| 1. |
- Bacelis, Jonas, 1984
(author)
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Genetic factors affecting pregnancy duration in humans
- 2018
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Doctoral thesis (other academic/artistic)abstract
- This thesis investigates the mechanisms behind human pregnancy duration. Too short gestation is a direct cause of perinatal, neonatal, and infant mortality. Deviation from normal pregnancy length is also associated with a child's morbidity, even in the adulthood. The mechanisms determining pregnancy duration are not understood well enough to design an effective preterm birth prevention method, nor a method that would prevent preterm birth sequelae. The three included studies use genomic and epidemiological methods to contribute to our understanding of causal factors triggering birth. Study I is a hypothesis-free genome-wide search for genetic variants affecting gestational age at birth. The study uses genotyped mothers (n=1921) and children (n=1199) from a Norwegian cohort MoBa. While finding no statistically significant associations, the study empirically shows that the top implicated loci are enriched in genes biologically relevant to the field of obstetrics and gynecology, and that the enrichment is mainly caused by infection/inflammation-related genes. Study II explores whether a well-known association between maternal height and duration of pregnancy could be causally linked. It utilizes a novel version of Mendelian randomization, which is based on the non-transmitted maternal haplotype and its polygenic risk score for human height. With the help of genomic data from 3485 mother-child pairs from Nordic countries, the study confirms the causal relationship. Study III follows up on the findings from the Mendelian randomization study, this time using non-genetic epidemiological data to explain the mechanism behind the causal relationship. A uterine distention hypothesis is formulated and tested by comparing the expected and observed patterns of interaction between fetal growth rate, maternal height and the child's gestational age at birth. The twin (n=2846) and singleton (n=527 868) data is obtained from the Swedish Medical Birth Register. Since the observed and expected interaction patterns agree with each other, the study concludes that uterine distention is likely to be one of the causal mechanisms regulating pregnancy duration.
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| 2. |
- Bacelis, Jonas, 1984, et al.
(author)
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Literature-Informed Analysis of a Genome-Wide Association Study of Gestational Age in Norwegian Women and Children Suggests Involvement of Inflammatory Pathways
- 2016
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:8
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Journal article (peer-reviewed)abstract
- Background Five-to-eighteen percent of pregnancies worldwide end in preterm birth, which is the major cause of neonatal death and morbidity. Approximately 30% of the variation in gestational age at birth can be attributed to genetic factors. Genome-wide association studies (GWAS) have not shown robust evidence of association with genomic loci yet. We separately investigated 1921 Norwegian mothers and 1199 children from pregnancies with spontaneous onset of delivery. Individuals were further divided based on the onset of delivery: initiated by labor or prelabor rupture of membranes. Genetic association with ultrasound- dated gestational age was evaluated using three genetic models and adaptive permutations. The top-ranked loci were tested for enrichment in 12 candidate gene-sets generated by text-mining PubMed abstracts containing pregnancy-related keywords. The six GWAS did not reveal significant associations, with the most extreme empirical p = 5.1 x 10(-7). The top loci from maternal GWAS with deliveries initiated by labor showed significant enrichment in 10 PubMed gene-sets, e.g., p = 0.001 and 0.005 for keywords "uterus" and "preterm" respectively. Enrichment signals were mainly caused by infection/inflammation-related genes TLR4, NFKB1, ABCA1, MMP9. Literature-informed analysis of top loci revealed further immunity genes: IL1A, IL1B, CAMP, TREM1, TFRC, NFKBIA, MEFV, IRF8, WNT5A. Our analyses support the role of inflammatory pathways in determining pregnancy duration and provide a list of 32 candidate genes for a follow-up work. We observed that the top regions from GWAS in mothers with labor-initiated deliveries significantly more often overlap with pregnancy-related genes than would be expected by chance, suggesting that increased sample size would benefit similar studies.
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| 3. |
- Bacelis, Jonas, et al.
(author)
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Uterine distention as a factor in birth timing: retrospective nationwide cohort study in Sweden.
- 2018
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In: BMJ open. - : BMJ. - 2044-6055. ; 8:10
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Journal article (peer-reviewed)abstract
- To determine whether uterine distention is associated with human pregnancy duration in a non-invasive observational setting.Retrospective cohort study modelling uterine distention by interaction between maternal height and uterine load.The study is based on the 1990-2013 population data from all delivery units in Sweden.Uncomplicated first pregnancies of healthy Nordic-born mothers with spontaneous onset of labour. Pregnancies were classified as twin (n=2846) or singleton (n=527868). Singleton pregnancies were further classified as carrying a large for gestational age fetus (LGA, n=24286) or small for gestational age fetus (SGA, n=33780).Statistical interaction between maternal height and uterine load categories (twin vs singleton pregnancies, and LGA vs SGA singleton pregnancies), where the outcome is pregnancy duration.In all models, statistically significant interaction was found. Mothers carrying twins had 2.9 times larger positive linear effect of maternal height on gestational age than mothers carrying singletons (interaction p=5e-14). Similarly, the effect of maternal height was strongly modulated by the fetal growth rate in singleton pregnancies: the effect size of maternal height on gestational age in LGA pregnancies was 2.1 times larger than that in SGA pregnancies (interaction p<1e-11). Preterm birth OR was 1.4 when the mother was short, and 2.8 when the fetus was extremely large for its gestational age; however, when both risk factors were present together, the OR for preterm birth was larger than expected, 10.2 (interaction p<0.0005).Across all classes, maternal height was significantly associated with child's gestational age at birth. Interestingly, in short-statured women with large uterine load (twins, LGA), spontaneous delivery occurred much earlier than expected. The interaction between maternal height, uterine load size and gestational age at birth strongly suggests the effect of uterine distention imposed by fetal growth on birth timing.
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| 4. |
- Bohman, Anton, et al.
(author)
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A family-based genome-wide association study of chronic rhinosinusitis with nasal polyps implicates several genes in the disease pathogenesis.
- 2017
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In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 12:12
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Journal article (peer-reviewed)abstract
- The pathogenesis of chronic rhinosinusitis with nasal polyps is largely unknown. Previous studies have given valuable information about genetic variants associated with this disease but much is still unexplained. Our goal was to identify genetic markers and genes associated with susceptibility to chronic rhinosinusitis with nasal polyps using a family-based genome-wide association study.427 patients (293 males and 134 females) with CRSwNP and 393 controls (175 males and 218 females) were recruited from several Swedish hospitals. SNP association values were generated using DFAM (implemented in PLINK) and Efficient Mixed Model Association eXpedited (EMMAX). Analyses of pathway enrichment, gene expression levels and expression quantitative trait loci were then performed in turn.None of the analysed SNPs reached genome wide significant association of 5.0 x 10-8. Pathway analyses using our top 1000 markers with the most significant association p-values resulted in 138 target genes. A comparison between our target genes and gene expression data from the NCBI Gene Expression Omnibus database showed significant overlap for 36 of these genes. Comparisons with data from expression quantitative trait loci showed the most skewed allelic distributions in cases with chronic rhinosinusitis with nasal polyps compared with controls for the genes HLCS, HLA-DRA, BICD2, VSIR and SLC5A1.Our study indicates that HLCS, HLA-DRA, BICD2, VSIR and SLC5A1 could be involved in the pathogenesis of chronic rhinosinusitis with nasal polyps. HLA-DRA has been associated with chronic rhinosinusitis with nasal polyps in previous studies and HLCS, BICD2, VSIR and SLC5A1 may be new targets for future research.
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| 5. |
- Bustamante, Mariona, et al.
(author)
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A genome-wide association meta-analysis of diarrhoeal disease in young children identifies FUT2 locus and provides plausible biological pathways.
- 2016
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In: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 25:18, s. 4127-4142
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Journal article (peer-reviewed)abstract
- More than a million childhood diarrhoeal episodes occur worldwide each year, and in developed countries a considerable part of them are caused by viral infections. In this study, we aimed to search for genetic variants associated with diarrhoeal disease in young children by meta-analyzing genome-wide association studies, and to elucidate plausible biological mechanisms. The study was conducted in the context of the Early Genetics and Lifecourse Epidemiology (EAGLE) consortium. Data about diarrhoeal disease in two time windows (around 1 year of age and around 2 years of age) was obtained via parental questionnaires, doctor interviews or medical records. Standard quality control and statistical tests were applied to the 1000 Genomes imputed genotypic data. The meta-analysis (N=5758) followed by replication (N=3784) identified a genome-wide significant association between rs8111874 and diarrhoea at age 1 year. Conditional analysis suggested that the causal variant could be rs601338 (W154X) in the FUT2 gene. Children with the A allele, which results in a truncated FUT2 protein, had lower risk of diarrhoea. FUT2 participates in the production of histo-blood group antigens and has previously been implicated in the susceptibility to infections, including Rotavirus and Norovirus Gene-set enrichment analysis suggested pathways related to the histo-blood group antigen production, and the regulation of ion transport and blood pressure. Among others, the gastrointestinal tract, and the immune and neuro-secretory systems were detected as relevant organs. In summary, this genome-wide association meta-analysis suggests the implication of the FUT2 gene in diarrhoeal disease in young children from the general population.
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| 6. |
- Helgeland, Øyvind, et al.
(author)
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Genome-wide association study reveals dynamic role of genetic variation in infant and early childhood growth.
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
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Journal article (peer-reviewed)abstract
- Infant and childhood growth are dynamic processes with large changes in BMI during development. By performing genome-wide association studies of BMI at 12 time points from birth to eight years (9286 children, 74,105 measurements) in the Norwegian Mother, Father, and Child Cohort Study, replicated in 5235 children, we identify a transient effect in the leptin receptor (LEPR) locus: no effect at birth, increasing effect in infancy, peaking at 6-12 months (rs2767486, P6m=2.0×10-21, β6m=0.16 sd-BMI), and little effect after age five. We identify a similar transient effect near the leptin gene (LEP), peaking at 1.5 years (rs10487505, P1.5y=1.3×10-8, β1.5y=0.079 sd-BMI). Both signals are protein quantitative trait loci for soluble-LEPR and LEP in plasma in adults independent from adult traits mapped to the respective genes, suggesting key roles of common variation in the leptin signaling pathway for healthy infant growth.
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| 7. |
- Juodakis, Julius, et al.
(author)
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Time-Variant Genetic Effects as a Cause for Preterm Birth: Insights from a Population of Maternal Cousins in Sweden.
- 2017
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In: G3: Genes Genomes Genetics. - : Oxford University Press (OUP). - 2160-1836. ; 7:4, s. 1349-1356
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Journal article (peer-reviewed)abstract
- Preterm delivery (PTD) is the leading cause of neonatal mortality worldwide, yet its etiology remains largely unexplained. We propose that the genetic factors controlling this trait could act in a nonuniform manner during pregnancy, with each factor having a unique "window of sensitivity." We test this hypothesis by modeling the distribution of gestational ages (GAs) observed in maternal cousins from the Swedish Medical Birth Register (MBR) (n = 35,541 pairs). The models were built using a time-to-event framework, with simulated genetic factors that increase the hazard of birth either uniformly across the pregnancy (constant effect) or only in particular windows (varying effect). By including various combinations of these factors, we obtained four models that were then optimized and compared. Best fit to the clinical data was observed when most of the factors had time-variant effects, independently of the number of loci simulated. Finally, power simulations were performed to assess the ability to discover varying-effect loci by usual methods for genome-wide association testing. We believe that the tools and concepts presented here should prove useful for the design of future studies of PTD and provide new insights into the genetic architecture determining human GA.
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| 8. |
- Liu, Xueping, et al.
(author)
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Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration.
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
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Journal article (peer-reviewed)abstract
- The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P=3.96×10-14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.
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| 9. |
- Middeldorp, C. M., et al.
(author)
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A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Pediatric Cohorts
- 2016
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In: Journal of the American Academy of Child and Adolescent Psychiatry. - : Elsevier BV. - 0890-8567. ; 55:10
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Journal article (peer-reviewed)abstract
- Objective The aims of this study were to elucidate the influence of common genetic variants on childhood attention-deficit/hyperactivity disorder (ADHD) symptoms, to identify genetic variants that explain its high heritability, and to investigate the genetic overlap of ADHD symptom scores with ADHD diagnosis. Method Within the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium, genome-wide single nucleotide polymorphisms (SNPs) and ADHD symptom scores were available for 17,666 children (<13 years of age) from nine population-based cohorts. SNP-based heritability was estimated in data from the three largest cohorts. Meta-analysis based on genome-wide association (GWA) analyses with SNPs was followed by gene-based association tests, and the overlap in results with a meta-analysis in the Psychiatric Genomics Consortium (PGC) case-control ADHD study was investigated. Results SNP-based heritability ranged from 5% to 34%, indicating that variation in common genetic variants influences ADHD symptom scores. The meta-analysis did not detect genome-wide significant SNPs, but three genes, lying close to each other with SNPs in high linkage disequilibrium (LD), showed a gene-wide significant association (p values between 1.46× 10−6 and 2.66× 10−6). One gene, WASL, is involved in neuronal development. Both SNP- and gene-based analyses indicated overlap with the PGC meta-analysis results with the genetic correlation estimated at 0.96. Conclusion The SNP-based heritability for ADHD symptom scores indicates a polygenic architecture, and genes involved in neurite outgrowth are possibly involved. Continuous and dichotomous measures of ADHD appear to assess a genetically common phenotype. A next step is to combine data from population-based and case-control cohorts in genetic association studies to increase sample size and to improve statistical power for identifying genetic variants. © 2016 American Academy of Child and Adolescent Psychiatry
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| 10. |
- Murray, Sarah R, et al.
(author)
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Geographical differences in preterm delivery rates in Sweden: a population-based cohort study.
- 2019
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In: Acta obstetricia et gynecologica Scandinavica. - : Wiley. - 1600-0412 .- 0001-6349. ; 98:1, s. 106-116
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Journal article (peer-reviewed)abstract
- Preterm delivery is a major global public health challenge. The objective of this study was to determine how the preterm delivery rates differ throughout a country of very high human-development index and to explore rural versus urban environmental and socio-economic factors which might be responsible for this variation.A population-based study was performed using data from the Swedish Medical Birth Register 1998 to 2013. Sweden was chosen as a model because of its validated routinely collected data and availability of individual social data. The total population comprised 1 335 802 singleton births. Multiple linear regression was used to adjust gestational age for known risk factors (maternal smoking, ethnicity, maternal education, maternal age, height, fetal gender, maternal diabetes, maternal hypertension and parity). A second and a third model were subsequently fitted allowing separate intercepts for each municipality (as fixed or random effects). Adjusted gestational ages were converted to preterm delivery rates and mapped to maternal residential municipalities. Additionally, the effects of six rural versus urban environmental and socio-economic factors on gestational age were tested using simple weighted linear regression.The study population preterm delivery rate was 4.12%. Marked differences from the overall preterm delivery rate were observed (rate estimates ranged from 1.73% - 6.31%). Statistical significance of this heterogeneity across municipalities was confirmed by a chi-squared test (p<0.001). Around 20% of the gestational age variance explained by the full model (after adjustment for known variables described above) could be attributed to municipality-level effects. In addition, gestational age was found to be longer in areas with higher fraction of built upon land and other urban features.After adjusting for known risk factors large geographical differences in rates of preterm delivery remain. Additional analyses to look at the effect of environmental and socio-economic factors on gestational age revealed an increased gestational age in urban areas. Future research strategies could focus on investigating the urbanity effect to try to explain the preterm delivery variation across countries with a very high human-development index. This article is protected by copyright. All rights reserved.
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| 11. |
- Papadopoulou, Eleni, et al.
(author)
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Maternal caffeine intake during pregnancy and childhood growth and overweight: results from a large Norwegian prospective observational cohort study.
- 2018
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In: BMJ open. - : BMJ. - 2044-6055. ; 8:3
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Journal article (peer-reviewed)abstract
- To study the association between maternal caffeine intake during pregnancy and the child's weight gain and overweight risk up to 8 years.Prospective nationwide pregnancy cohort.The Norwegian Mother and Child Cohort Study.A total of 50943 mothers recruited from 2002 to 2008 and their children, after singleton pregnancies, with information about average caffeine intake assessed at mid-pregnancy.Child's body size information at 11 age points from 6 weeks to 8 years. We defined excess growth in infancy as a WHO weight gain z-score of >0.67 from birth to age 1year, and overweight according to the International Obesity Task Force. We used a growth model to assess individual growth trajectories.Compared with pregnant women with low caffeine intake (<50mg/day, 46%), women with average (50-199mg/day, 44%), high (≥200-299mg/day, 7%) and very high (≥300mg/day, 3%) caffeine intakes had an increased risk of their child experiencing excess growth in infancy, after adjustment for confounders (OR=1.15, 95% CI 1.09 to 1.22, OR=1.30, 95%CI 1.16 to 1.45, OR=1.66, 95%CI 1.42 to 1.93, respectively). In utero exposure to any caffeine was associated with higher risk of overweight at age 3 years and 5 years, while the association persisted at 8 years, only for very high exposures. Any caffeine intake was associated with increased body mass index from infancy to childhood. Children prenatally exposed to caffeine intake >200mg/day had consistently higher weight. Very high caffeine exposures were associated with higher weight gain velocity from infancy to age 8 years.Any caffeine consumption during pregnancy is associated with a higher risk of excess infant growth and of childhood overweight, mainly at preschool ages. Maternal caffeine intake may modify the overall weight growth trajectory of the child from birth to 8 years. This study adds supporting evidence for the current advice to reduce caffeine intake during pregnancy.
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| 12. |
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| 13. |
- Smith, Jennifer A, et al.
(author)
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Genome-wide association study identifies 74 loci associated with educational attainment
- 2016
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In: Nature (London). - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 533:7604, s. 539-542
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Journal article (peer-reviewed)abstract
- Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
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| 14. |
- Zhang, Ge, et al.
(author)
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Assessing the Causal Relationship of Maternal Height on Birth Size and Gestational Age at Birth: A Mendelian Randomization Analysis.
- 2015
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In: PLoS medicine. - : Public Library of Science (PLoS). - 1549-1676. ; 12:8
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Journal article (peer-reviewed)abstract
- Observational epidemiological studies indicate that maternal height is associated with gestational age at birth and fetal growth measures (i.e., shorter mothers deliver infants at earlier gestational ages with lower birth weight and birth length). Different mechanisms have been postulated to explain these associations. This study aimed to investigate the casual relationships behind the strong association of maternal height with fetal growth measures (i.e., birth length and birth weight) and gestational age by a Mendelian randomization approach.
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| 15. |
- Zhang, G., et al.
(author)
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Genetic Associations with Gestational Duration and Spontaneous Preterm Birth
- 2017
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In: New England Journal of Medicine. - 0028-4793. ; 377:12, s. 1156-1167
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Journal article (peer-reviewed)abstract
- BACKGROUND Despite evidence that genetic factors contribute to the duration of gestation and the risk of preterm birth, robust associations with genetic variants have not been identified. We used large data sets that included the gestational duration to determine possible genetic associations. We performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (< 37 weeks) birth as a dichotomous outcome. We used samples from three Nordic data sets (involving a total of 8643 women) to test for replication of genomic loci that had significant genomewide association (P< 5.0x10(-8)) or an association with suggestive significance (P< 1.0x10(-6)) in the discovery set. In the discovery and replication data sets, four loci (EBF1, EEFSEC, AGTR2, and WNT4) were significantly associated with gestational duration. Functional analysis showed that an implicated variant in WNT4 alters the binding of the estrogen receptor. The association between variants in ADCY5 and RAP2C and gestational duration had suggestive significance in the discovery set and significant evidence of association in the replication sets; these variants also showed genomewide significance in a joint analysis. Common variants in EBF1, EEFSEC, and AGTR2 showed association with preterm birth with genomewide significance. An analysis of mother-infant dyads suggested that these variants act at the level of the maternal genome. In this genomewide association study, we found that variants at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were associated with gestational duration and variants at the EBF1, EEFSEC, and AGTR2 loci with preterm birth. Previously established roles of these genes in uterine development, maternal nutrition, and vascular control support their mechanistic involvement.
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| 16. |
- Zhang, Ge, et al.
(author)
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Genetic studies of gestational duration and preterm birth.
- 2018
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In: Best practice & research. Clinical obstetrics & gynaecology. - : Elsevier BV. - 1532-1932 .- 1521-6934. ; 52, s. 33-47
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Research review (peer-reviewed)abstract
- The fine control of birth timing is important to human survival and evolution. A key challenge in studying the mechanisms underlying the regulation of human birth timing is that human parturition is a unique to human event - animal models provide only limited information. The duration of gestation or the risk of preterm birth is a complex human trait under genetic control from both maternal and fetal genomes. Genomic discoveries through genome-wide association (GWA) studies would implicate relevant genes and pathways. Similar to other complex human traits, gestational duration is likely to be influenced by numerous genetic variants of small effect size. The detection of these small-effect genetic variants requires very large sample sizes. In addition, several practical and analytical challenges, in particular the involvement of both maternal and fetal genomes, further complicate the genetic studies of gestational duration and other pregnancy phenotypes. Despite these challenges, large-scale GWA studies have already identified several genomic loci associated with gestational duration or the risk of preterm birth. These genomic discoveries have revealed novel insights about the biology of human birth timing. Expanding genomic discoveries in larger datasets by more refined analytical approaches, together with the functional analysis of the identified genomic loci, will collectively elucidate the biological processes underlying the control of human birth timing.
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