| 1. |
- 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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| 2. |
- Tsao, K., et al.
(författare)
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Effects of regional differences and demography in modelling foot-and-mouth disease in cattle at the national scale
- 2020
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Ingår i: Interface Focus. - : Royal Society Publishing. - 2042-8898 .- 2042-8901. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Foot-and-mouth disease (FMD) is a fast-spreading viral infection that can produce large and costly outbreaks in livestock populations. Transmission occurs at multiple spatial scales, as can the actions used to control outbreaks. The US cattle industry is spatially expansive, with heterogeneous distributions of animals and infrastructure. We have developed a model that incorporates the effects of scale for both disease transmission and control actions, applied here in simulating FMD outbreaks in US cattle. We simulated infection initiating in each of the 3049 counties in the contiguous US, 100 times per county. When initial infection was located in specific regions, large outbreaks were more likely to occur, driven by infrastructure and other demographic attributes such as premises clustering and number of cattle on premises. Sensitivity analyses suggest these attributes had more impact on outbreak metrics than the ranges of estimated disease parameter values. Additionally, although shipping accounted for a small percentage of overall transmission, areas receiving the most animal shipments tended to have other attributes that increase the probability of large outbreaks. The importance of including spatial and demographic heterogeneity in modelling outbreak trajectories and control actions is illustrated by specific regions consistently producing larger outbreaks than others. © 2019 The Author(s) Published by the Royal Society. All rights reserved.
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| 3. |
- 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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| 4. |
- Gilbertson, Kendra, et al.
(författare)
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The Importance of Livestock Demography and Infrastructure in Driving Foot and Mouth Disease Dynamics
- 2022
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Ingår i: Life. - : MDPI. - 2075-1729. ; 12:10
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Tidskriftsartikel (refereegranskat)abstract
- Transboundary animal diseases, such as foot and mouth disease (FMD) pose a significant and ongoing threat to global food security. Such diseases can produce large, spatially complex outbreaks. Mathematical models are often used to understand the spatio-temporal dynamics and create response plans for possible disease introductions. Model assumptions regarding transmission behavior of premises and movement patterns of livestock directly impact our understanding of the ecological drivers of outbreaks and how to best control them. Here, we investigate the impact that these assumptions have on model predictions of FMD outbreaks in the U.S. using models of livestock shipment networks and disease spread. We explore the impact of changing assumptions about premises transmission behavior, both by including within-herd dynamics, and by accounting for premises type and increasing the accuracy of shipment predictions. We find that the impact these assumptions have on outbreak predictions is less than the impact of the underlying livestock demography, but that they are important for investigating some response objectives, such as the impact on trade. These results suggest that demography is a key ecological driver of outbreaks and is critical for making robust predictions but that understanding management objectives is also important when making choices about model assumptions.
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| 5. |
- 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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| 6. |
- Larisch, Lisa-Marie, et al.
(författare)
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Effects of two randomized and controlled multi-component interventions focusing on 24-hour movement behavior among office workers: A compositional data analysis
- 2021
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Ingår i: International Journal of Environmental Research and Public Health. - : MDPI AG. - 1661-7827 .- 1660-4601. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Intervention studies aiming at changing movement behavior have usually not accounted for the compositional nature of time-use data. Compositional data analysis (CoDA) has been sug-gested as a useful strategy for analyzing such data. The aim of this study was to examine the effects of two multi-component interventions on 24-h movement behavior (using CoDA) and on cardi-orespiratory fitness among office workers; one focusing on reducing sedentariness and the other on increasing physical activity. Office workers (n = 263) were cluster randomized into one of two 6-month intervention groups, or a control group. Time spent in sedentary behavior, light-intensity, moderate and vigorous physical activity, and time in bed were assessed using accelerometers and diaries, both for 24 h in total, and for work and leisure time separately. Cardiorespiratory fitness was estimated using a sub-maximal cycle ergometer test. Intervention effects were analyzed using linear mixed models. No intervention effects were found, either for 24-h behaviors in total, or for work and leisure time behaviors separately. Cardiorespiratory fitness did not change significantly. Despite a thorough analysis of 24-h behaviors using CoDA, no intervention effects were found, nei-ther for behaviors in total, nor for work and leisure time behaviors separately. Cardiorespiratory fitness did not change significantly. Although the design of the multi-component interventions was based on theoretical frameworks, and included cognitive behavioral therapy counselling, which has been proven effective in other populations, issues related to implementation of and compliance with some intervention components may have led to the observed lack of intervention effect.
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| 7. |
- 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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| 8. |
- Sellman, Stefan, et al.
(författare)
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Realistic assumptions about spatial locations and clustering of premises matter for models of foot-and-mouth disease spread in the United States
- 2020
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Ingår i: PloS Computational Biology. - : PUBLIC LIBRARY SCIENCE. - 1553-734X .- 1553-7358. ; 16:2
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Tidskriftsartikel (refereegranskat)abstract
- Spatially explicit livestock disease models require demographic data for individual farms or premises. In the U.S., demographic data are only available aggregated at county or coarser scales, so disease models must rely on assumptions about how individual premises are distributed within counties. Here, we addressed the importance of realistic assumptions for this purpose. We compared modeling of foot and mouth disease (FMD) outbreaks using simple randomization of locations to premises configurations predicted by the Farm Location and Agricultural Production Simulator (FLAPS), which infers location based on features such as topography, land-cover, climate, and roads. We focused on three premises-level Susceptible-Exposed-Infectious-Removed models available from the literature, all using the same kernel approach but with different parameterizations and functional forms. By computing the basic reproductive number of the infection (R-0) for both FLAPS and randomized configurations, we investigated how spatial locations and clustering of premises affects outbreak predictions. Further, we performed stochastic simulations to evaluate if identified differences were consistent for later stages of an outbreak. Using Ripleys K to quantify clustering, we found that FLAPS configurations were substantially more clustered at the scales relevant for the implemented models, leading to a higher frequency of nearby premises compared to randomized configurations. As a result, R-0 was typically higher in FLAPS configurations, and the simulation study corroborated the pattern for later stages of outbreaks. Further, both R-0 and simulations exhibited substantial spatial heterogeneity in terms of differences between configurations. Thus, using realistic assumptions when de-aggregating locations based on available data can have a pronounced effect on epidemiological predictions, affecting if, where, and to what extent FMD may invade the population. We conclude that methods such as FLAPS should be preferred over randomization approaches.
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| 9. |
- 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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