| 1. |
- Laisk, Triin, et al.
(författare)
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The genetic architecture of sporadic and multiple consecutive miscarriage.
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P=3.2 × 10-8, odds ratio (OR)=1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF=6.4%, P=1.3 × 10-8, OR=1.7; rs143445068, MAF=0.8%, P=5.2 × 10-9, OR=3.4; rs183453668, MAF=0.5%, P=2.8 × 10-8, OR=3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.
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| 2. |
- Bacelis, Jonas, 1984
(författare)
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Genetic factors affecting pregnancy duration in humans
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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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| 3. |
- Bacelis, Jonas, 1984, et al.
(författare)
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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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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:8
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Tidskriftsartikel (refereegranskat)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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| 4. |
- Bacelis, Jonas, et al.
(författare)
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Uterine distention as a factor in birth timing: retrospective nationwide cohort study in Sweden.
- 2018
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 8:10
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Tidskriftsartikel (refereegranskat)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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| 5. |
- Bohman, Anton, et al.
(författare)
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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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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 12:12
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Tidskriftsartikel (refereegranskat)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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| 6. |
- Brantsæter, A. L., et al.
(författare)
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Diet matters, particularly in pregnancy – Results from MoBa studies of maternal diet and pregnancy outcomes
- 2014
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Ingår i: Norsk Epidemiologi. - 0803-2491. ; 24:1-2, s. 63-77
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Forskningsöversikt (refereegranskat)abstract
- Awareness that maternal diet may influence the outcome of pregnancy as well as the long-term health of mother and child has increased in recent years. A new food frequency questionnaire (FFQ) was developed and validated specifically for the Norwegian Mother and Child Cohort Study (MoBa). The MoBa FFQ is a semi-quantitative tool which covers the average intake of food, beverages and dietary supplements during the first 4 to 5 months of pregnancy. It includes questions about intakes of 255 foods and dishes and was used from 2002 onwards. Data assessed by the MoBa FFQ is available for 87,700 pregnancies. Numerous sub-studies have examined associations between dietary factors and health outcomes in MoBa. The aim of this paper is to summarize the results from 19 studies of maternal diet and pregnancy outcomes, which is the complete collection of studies based on the MoBa FFQ and published before September 2014. The overall research question is whether maternal diet – from single substances to dietary patterns – matters for pregnancy outcome. The pregnancy outcomes studied till now include birth size measures, infants being small and large for gestational age, pregnancy duration, preterm delivery, preeclampsia, as well as maternal gestational weight gain and postpartum weight retention. As a whole, the results from these studies corroborate that the current dietary recommendations to pregnant women are sound and that maternal diet during pregnancy is likely to contribute to reduce the risk of pregnancy complications including preterm birth, preeclampsia, and reduced foetal growth. The results provide supporting evidence for recommending pregnant women to consume vegetables, fruit, whole grain, fish, dairy, and water regularly and lower the intake of sugar sweetened beverages, processed meat products and salty snacks. The results showing negative impact of even low levels of environmental contaminants support the precautionary advice on consumption of foods containing these. New findings are that particularly lean fish explained the positive association between seafood intake and foetal growth, and the indications of a protective effect of probiotic and antimicrobial foods on pregnancy outcomes. This points to the importance of diet composition for a healthy gut flora and the body’s immune response. Although these studies are observational and cannot infer causality, the results identify diet as an important modifiable lifestyle factor, suggesting that healthy eating, defined as following the official recommendations, is particularly important in pregnancy.
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| 7. |
- Bustamante, Mariona, et al.
(författare)
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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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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 25:18, s. 4127-4142
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Tidskriftsartikel (refereegranskat)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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| 8. |
- Chen, Jing, et al.
(författare)
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Dissecting maternal and fetal genetic effects underlying the associations between maternal phenotypes, birth outcomes, and adult phenotypes: A mendelian-randomization and haplotype-based genetic score analysis in 10,734 mother-infant pairs.
- 2020
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Ingår i: PLoS medicine. - : Public Library of Science (PLoS). - 1549-1676. ; 17:8
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Tidskriftsartikel (refereegranskat)abstract
- Many maternal traits are associated with a neonate's gestational duration, birth weight, and birth length. These birth outcomes are subsequently associated with late-onset health conditions. The causal mechanisms and the relative contributions of maternal and fetal genetic effects behind these observed associations are unresolved.Based on 10,734 mother-infant duos of European ancestry from the UK, Northern Europe, Australia, and North America, we constructed haplotype genetic scores using single-nucleotide polymorphisms (SNPs) known to be associated with adult height, body mass index (BMI), blood pressure (BP), fasting plasma glucose (FPG), and type 2 diabetes (T2D). Using these scores as genetic instruments, we estimated the maternal and fetal genetic effects underlying the observed associations between maternal phenotypes and pregnancy outcomes. We also used infant-specific birth weight genetic scores as instrument and examined the effects of fetal growth on pregnancy outcomes, maternal BP, and glucose levels during pregnancy. The maternal nontransmitted haplotype score for height was significantly associated with gestational duration (p = 2.2 × 10-4). Both maternal and paternal transmitted height haplotype scores were highly significantly associated with birth weight and length (p < 1 × 10-17). The maternal transmitted BMI scores were associated with birth weight with a significant maternal effect (p = 1.6 × 10-4). Both maternal and paternal transmitted BP scores were negatively associated with birth weight with a significant fetal effect (p = 9.4 × 10-3), whereas BP alleles were significantly associated with gestational duration and preterm birth through maternal effects (p = 3.3 × 10-2 and p = 4.5 × 10-3, respectively). The nontransmitted haplotype score for FPG was strongly associated with birth weight (p = 4.7 × 10-6); however, the glucose-increasing alleles in the fetus were associated with reduced birth weight through a fetal effect (p = 2.2 × 10-3). The haplotype scores for T2D were associated with birth weight in a similar way but with a weaker maternal effect (p = 6.4 × 10-3) and a stronger fetal effect (p = 1.3 × 10-5). The paternal transmitted birth weight score was significantly associated with reduced gestational duration (p = 1.8 × 10-4) and increased maternal systolic BP during pregnancy (p = 2.2 × 10-2). The major limitations of the study include missing and heterogenous phenotype data in some data sets and different instrumental strength of genetic scores for different phenotypic traits.We found that both maternal height and fetal growth are important factors in shaping the duration of gestation: genetically elevated maternal height is associated with longer gestational duration, whereas alleles that increase fetal growth are associated with shorter gestational duration. Fetal growth is influenced by both maternal and fetal effects and can reciprocally influence maternal phenotypes: taller maternal stature, higher maternal BMI, and higher maternal blood glucose are associated with larger birth size through maternal effects; in the fetus, the height- and metabolic-risk-increasing alleles are associated with increased and decreased birth size, respectively; alleles raising birth weight in the fetus are associated with shorter gestational duration and higher maternal BP. These maternal and fetal genetic effects may explain the observed associations between the studied maternal phenotypes and birth outcomes, as well as the life-course associations between these birth outcomes and adult phenotypes.
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| 9. |
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| 10. |
- Helgeland, Øyvind, et al.
(författare)
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Characterization of the genetic architecture of infant and early childhood body mass index.
- 2022
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 4:3, s. 344-358
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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.
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| 11. |
- Helgeland, Øyvind, et al.
(författare)
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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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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
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Tidskriftsartikel (refereegranskat)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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| 12. |
- Juodakis, Julius, et al.
(författare)
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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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Ingår i: G3: Genes Genomes Genetics. - : Oxford University Press (OUP). - 2160-1836. ; 7:4, s. 1349-1356
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Tidskriftsartikel (refereegranskat)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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| 13. |
- Liu, Xueping, et al.
(författare)
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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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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
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Tidskriftsartikel (refereegranskat)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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| 14. |
- Middeldorp, C. M., et al.
(författare)
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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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Ingår i: Journal of the American Academy of Child and Adolescent Psychiatry. - : Elsevier BV. - 0890-8567. ; 55:10
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Tidskriftsartikel (refereegranskat)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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| 15. |
- Murray, Sarah R, et al.
(författare)
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Geographical differences in preterm delivery rates in Sweden: a population-based cohort study.
- 2019
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Ingår i: Acta obstetricia et gynecologica Scandinavica. - : Wiley. - 1600-0412 .- 0001-6349. ; 98:1, s. 106-116
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Tidskriftsartikel (refereegranskat)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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| 16. |
- Papadopoulou, Eleni, et al.
(författare)
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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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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 8:3
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Tidskriftsartikel (refereegranskat)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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| 17. |
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| 18. |
- Sengpiel, Verena, 1977, et al.
(författare)
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Folic acid supplementation, dietary folate intake during pregnancy and risk for spontaneous preterm delivery: a prospective observational cohort study
- 2014
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Ingår i: BMC Pregnancy and Childbirth. - : Springer Science and Business Media LLC. - 1471-2393. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Health authorities in numerous countries recommend periconceptional folic acid supplementation to prevent neural tube defects. The objective of this study was to examine the association of dietary folate intake and folic acid supplementation during different periods of pregnancy with the risk of spontaneous preterm delivery (PTD).MethodsThe Norwegian Mother and Child Cohort Study is a population-based prospective cohort study. A total of 66,014 women with singleton pregnancies resulting in live births in 2002¿2009 were included. Folic acid supplementation was self-reported from 26 weeks before pregnancy until pregnancy week 24. At gestational week 22, the women completed a food frequency questionnaire, which allowed the calculation of their average total folate intake from foods and supplements for the first 4¿5 months of pregnancy. Spontaneous PTD was defined as the spontaneous onset of delivery between weeks 22+0 and 36+6 (n = 1,755).ResultsThe median total folate intake was 313 ¿g/d (interquartile range IQR 167¿558) in the overall population and 530 ¿g/d (IQR 355¿636) in the supplement users. Eighty-five percent reported any folic acid supplementation from <8 weeks before to 24 weeks after conception while only 44% initiated folic acid supplementation before pregnancy. Cox regression analysis showed that the amount of dietary folate intake (hazard ratio HR 1.00; confidence interval 95% CI 0.61-1.65) and supplemental folate intake (HR 1.00; CI 1.00-1.00) was not significantly associated with the risk of PTD. The initiation of folic acid supplementation more than 8 weeks before conception was associated with an increased risk for spontaneous PTD (HR 1.18; CI 1.05-1.32) compared to no folic acid supplementation preconception. There was no significant association with PTD when supplementation was initiated within 8 weeks preconception (HR 0.99; CI 0.87-1.13). All analyses were adjusted for maternal characteristics and socioeconomic, health and dietary variables.ConclusionsOur findings do not support a protective effect of dietary folate intake or folic acid supplementation on spontaneous PTD. Preconceptional folic acid supplementation starting more than 8 weeks before conception was associated with an increased risk of spontaneous PTD. These results require further investigation before discussing an expansion of folic acid supplementation guidelines.
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| 19. |
- Sengpiel, Verena, 1977, et al.
(författare)
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Maternal caffeine intake during pregnancy is associated with birth weight but not with gestational length: results from a large prospective observational cohort study.
- 2013
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Ingår i: BMC Medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Pregnant women consume caffeine daily. The aim of this study was to examine the association between maternal caffeine intake from different sources and (a) gestational length, particularly the risk for spontaneous preterm delivery (PTD), and (b) birth weight (BW) and the baby being small for gestational age (SGA). METHODS: This study is based on the Norwegian Mother and Child Cohort Study conducted by the Norwegian Institute of Public Health. A total of 59,123 women with uncomplicated pregnancies giving birth to a live singleton were identified. Caffeine intake from different sources was self-reported at gestational weeks 17, 22 and 30. Spontaneous PTD was defined as spontaneous onset of delivery between 22+0 and 36+6 weeks (n = 1,451). As there is no consensus, SGA was defined according to ultrasound-based (Marsal, n = 856), population-based (Skjaerven, n = 4,503) and customized (Gardosi, n = 4,733) growth curves. RESULTS: The main caffeine source was coffee, but tea and chocolate were the main sources in women with low caffeine intake. Median pre-pregnancy caffeine intake was 126 mg/day (IQR 40 to 254), 44 mg/day (13 to 104) at gestational week 17 and 62 mg/day (21 to 130) at gestational week 30. Coffee caffeine, but not caffeine from other sources, was associated with prolonged gestation (8 h/100 mg/day, P <10-7). Neither total nor coffee caffeine was associated with spontaneous PTD risk. Caffeine intake from different sources, measured repeatedly during pregnancy, was associated with lower BW (Marsal -28 g, Skjaerven -25 g, Gardosi -21 g per 100 mg/day additional total caffeine for a baby with expected BW 3,600 g, P <10-25). Caffeine intake of 200 to 300 mg/day increased the odds for SGA (OR Marsal 1.62, Skjaerven 1.44, Gardosi 1.27, P <0.05), compared to 0 to 50 mg/day. CONCLUSIONS: Coffee, but not caffeine, consumption was associated with marginally increased gestational length but not with spontaneous PTD risk. Caffeine intake was consistently associated with decreased BW and increased odds of SGA. The association was strengthened by concordant results for caffeine sources, time of survey and different SGA definitions. This might have clinical implications as even caffeine consumption below the recommended maximum (200 mg/day in the Nordic countries and USA, 300 mg/day according to the World Health Organization (WHO)) was associated with increased risk for SGA.
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| 20. |
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| 21. |
- Smith, Jennifer A, et al.
(författare)
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Genome-wide association study identifies 74 loci associated with educational attainment
- 2016
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Ingår i: Nature (London). - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 533:7604, s. 539-542
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Tidskriftsartikel (refereegranskat)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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| 22. |
- Solé Navais, Pol, et al.
(författare)
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Autozygosity mapping and time-to-spontaneous delivery in Norwegian parent-offspring trios.
- 2020
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 29:23, s. 3845-3858
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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.
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| 23. |
- Solé Navais, Pol, et al.
(författare)
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Genetic effects on the timing of parturition and links to fetal birth weight.
- 2023
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Ingår i: Nature genetics. - 1546-1718. ; 55:4, s. 559-567
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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.
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| 24. |
- Vogelezang, Suzanne, et al.
(författare)
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Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.
- 2020
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 16:10
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Tidskriftsartikel (refereegranskat)abstract
- The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.
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| 25. |
- Zhang, Ge, et al.
(författare)
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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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Ingår i: PLoS medicine. - : Public Library of Science (PLoS). - 1549-1676. ; 12:8
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Tidskriftsartikel (refereegranskat)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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