| 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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