| 1. |
- Beaumont, Robin N, et al.
(författare)
-
Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth.
- 2023
-
Ingår i: Nature genetics. - 1546-1718 .- 1061-4036. ; 55:11, s. 1807-19
-
Tidskriftsartikel (refereegranskat)abstract
- A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n=65,405), maternal (n=61,228) and paternal (n=52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth.
|
|
| 2. |
- Flatley, Christopher, et al.
(författare)
-
Placental weight centiles adjusted for age, parity and fetal sex
- 2022
-
Ingår i: Placenta. - : Elsevier BV. - 1532-3102 .- 0143-4004. ; 117, s. 87-94
-
Tidskriftsartikel (refereegranskat)abstract
- The weight of the placenta can be indicative of efficacy in nutrient and oxygen supply. Furthermore, it has been suggested that a measure of the placenta's ability to adequately supply nutrients to the fetus can be found in the relationship between birth weight and placental weight expressed as a ratio. Our aim was to develop age adjusted placenta weight and birth weight to placenta weight ratio reference curves that are stratified by maternal parity and fetal sex.We included singleton, non-anomalous births with a gestational age inclusive of 28+0 weeks to 42+6 weeks. Excluded were pregnancies of multiplicity, fetuses with congenital abnormalities, stillbirths and pregnancies that had placental complications (ie placenta previa or abruption). Generalised additive model for location, shape and scale (GAMLSS) was used to fit reference curves.We stratified 97,882 pregnancies by maternal nulliparity status and fetal sex. Extensive assessment model goodness-of-fit showed appropriate modeling and accurate fit to the four parameters of distribution. Our results show accurate model fit of the reference curves to the data. We demonstrated that the influence that parity has on the placenta weight is far greater than that exerted by fetal sex, and that the difference is dependent on gestational age.This is the largest presentation of age and parity adjusted placenta weight and feto-placental weight ratio reference ranges to date. The difference observed between nulliparous and multiparous pregnancies could be explained by biological memory and the remnants of maternal endo-myometrial vascularity after the first pregnancy.
|
|
| 3. |
|
|
| 4. |
- Helgeland, Øyvind, et al.
(författare)
-
Characterization of the genetic architecture of infant and early childhood body mass index.
- 2022
-
Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 4:3, s. 344-358
-
Tidskriftsartikel (refereegranskat)abstract
- Early childhood obesity is a growing global concern; however, the role of common genetic variation on infant and child weight development is unclear. Here, we identify 46 loci associated with early childhood body mass index at specific ages, matching different child growth phases, and representing four major trajectory patterns. We perform genome-wide association studies across 12 time points from birth to 8 years in 28,681 children and their parents (27,088 mothers and 26,239 fathers) in the Norwegian Mother, Father and Child Cohort Study. Monogenic obesity genes are overrepresented near identified loci, and several complex association signals near LEPR, GLP1R, PCSK1 and KLF14 point towards a major influence for common variation affecting the leptin-melanocortin system in early life, providing a link to putative treatment strategies. We also demonstrate how different polygenic risk scores transition from birth to adult profiles through early child growth. In conclusion, our results offer a fine-grained characterization of a changing genetic landscape sustaining early childhood growth.
|
|
| 5. |
- Juodakis, Julius, et al.
(författare)
-
Time-varying effects are common in genetic control of gestational duration
- 2023
-
Ingår i: Human Molecular Genetics. - 0964-6906 .- 1460-2083. ; 32:14, s. 2399-2407
-
Tidskriftsartikel (refereegranskat)abstract
- Preterm birth is a major burden to neonatal health worldwide, determined in part by genetics. Recently, studies discovered several genes associated with this trait or its continuous equivalent - gestational duration. However, their effect timing, and thus clinical importance, is still unclear. Here, we use genotyping data of 31 000 births from the Norwegian Mother, Father and Child cohort (MoBa) to investigate different models of the genetic pregnancy 'clock'. We conduct genome-wide association studies using gestational duration or preterm birth, replicating known maternal associations and finding one new fetal variant. We illustrate how the interpretation of these results is complicated by the loss of power when dichotomizing. Using flexible survival models, we resolve this complexity and find that many of the known loci have time-varying effects, often stronger early in pregnancy. The overall polygenic control of birth timing appears to be shared in the term and preterm, but not very preterm, periods and exploratory results suggest involvement of the major histocompatibility complex genes in the latter. These findings show that the known gestational duration loci are clinically relevant and should help design further experimental studies.
|
|
| 6. |
- Modzelewska, Dominika, et al.
(författare)
-
Changes in data management contribute to temporal variation in gestational duration distribution in the Swedish Medical Birth Registry
- 2020
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203 .- 1932-6203. ; 15:11
-
Tidskriftsartikel (refereegranskat)abstract
- Multiple factors contribute to gestational duration variability. Understanding the sources of variability allows to design better association studies and assess public health measures. Here, we aimed to assess geographical and temporal changes in the determination of gestational duration and its reporting in Sweden between 1973 and 2012. Singleton live births between 1973 and 2012 were retrieved from the Swedish Medical Birth Register. Gestational duration trends in percentiles and rates of pre- and post-term deliveries were analyzed by plotting the values over time. Temporal changes in gestational duration based on ultrasound and last menstrual period (LMP) estimation methods were compared. Intervals between LMP date and LMP-based due date were analyzed to assess changes in expected gestational duration. In total, 3 940 577 pregnancies were included. From 1973 until 1985, the median of gestational duration estimated based on LMP or ultrasound decreased from 283 to 278 days, and remained stable until 2012. The distribution was relatively stable when ultrasound-based estimates were used. Until the mid-1990s, there was a higher incidence than expected of births occurring on every seventh gestational day from day 157 onward. On an average, these gestational durations were reported 1.8 times more often than adjacent durations. Until 1989, the most common expected gestational duration was 280 days, and thereafter, it was 279 days. The expected gestational duration varied from 279 to 281 days across different Swedish counties. During leap years, the expected gestational duration was one day longer. Consequently, leap years were also associated with significantly higher preterm and lower post-term delivery rates than non-leap years. Changes in data handling and obstetrical practices over the years contribute to gestational duration variation. The resulting increase in variability might reduce precision in association studies and hamper the assessment of public health measures aimed to improve pregnancy outcomes.
|
|
| 7. |
- Modzelewska, Dominika, et al.
(författare)
-
Maternal dietary selenium intake during pregnancy and neonatal outcomes in the norwegian mother, father, and child cohort study
- 2021
-
Ingår i: Nutrients. - : MDPI AG. - 2072-6643 .- 2072-6643. ; 13:4
-
Tidskriftsartikel (refereegranskat)abstract
- Properly working antioxidant defence systems are important for fetal development. One of the nutrients with antioxidant activity is selenium. Increased maternal selenium intake has been associated with reduced risk for being small for gestational age and preterm delivery. Based on the Norwegian Mother, Father, and Child Cohort Study and the Medical Birth Registry of Norway, we in-vestigated the association of maternal selenium intake from food and dietary supplements during the first half of pregnancy (n = 71,728 women) and selenium status in mid-pregnancy (n = 2628 women) with neonatal health, measured as two composite variables (neonatal morbidity/mortality and neonatal intervention). Low maternal dietary selenium intake (<30 µg/day) was associated with increased risk for neonatal morbidity/mortality (adjusted odds ratio (adjOR) 1.36, 95% confidence interval (95% CI) 1.08–1.69) and neonatal intervention (adjOR 1.16, 95% CI 1.01–1.34). Using continuous variables, there were no associations between maternal selenium intake (from diet or supplements) or whole-blood selenium concentration and neonatal outcome in the adjusted models. Our findings suggest that sufficient maternal dietary selenium intake is associated with neonatal outcome. Adher-ing to the dietary recommendations may help ensure an adequate supply of selenium for a healthy pregnancy and optimal fetal development.
|
|
| 8. |
- Scull, Margaret A, et al.
(författare)
-
Hepatitis C virus infects rhesus macaque hepatocytes and simianized mice.
- 2015
-
Ingår i: Hepatology. - : Ovid Technologies (Wolters Kluwer Health). - 0270-9139 .- 1527-3350. ; 62:1, s. 57-67
-
Tidskriftsartikel (refereegranskat)abstract
- UNLABELLED: At least 170 million people are chronically infected with hepatitis C virus (HCV). Owing to the narrow host range of HCV and restricted use of chimpanzees, there is currently no suitable animal model for HCV pathogenesis studies or the development of a HCV vaccine. To identify cellular determinants of interspecies transmission and establish a novel immunocompetent model system, we examined the ability of HCV to infect hepatocytes from a small nonhuman primate, the rhesus macaque (Macaca mulatta). We show that the rhesus orthologs of critical HCV entry factors support viral glycoprotein-dependent virion uptake. Primary hepatocytes from rhesus macaques are also permissive for HCV-RNA replication and particle production, which is enhanced when antiviral signaling is suppressed. We demonstrate that this may be owing to the diminished capacity of HCV to antagonize mitochondrial antiviral-signaling protein-dependent innate cellular defenses. To test the ability of HCV to establish persistent replication in vivo, we engrafted primary rhesus macaque hepatocytes into immunocompromised xenorecipients. Inoculation of resulting simian liver chimeric mice with either HCV genotype 1a or 2a resulted in HCV serum viremia for up to 10 weeks.CONCLUSION: Together, these data indicate that rhesus macaques may be a viable model for HCV and implicate host immunity as a potential species-specific barrier to HCV infection. We conclude that suppression of host immunity or further viral adaptation may allow robust HCV infection in rhesus macaques and creation of a new animal model for studies of HCV pathogenesis, lentivirus coinfection, and vaccine development.
|
|
| 9. |
- Solé Navais, Pol, et al.
(författare)
-
Autozygosity mapping and time-to-spontaneous delivery in Norwegian parent-offspring trios.
- 2020
-
Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 29:23, s. 3845-3858
-
Tidskriftsartikel (refereegranskat)abstract
- Parental genetic relatedness may lead to adverse health and fitness outcomes in the offspring. However, the degree to which it affects human delivery timing is unknown. We use genotype data from ≃25000 parent-offspring trios from the Norwegian Mother, Father and Child Cohort Study to optimize runs of homozygosity (ROH) calling by maximising the correlation between parental genetic relatedness and offspring ROHs. We then estimate the effect of maternal, paternal, and fetal autozygosity and that of autozygosity mapping (common segments and gene burden test) on the timing of spontaneous onset of delivery. The correlation between offspring ROH using a variety of parameters and parental genetic relatedness ranged between -0.2 and 0.6, revealing the importance of the minimum number of genetic variants included in a ROH and the use of genetic distance. The optimized compared to predefined parameters showed a ≃45% higher correlation between parental genetic relatedness and offspring ROH. We found no evidence of an effect of maternal, paternal nor fetal overall autozygosity on spontaneous delivery timing. Yet, through autozygosity mapping, we identified three maternal loci TBC1D1, SIGLECs and EDN1 gene regions reducing median time-to-spontaneous onset of delivery by ≃2-5% (P-value< 2.3 × 10-6). We also found suggestive evidence of a fetal locus at 3q22.2, near the RYK gene region (P-value= 2.0 × 10-6). Autozygosity mapping may provide new insights on the genetic determinants of delivery timing beyond traditional genome-wide association studies, but particular and rigorous attention should be given to ROH calling parameter selection.
|
|
| 10. |
- Solé Navais, Pol, et al.
(författare)
-
Genetic effects on the timing of parturition and links to fetal birth weight.
- 2023
-
Ingår i: Nature genetics. - 1546-1718. ; 55:4, s. 559-567
-
Tidskriftsartikel (refereegranskat)abstract
- The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n=195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed six associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n=136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal-fetal relationship between gestational duration and birth weight.
|
|
