| 1. |
- 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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| 2. |
- 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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| 3. |
- 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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| 4. |
- 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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| 5. |
- 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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| 6. |
- Hiltunen, Anniina E., et al.
(författare)
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Variant in NHLRC2 leads to increased hnRNP C2 in developing neurons and the hippocampus of a mouse model of FINCA disease
- 2020
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Ingår i: Molecular Medicine. - : SPRINGER. - 1076-1551 .- 1528-3658. ; 26:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundFINCA disease is a pediatric cerebropulmonary disease caused by variants in the NHL repeat-containing 2 (NHLRC2) gene. Neurological symptoms are among the first manifestations of FINCA disease, but the consequences of NHLRC2 deficiency in the central nervous system are currently unexplored.MethodsThe orthologous mouse gene is essential for development, and its complete loss leads to early embryonic lethality. In the current study, we used CRISPR/Cas9 to generate an Nhlrc2 knockin (KI) mouse line, harboring the FINCA patient missense mutation (c.442G>T, p.Asp148Tyr). A FINCA mouse model, resembling the compound heterozygote genotype of FINCA patients, was obtained by crossing the KI and Nhlrc2 knockout mouse lines. To reveal NHLRC2-interacting proteins in developing neurons, we compared cortical neuronal precursor cells of E13.5 FINCA and wild-type mouse embryos by two-dimensional difference gel electrophoresis.ResultsDespite the significant decrease in NHLRC2, the mice did not develop severe early onset multiorgan disease in either sex. We discovered 19 altered proteins in FINCA neuronal precursor cells; several of which are involved in vesicular transport pathways and actin dynamics which have been previously reported in other cell types including human to have an association with dysfunctional NHLRC2. Interestingly, isoform C2 of hnRNP C1/C2 was significantly increased in both developing neurons and the hippocampus of adult female FINCA mice, connecting NHLRC2 dysfunction with accumulation of RNA binding protein.ConclusionsWe describe here the first NHLRC2-deficient mouse model to overcome embryonic lethality, enabling further studies on predisposing and causative mechanisms behind FINCA disease. Our novel findings suggest that disrupted RNA metabolism may contribute to the neurodegeneration observed in FINCA patients.
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| 7. |
- Kleberg, Johan L., et al.
(författare)
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No transfer of arousal from other’s eyes in Williams syndrome
- 2023
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Typically developing humans automatically synchronize their arousal levels, resulting in pupillary contagion, or spontaneous adaptation of pupil size to that of others. This phenomenon emerges in infancy and is believed to facilitate social interaction. Williams syndrome (WS) is a genetic condition characterized by a hyper-social personality and social interaction challenges. Pupillary contagion was examined in individuals with WS (n = 44), age-parallel-matched typically developing children and adults (n = 65), and infants (n = 79). Bayesian statistics were used. As a group, people with WS did not show pupillary contagion (Bayes factors supporting the null: 25–50) whereas control groups did. This suggests a very early emerging atypical developmental trajectory. In WS, higher pupillary contagion was associated with lower autistic symptoms of social communication. Diminished synchronization of arousal may explain why individuals with WS have social challenges, whereas synchronization of arousal is not a necessary correlate of high social motivation.
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| 8. |
- 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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| 9. |
- Sellman, Stefan, et al.
(författare)
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Modeling nation-wide US swine movement networks at the resolution of the individual premises
- 2022
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Ingår i: Epidemics. - : Elsevier. - 1755-4365 .- 1878-0067. ; 41
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Tidskriftsartikel (refereegranskat)abstract
- The spread of infectious livestock diseases is a major cause for concern in modern agricultural systems. In the dynamics of the transmission of such diseases, movements of livestock between herds play an important role. When constructing mathematical models used for activities such as forecasting epidemic development, evaluating mitigation strategies, or determining important targets for disease surveillance, including between -premises shipments is often a necessity. In the United States (U.S.), livestock shipment data is not routinely collected, and when it is, it is not readily available and mostly concerned with between-state shipments. To bridge this gap in knowledge and provide insight into the complete livestock shipment network structure, we have developed the U.S. Animal Movement Model (USAMM). Previously, USAMM has only existed for cattle shipments, but here we present a version for domestic swine. This new version of USAMM consists of a Bayesian model fit to premises demography, county-level livestock industry variables, and two limited data sets of between-state swine movements. The model scales up the data to simulate nation-wide networks of both within-and between-state shipments at the level of individual premises. Here we describe this shipment model in detail and subsequently explore its usefulness with a rudimentary predictive model of the prevalence of porcine epidemic diarrhea virus (PEDv) across the U.S. Additionally, in order to promote further research on livestock disease and other topics involving the movements of swine in the U.S., we also make 250 synthetic premises-level swine shipment networks with complete coverage of the entire conterminous U.S. freely available to the research community as a useful surrogate for the absent shipment data.
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| 10. |
- Sellman, Stefan, et al.
(författare)
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Modeling US cattle movements until the cows come home: Who ships to whom and how many?
- 2022
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Ingår i: Computers and Electronics in Agriculture. - : ELSEVIER SCI LTD. - 0168-1699 .- 1872-7107. ; 203
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Tidskriftsartikel (refereegranskat)abstract
- Livestock movements between agricultural premises is an important pathway for the spread of infectious disease. Data providing details about the origin and destination of shipments, as well as information about the shipment size is an important component of computer models used to formulate mitigation strategies and design surveillance programs. The United States (U.S.) currently lacks a comprehensive database of farm animal shipments, which hinders such efforts. With the U.S. Animal Movement Model (USAMM), earlier work has successfully scaled up from limited data based on interstate certificates of veterinary inspection (CVI) to comprehensive county-level shipment networks at the national scale. In this work, we present three major improvements to earlier versions of USAMM: (1) increased resolution of the model and simulated networks to the level of individual premises; (2) predictions of shipment sizes; (3) taking into account the types and herd sizes of the premises. We fitted parameters in a Bayesian framework to two sets of CVI data consisting of sub-samples of one years between-state beef and dairy shipments. Through posterior predictive simulation, we then created 1,000 synthetic beef and dairy networks, which we make publicly available to support livestock disease modeling. The simulated networks were validated against summary statistics of the training data as well as out-of-sample CVI data from subsequent years. This new development opens up the possibility of using USAMM in a broader spectrum of applications where information about shipment size and premises identity is necessary and gives novel insights into the U.S. cattle shipment network.
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| 11. |
- Wijk, Katarina, et al.
(författare)
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Sense of Coherence, Health, Well-Being, and Work Satisfaction before and after Implementing Activity-Based Workplaces
- 2020
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Ingår i: International Journal of Environmental Research and Public Health. - : MDPI. - 1661-7827 .- 1660-4601. ; 17:14
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Tidskriftsartikel (refereegranskat)abstract
- Activity-based workplaces (ABWs) are implemented with possible implications for health, well-being, and work satisfaction in the workplace. Drawing on the theoretical framework, i.e., sense of coherence (SOC), the aim was to investigate how indicators pf SOC-meaningfulness, manageability and comprehensibility-are associated with, or function as barriers or facilitators for, health, well-being and work satisfaction during relocation to an ABW. We followed the implementation of ABWs at the Swedish Transport Administration (2018-2019). Questionnaires were administered before (n= 536), 3 months (n= 409) and 9 months (n= 373) after relocation. Focus group interviews (15) were conducted before and after. Data were analyzed using repeated measures ANOVA and content analysis. Relocation to an ABW was associated with a reduced work satisfaction (physicalp< 0.001; psychosocialp< 0.001), and minor changes in health and occupational well-being during relocation (p> 0.001). The reduction in work satisfaction was smaller among employees with high meaningfulness in the relocation process (p< 0.001). All SOC indicators were positively associated with overall health, well-being and work satisfaction (p< 0.001). Interviews suggested that meaningfulness was facilitated by participation in the presented activities and that communication before relocation was crucial. The results indicate that organizations implementing ABWs should promote perceived meaningfulness in the process to mitigate possible declines in satisfaction with the physical and psychosocial work environment.
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