| 1. |
- Beaumont, Robin N, et al.
(författare)
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Genome-wide association study of offspring birth weight in 86,577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics.
- 2018
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Ingår i: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 1460-2083 .- 0964-6906. ; 27:4, s. 742-756
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) of birth weight have focused on fetal genetics, while relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86,577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother-child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P<5x10-8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.
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| 2. |
- 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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| 3. |
- Sakabe, Noboru J, et al.
(författare)
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Transcriptome and regulatory maps of decidua-derived stromal cells inform gene discovery in preterm birth.
- 2020
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Ingår i: Science advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 6:49
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Tidskriftsartikel (refereegranskat)abstract
- While a genetic component of preterm birth (PTB) has long been recognized and recently mapped by genome-wide association studies (GWASs), the molecular determinants underlying PTB remain elusive. This stems in part from an incomplete availability of functional genomic annotations in human cell types relevant to pregnancy and PTB. We generated transcriptome (RNA-seq), epigenome (ChIP-seq of H3K27ac, H3K4me1, and H3K4me3 histone modifications), open chromatin (ATAC-seq), and chromatin interaction (promoter capture Hi-C) annotations of cultured primary decidua-derived mesenchymal stromal/stem cells and in vitro differentiated decidual stromal cells and developed a computational framework to integrate these functional annotations with results from a GWAS of gestational duration in 56,384 women. Using these resources, we uncovered additional loci associated with gestational duration and target genes of associated loci. Our strategy illustrates how functional annotations in pregnancy-relevant cell types aid in the experimental follow-up of GWAS for PTB and, likely, other pregnancy-related conditions.
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| 4. |
- Plunkett, Jevon, et al.
(författare)
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Primate-specific evolution of noncoding element insertion into PLA2G4C and human preterm birth
- 2010
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Ingår i: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- Background: The onset of birth in humans, like other apes, differs from non-primate mammals in its endocrine physiology. We hypothesize that higher primate-specific gene evolution may lead to these differences and target genes involved in human preterm birth, an area of global health significance. Methods: We performed a comparative genomics screen of highly conserved noncoding elements and identified PLA2G4C, a phospholipase A isoform involved in prostaglandin biosynthesis as human accelerated. To examine whether this gene demonstrating primate-specific evolution was associated with birth timing, we genotyped and analyzed 8 common single nucleotide polymorphisms (SNPs) in PLA2G4C in US Hispanic (n = 73 preterm, 292 control), US White (n = 147 preterm, 157 control) and US Black (n = 79 preterm, 166 control) mothers. Results: Detailed structural and phylogenic analysis of PLA2G4C suggested a short genomic element within the gene duplicated from a paralogous highly conserved element on chromosome 1 specifically in primates. SNPs rs8110925 and rs2307276 in US Hispanics and rs11564620 in US Whites were significant after correcting for multiple tests (p < 0.006). Additionally, rs11564620 (Thr360Pro) was associated with increased metabolite levels of the prostaglandin thromboxane in healthy individuals (p = 0.02), suggesting this variant may affect PLA2G4C activity. Conclusions: Our findings suggest that variation in PLA2G4C may influence preterm birth risk by increasing levels of prostaglandins, which are known to regulate labor.
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| 5. |
- 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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| 6. |
- 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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| 7. |
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| 8. |
- Huusko, Johanna M, et al.
(författare)
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Integrative genetic, genomic and transcriptomic analysis of heat shock protein and nuclear hormone receptor gene associations with spontaneous preterm birth.
- 2021
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Heat shock proteins are involved in the response to stress including activation of the immune response. Elevated circulating heat shock proteins are associated with spontaneous preterm birth (SPTB). Intracellular heat shock proteins act as multifunctional molecular chaperones that regulate activity of nuclear hormone receptors. Since SPTB has a significant genetic predisposition, our objective was to identify genetic and transcriptomic evidence of heat shock proteins and nuclear hormone receptors that may affect risk for SPTB. We investigated all 97 genes encoding members of the heat shock protein families and all 49 genes encoding nuclear hormone receptors for their potential role in SPTB susceptibility. We used multiple genetic and genomic datasets including genome-wide association studies (GWASs), whole-exome sequencing (WES), and placental transcriptomics to identify SPTB predisposing factors from the mother, infant, and placenta. There were multiple associations of heat shock protein and nuclear hormone receptor genes with SPTB. Several orthogonal datasets supported roles for SEC63, HSPA1L, SACS, RORA, and AR in susceptibility to SPTB. We propose that suppression of specific heat shock proteins promotes maintenance of pregnancy, whereas activation of specific heat shock protein mediated signaling may disturb maternal-fetal tolerance and promote labor.
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| 9. |
- Huusko, Johanna M, et al.
(författare)
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Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth.
- 2018
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 14:7
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Tidskriftsartikel (refereegranskat)abstract
- Preterm birth is a leading cause of morbidity and mortality in infants. Genetic and environmental factors play a role in the susceptibility to preterm birth, but despite many investigations, the genetic basis for preterm birth remain largely unknown. Our objective was to identify rare, possibly damaging, nucleotide variants in mothers from families with recurrent spontaneous preterm births (SPTB). DNA samples from 17 Finnish mothers who delivered at least one infant preterm were subjected to whole exome sequencing. All mothers were of northern Finnish origin and were from seven multiplex families. Additional replication samples of European origin consisted of 93 Danish sister pairs (and two sister triads), all with a history of a preterm delivery. Rare exonic variants (frequency <1%) were analyzed to identify genes and pathways likely to affect SPTB susceptibility. We identified rare, possibly damaging, variants in genes that were common to multiple affected individuals. The glucocorticoid receptor signaling pathway was the most significant (p<1.7e-8) with genes containing these variants in a subgroup of ten Finnish mothers, each having had 2-4 SPTBs. This pathway was replicated among the Danish sister pairs. A gene in this pathway, heat shock protein family A (Hsp70) member 1 like (HSPA1L), contains two likely damaging missense alleles that were found in four different Finnish families. One of the variants (rs34620296) had a higher frequency in cases compared to controls (0.0025 vs. 0.0010, p = 0.002) in a large preterm birth genome-wide association study (GWAS) consisting of mothers of general European ancestry. Sister pairs in replication samples also shared rare, likely damaging HSPA1L variants. Furthermore, in silico analysis predicted an additional phosphorylation site generated by rs34620296 that could potentially affect chaperone activity or HSPA1L protein stability. Finally, in vitro functional experiment showed a link between HSPA1L activity and decidualization. In conclusion, rare, likely damaging, variants in HSPA1L were observed in multiple families with recurrent SPTB.
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| 10. |
- 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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| 11. |
- Pasanen, Anu, et al.
(författare)
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Meta-analysis of genome-wide association studies of gestational duration and spontaneous preterm birth identifies new maternal risk loci.
- 2023
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Ingår i: PLoS genetics. - 1553-7404. ; 19:10
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Tidskriftsartikel (refereegranskat)abstract
- Preterm birth (<37 weeks of gestation) is a major cause of neonatal death and morbidity. Up to 40% of the variation in timing of birth results from genetic factors, mostly due to the maternal genome.We conducted a genome-wide meta-analysis of gestational duration and spontaneous preterm birth in 68,732 and 98,370 European mothers, respectively.The meta-analysis detected 15 loci associated with gestational duration, and four loci associated with preterm birth. Seven of the associated loci were novel. The loci mapped to several biologically plausible genes, for example HAND2 whose expression was previously shown to decrease during gestation, associated with gestational duration, and GC (Vitamin D-binding protein), associated with preterm birth. Downstream in silico-analysis suggested regulatory roles as underlying mechanisms for the associated loci. LD score regression found birth weight measures as the most strongly correlated traits, highlighting the unique nature of spontaneous preterm birth phenotype. Tissue expression and colocalization analysis revealed reproductive tissues and immune cell types as the most relevant sites of action.We report novel genetic risk loci that associate with preterm birth or gestational duration, and reproduce findings from previous genome-wide association studies. Altogether, our findings provide new insight into the genetic background of preterm birth. Better characterization of the causal genetic mechanisms will be important to public health as it could suggest new strategies to treat and prevent preterm birth.
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| 12. |
- Plunkett, Jevon, et al.
(författare)
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An Evolutionary Genomic Approach to Identify Genes Involved in Human Birth Timing
- 2011
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 7:4
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Tidskriftsartikel (refereegranskat)abstract
- Coordination of fetal maturation with birth timing is essential for mammalian reproduction. In humans, preterm birth is a disorder of profound global health significance. The signals initiating parturition in humans have remained elusive, due to divergence in physiological mechanisms between humans and model organisms typically studied. Because of relatively large human head size and narrow birth canal cross-sectional area compared to other primates, we hypothesized that genes involved in parturition would display accelerated evolution along the human and/or higher primate phylogenetic lineages to decrease the length of gestation and promote delivery of a smaller fetus that transits the birth canal more readily. Further, we tested whether current variation in such accelerated genes contributes to preterm birth risk. Evidence from allometric scaling of gestational age suggests human gestation has been shortened relative to other primates. Consistent with our hypothesis, many genes involved in reproduction show human acceleration in their coding or adjacent noncoding regions. We screened.8,400 SNPs in 150 human accelerated genes in 165 Finnish preterm and 163 control mothers for association with preterm birth. In this cohort, the most significant association was in FSHR, and 8 of the 10 most significant SNPs were in this gene. Further evidence for association of a linkage disequilibrium block of SNPs in FSHR, rs11686474, rs11680730, rs12473870, and rs1247381 was found in African Americans. By considering human acceleration, we identified a novel gene that may be associated with preterm birth, FSHR. We anticipate other human accelerated genes will similarly be associated with preterm birth risk and elucidate essential pathways for human parturition.
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| 13. |
- Plunkett, Jevon, et al.
(författare)
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Mother's Genome or Maternally-Inherited Genes Acting in the Fetus Influence Gestational Age in Familial Preterm Birth
- 2009
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Ingår i: Human Heredity. - : S. Karger AG. - 1423-0062 .- 0001-5652. ; 68:3, s. 209-219
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Tidskriftsartikel (refereegranskat)abstract
- Objective: While multiple lines of evidence suggest the importance of genetic contributors to risk of preterm birth, the nature of the genetic component has not been identified. We perform segregation analyses to identify the best fitting genetic model for gestational age, a quantitative proxy for preterm birth. Methods: Because either mother or infant can be considered the proband from a preterm delivery and there is evidence to suggest that genetic factors in either one or both may influence the trait, we performed segregation analysis for gestational age either attributed to the infant (infant's gestational age), or the mother (by averaging the gestational ages at which her children were delivered), using 96 multiplex preterm families. Results: These data lend further support to a genetic component contributing to birth timing since sporadic (i.e. no familial resemblance) and nontransmission (i.e. environmental factors alone contribute to gestational age) models are strongly rejected. Analyses of gestational age attributed to the infant support a model in which mother's genome and/or maternally-inherited genes acting in the fetus are largely responsible for birth timing, with a smaller contribution from the paternally-inherited alleles in the fetal genome. Conclusion: Our findings suggest that genetic influences on birth timing are important and likely complex. Copyright (C) 2009 S. Karger AG, Basel
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| 14. |
- 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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| 15. |
- 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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| 16. |
- Srivastava, Amit K, et al.
(författare)
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Recent Advances in Genomic Studies of Gestational Duration and Preterm Birth.
- 2024
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Ingår i: Clinics in perinatology. - 1557-9840. ; 51:2, s. 313-329
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Forskningsöversikt (refereegranskat)abstract
- Preterm birth (PTB) is the leading cause of infant mortality and morbidity. For several decades, extensive epidemiologic and genetic studies have highlighted the significant contribution of maternal and offspring genetic factors to PTB. This review discusses the challenges inherent in conventional genomic analyses of PTB and underscores the importance of adopting nonconventional approaches, such as analyzing the mother-child pair as a single analytical unit, to disentangle the intertwined maternal and fetal genetic influences. We elaborate on studies investigating PTB phenotypes through 3 levels of genetic analyses: single-variant, multi-variant, and genome-wide variants.
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| 17. |
- Wang, Li, et al.
(författare)
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A functional mechanism for a non-coding variant near AGTR2 associated with risk for preterm birth.
- 2023
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Ingår i: BMC medicine. - 1741-7015. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Preterm birth (PTB), defined as delivery before 37 gestational weeks, imposes significant public health burdens. A recent maternal genome-wide association study of spontaneous PTB identified a noncoding locus near the angiotensin II receptor type 2 (AGTR2) gene. Genotype-Tissue Expression data revealed that alleles associated with decreased AGTR2 expression in the uterus were linked to an increased risk of PTB and shortened gestational duration. We hypothesized that a causative variant in this locus modifies AGTR2 expression by altering transcription factor (TF) binding.To investigate this hypothesis, we performed bioinformatics analyses and functional characterizations at the implicated locus. Potential causal single nucleotide polymorphisms (SNPs) were prioritized, and allele-dependent binding of TFs was predicted. Reporter assays were employed to assess the enhancer activity of the top PTB-associated non-coding variant, rs7889204, and its impact on TF binding.Our analyses revealed that rs7889204, a top PTB-associated non-coding genetic variant is one of the strongest eQTLs for the AGTR2 gene in uterine tissue samples. We observed differential binding of CEBPB (CCAAT enhancer binding protein beta) and HOXA10 (homeobox A10) to the alleles of rs7889204. Reporter assays demonstrated decreased enhancer activity for the rs7889204 risk "C" allele.Collectively, these results demonstrate that decreased AGTR2 expression caused by reduced transcription factor binding increases the risk for PTB and suggest that enhancing AGTR2 activity may be a preventative measure in reducing PTB risk.
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| 18. |
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| 19. |
- Zhang, Ge, et al.
(författare)
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Genetic studies of gestational duration and preterm birth.
- 2018
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Ingår i: Best practice & research. Clinical obstetrics & gynaecology. - : Elsevier BV. - 1532-1932 .- 1521-6934. ; 52, s. 33-47
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Forskningsöversikt (refereegranskat)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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