA-induced epigenetic abnormalities and provides new insights for explaining the increased risks of pregnancy complications in AMA pregnancies.

Familial clustering of intrahepatic cholestasis of pregnancy: A nationwide population-based study in Denmark.

BACKGROUND AND AIMS: Genetics plays a role in the pathogenesis of intrahepatic cholestasis of pregnancy (ICP); however, empirical evidence on familial clustering of ICP is scarce. We aimed to assess the extent of familial recurrence of ICP. APPROACH AND RESULTS: This population-based cohort study included all 668,461 primiparous women who gave birth between 1995 and 2018 in Denmark. Women diagnosed with ICP were included to the index cohort. Kinship with index women was determined with the Danish Civil Registration System. Log-binomial regression was used to calculate the relative recurrence risk (RRR) of ICP in relatives of index women. A total of 6722 (1.0%) primiparous women were diagnosed with ICP. In co-twins (n=57), first-degree (n=2279), second-degree (n=1373), and third-degree (n=1758) relatives of the index women, the incidence of ICP reached 5.3%, 2.6%, 0.7%, and 1.4%, respectively, corresponding to adjusted RRRs of 4.82 (95% CI, 1.60-14.48), 2.54 (1.98-3.26), 0.81 (0.44-1.51), and 1.15 (0.77-1.71), respectively. The first-degree relatives of women who had recurrent ICP or first-trimester ICP seemed to be at higher risks [RRR, 4.30 (2.85-6.48), 3.04 (1.93-4.77), respectively]. A minor increased risk was observed in nonbiological relatives [RRR, 1.35 (1.05-1.73); n=4274, including women's full-brothers' partner and women's husbands' full sisters]. CONCLUSIONS: Co-twins and first-degree relatives of ICP patients were at ~5- and ~2.5-fold increased risk of ICP, respectively. No increased risk was observed in second-degree and third-degree relatives. Recurrent ICP and first-trimester ICP might indicate a higher degree of family clustering. Further investigation is needed to investigate the increased risk of ICP in nonbiological relatives.

VPAC1 and VPAC2 receptor deficiencies negatively influence pregnancy outcome through distinct and overlapping modulations of immune, trophoblast and vascular functions.

Pregnancy outcome relies on the maintenance of immune and metabolic homeostasis at the maternal fetal interface. Maternal and perinatal morbidity and mortality is associated with impaired placental development. Multiple regulatory effects of the endogenous-produced vasoactive intestinal peptide (VIP) on vascular, metabolic and immune functions at the maternal-fetal interface have been reported. Here we studied the involvement of the two primary high affinity receptors for VIP (VPAC1 and VPAC2) on maternal immune response, placental homeostasis and pregnancy outcome. Targeted disruption of each receptor gene led to altered placental structure, vascular and trophoblast functional markers and shaped the functional profiles of macrophages and neutrophils towards a proinflammatory state. Several changes in pregnant mice were receptor specific: ROS production elicited by VIP on neutrophils was selectively dependent on the presence of VPAC1 whereas apoptosis rate was associated with the VPAC2 deletion. In peritoneal macrophages from pregnant mice, levels of MHC-II, TLR2, and IL-10 were selectively altered in VPAC2 receptor-deficient mice, whereas IL-6 gene expression was reduced only in mice lacking VPAC1 receptors. Additionally, MMP9 mRNA in isolated TGCs was reduced in VPAC2 receptor deleted mice, while the percentage of IL-12 cells in post-phagocytosis macrophage cultures was selectively reduced in VPAC2 receptor deficient mice. The results indicate that manipulation of VPAC1 and VPAC2 receptor affects immune, vascular and metabolic environment at the maternal fetal interface. These mouse models offer new approaches to study pregnancy complications adding new perspectives to the development of VPAC receptor-selective drugs.

Emerging role of miRNAs, lncRNAs, and circRNAs in pregnancy-associated diseases / 中华医学杂志(英文版)

Accumulating studies have demonstrated that non-coding RNAs (ncRNAs), functioning as important regulators of transcription and translation, are involved in the establishment and maintenance of pregnancy, especially the maternal immune adaptation process. The endometrial stromal cells (ESCs), trophoblast cells, and decidua immune cells that reside at the maternal-fetal interface are thought to play significant roles in normal pregnancy and pregnancy-associated diseases. Here, we reviewed the up-to-date evidence on how microRNA, long non-coding RNA, and circular RNA regulate ESCs, trophoblast cells, and immune cells and discussed the potential applications of these ncRNAs as diagnostic and therapeutic markers in pregnancy complications.