| 1. |
- Basu, Swaraj, et al.
(författare)
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Accurate mapping of mitochondrial DNA deletions and duplications using deep sequencing
- 2020
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 16:12
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Tidskriftsartikel (refereegranskat)abstract
- Deletions and duplications in mitochondrial DNA (mtDNA) cause mitochondrial disease and accumulate in conditions such as cancer and age-related disorders, but validated high-throughput methodology that can readily detect and discriminate between these two types of events is lacking. Here we establish a computational method, MitoSAlt, for accurate identification, quantification and visualization of mtDNA deletions and duplications from genomic sequencing data. Our method was tested on simulated sequencing reads and human patient samples with single deletions and duplications to verify its accuracy. Application to mouse models of mtDNA maintenance disease demonstrated the ability to detect deletions and duplications even at low levels of heteroplasmy. Author summary Deletions in the mitochondrial genome cause a wide variety of rare disorders, but are also linked to more common conditions such as neurodegeneration, diabetes type 2, and the normal ageing process. There is also a growing awareness that mtDNA duplications, which are also relevant for human disease, may be more common than previously thought. Despite their clinical importance, our current knowledge about the abundance, characteristics and diversity of mtDNA deletions and duplications is fragmented, and based to large extent on a limited view provided by traditional low-throughput analyses. Here, we describe a bioinformatics method, MitoSAlt, that can accurately map and classify mtDNA deletions and duplications using high-throughput sequencing. Application of this methodology to mouse models of mitochondrial deficiencies revealed a large number of duplications, suggesting that these may previously have been underestimated.
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| 2. |
- Berndt, Sonja I., et al.
(författare)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
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Tidskriftsartikel (refereegranskat)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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| 3. |
- Engström, Katarina, 1956, et al.
(författare)
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The myxoid/round cell liposarcoma fusion oncogene FUS-DDIT3 and the normal DDIT3 induce a liposarcoma phenotype in transfected human fibrosarcoma cells.
- 2006
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Ingår i: The American journal of pathology. - : Elsevier BV. - 0002-9440 .- 1525-2191. ; 168:5, s. 1642-53
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Tidskriftsartikel (refereegranskat)abstract
- Myxoid/round cell liposarcoma (MLS/RCLS) is the most common subtype of liposarcoma. Most MLS/RCLS carry a t(12;16) translocation, resulting in a FUS-DDIT3 fusion gene. We investigated the role of the FUS-DDIT3 fusion in the development of MLS/RCLS in FUS-DDIT3- and DDIT3-transfected human HT1080 sarcoma cells. Cells expressing FUS-DDIT3 and DDIT3 grew as liposarcomas in severe combined immunodeficient mice and exhibited a capillary network morphology that was similar to networks of MLS/RCLS. Microarray-based comparison of HT1080, the transfected cells, and an MLS/RCLS-derived cell line showed that the FUS-DDIT3- and DDIT3-transfected variants shifted toward an MLS/RCLS-like expression pattern. DDIT3-transfected cells responded in vitro to adipogenic factors by accumulation of fat and transformation to a lipoblast-like morphology. In conclusion, because the fusion oncogene FUS-DDIT3 and the normal DDIT3 induce a liposarcoma phenotype when expressed in a primitive sarcoma cell line, MLS/RCLS may develop from cell types other than preadipocytes. This may explain the preferential occurrence of MLS/RCLS in nonadipose tissues. In addition, development of lipoblasts and the typical MLS/RCLS capillary network could be an effect of the DDIT3 transcription factor partner of the fusion oncogene.
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| 4. |
- Gustafsson, Jasmine, et al.
(författare)
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Parental Mental Well-Being and Frequency of Adult-Child Nature Visits : The Mediating Roles of Parents' Perceived Barriers
- 2021
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Ingår i: International Journal of Environmental Research and Public Health. - : MDPI. - 1661-7827 .- 1660-4601. ; 18:13
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Tidskriftsartikel (refereegranskat)abstract
- Regular access to green space has been shown to provide several health benefits for children. However, children today spend less time outdoors. Thus, it has become important to understand what drives and limits children's activities in nature. Based on a Finnish online survey of 1463 parents of children aged 2-7 conducted in 2019, the current study examined parents' perceived barriers to visiting nature with their children. It also examined how parental mental well-being is related to families' frequency of nature visits, and whether this association is mediated by different categories of parents' perceived barriers. Eleven out of 12 barriers were largely perceived by parents as reasons that did not prevent them from visiting nature with their children. Next, factor analysis indicated a three-factor solution to the barriers. The results of a multiple mediation analysis showed that better parental mental well-being was associated with more frequent adult-child nature visits, and this relationship was partially mediated by a "lack of competence and logistics" and a "lack of time and interest", but not by "insecurity and fear". The results indicated that parents with poor mental well-being were more likely to perceive barriers to visiting nature, which in turn appeared to be related to a higher likelihood of having children who visited nature less frequently.
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| 5. |
- Gustafsson, Jasmine, et al.
(författare)
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Role of early childhood educators' demographic characteristics and perceived work environment in implementation of a preschool health promotion intervention
- 2023
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Ingår i: Archives of Public Health. - : Springer Nature. - 0778-7367 .- 2049-3258. ; 81:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Research has indicated that the effectiveness of intervention programs is affected by how well these programs are implemented, but key gaps remain in our understanding of the factors that promote or inhibit implementation. This study examined how demographic characteristics and perceived work environment among early childhood educators were associated with implementation outcomes of the Increased Health and Wellbeing in Preschools (DAGIS) intervention, which was conducted as a cluster randomized trial.Methods: Participants included 101 educators from 32 intervention preschool classrooms. Data were analyzed at the classroom level, as the DAGIS intervention was delivered in preschool classrooms consisting of several educators instead of individual implementers. Linear regression was used to estimate the associations of educators' demographic characteristics and perceived work environment with different aspects of implementation (i.e., dose delivered; dose received - exposure; dose received - satisfaction; and perceived quality, as well as a total sum score based on these four dimensions). Municipality was controlled in the adjusted models.Results: Findings indicated that having a higher proportion of educators with a Bachelor's or Master's degree in education within the classroom was associated with higher dose received - exposure and higher total degree of implementation, and the significance of the models was unaffected by adjustment for municipality. Moreover, having a higher proportion of educators younger than 35 years within the classroom was associated with higher dose received - exposure. However, the association was non-significant when adjusted for municipality. No other educator factor (i.e., work experience in years and perceived support from coworkers, group work, and innovative climate) predicted implementation outcomes.Conclusions: Higher educational attainment and younger age among educators at the classroom level were associated with higher scores for some of the implementation outcomes. Educators' work experience in years at the current preschool and in early childhood education, support from coworkers, group work, and innovative climate were not significantly associated with any implementation outcomes. Future research should explore ways to improve educators' implementation of interventions aimed at promoting children's health behaviors.
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| 6. |
- Hammarström, Anne, et al.
(författare)
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Central gender theoretical concepts in health research : the state of the art
- 2014
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Ingår i: Journal of Epidemiology and Community Health. - : BMJ Publishing Group Ltd. - 0143-005X .- 1470-2738. ; 68:2, s. 185-190
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Tidskriftsartikel (refereegranskat)abstract
- Despite increasing awareness of the importance of gender perspectives in health science, there is conceptual confusion regarding the meaning and the use of central gender theoretical concepts. We argue that it is essential to clarify how central concepts are used within gender theory and how to apply them to health research. We identify six gender theoretical concepts as central and interlinked-but problematic and ambiguous in health science: sex, gender, intersectionality, embodiment, gender equity and gender equality. Our recommendations are that: the concepts sex and gender can benefit from a gender relational theoretical approach (ie, a focus on social processes and structures) but with additional attention to the interrelations between sex and gender; intersectionality should go beyond additive analyses to study complex intersections between the major factors which potentially influence health and ensure that gendered power relations and social context are included; we need to be aware of the various meanings given to embodiment, which achieve an integration of gender and health and attend to different levels of analyses to varying degrees; and appreciate that gender equality concerns absence of discrimination between women and men while gender equity focuses on women's and men's health needs, whether similar or different. We conclude that there is a constant need to justify and clarify our use of these concepts in order to advance gender theoretical development. Our analysis is an invitation for dialogue but also a call to make more effective use of the knowledge base which has already developed among gender theorists in health sciences in the manner proposed in this paper.
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| 7. |
- Hedberg, Carola, 1969, et al.
(författare)
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Hereditary myopathy with early respiratory failure is associated with misfolding of the titin fibronectin III 119 subdomain
- 2014
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Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966. ; 24:5, s. 373-379
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Tidskriftsartikel (refereegranskat)abstract
- Hereditary myopathy with early respiratory failure is a rare disease with muscle weakness and respiratory failure as early symptoms. Muscle pathology is characterized by the presence of multiple cytoplasmic bodies and other protein aggregates in muscle fibers. The disease is associated with mutations in the titin gene (TTN). All patients harbor mutations located in exon 343 in the TTN gene that codes for the fibronectin III domain 119 (FN3 119) in the 10th motif of the 11-element motif A-band super-repeat. We investigated how such disease-causing mutations affect the biochemical behavior of this titin domain. All five disease-causing amino acid changes analyzed by us (p.P30068R, p.C30071R, p.W30088R, p.W30088C and p.P30091L) resulted in impaired FN3 119 domain solubility. In contrast, amino acid changes associated with common SNPs (p.V30076I, p.R30107C and p.S30125F) did not have this effect. In silica analyses further support the notion that disease-causing mutations impair proper folding of the FN3 119 domain. The results suggest that hereditary myopathy with early respiratory failure is caused by defective protein folding. (C) 2014 Elsevier B.V. All rights reserved.
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| 8. |
- Justice, Anne E., et al.
(författare)
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Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 452-469
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Tidskriftsartikel (refereegranskat)abstract
- Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF >= 5%) and nine low-frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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| 9. |
- Kanoni, Stavroula, et al.
(författare)
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Total zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant : a 14-cohort meta-analysis
- 2011
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Ingår i: Diabetes. - Alexandria : American diabetes association. - 0012-1797 .- 1939-327X. ; 60:9, s. 2407-2416
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for β-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants.RESEARCH DESIGN AND METHODS We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes.RESULTS We observed a significant association of total zinc intake with lower fasting glucose levels (β-coefficient ± SE per 1 mg/day of zinc intake: -0.0012 ± 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (β-coefficient ± SE per A allele for 1 mg/day of greater total zinc intake: -0.0017 ± 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant.CONCLUSIONS Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels.
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