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- Franks, P. W., et al.
(författare)
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Technological readiness and implementation of genomic-driven precision medicine for complex diseases
- 2021
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 290:3, s. 602-620
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Forskningsöversikt (refereegranskat)abstract
- The fields of human genetics and genomics have generated considerable knowledge about the mechanistic basis of many diseases. Genomic approaches to diagnosis, prognostication, prevention and treatment - genomic-driven precision medicine (GDPM) - may help optimize medical practice. Here, we provide a comprehensive review of GDPM of complex diseases across major medical specialties. We focus on technological readiness: how rapidly a test can be implemented into health care. Although these areas of medicine are diverse, key similarities exist across almost all areas. Many medical areas have, within their standards of care, at least one GDPM test for a genetic variant of strong effect that aids the identification/diagnosis of a more homogeneous subset within a larger disease group or identifies a subset with different therapeutic requirements. However, for almost all complex diseases, the majority of patients do not carry established single-gene mutations with large effects. Thus, research is underway that seeks to determine the polygenic basis of many complex diseases. Nevertheless, most complex diseases are caused by the interplay of genetic, behavioural and environmental risk factors, which will likely necessitate models for prediction and diagnosis that incorporate genetic and non-genetic data.
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- Howe, LJ, et al.
(författare)
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Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects
- 2022
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:65, s. 581-
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Tidskriftsartikel (refereegranskat)abstract
- Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.
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- Marttila, S, et al.
(författare)
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Methylation status of VTRNA2-1/nc886 is stable across populations, monozygotic twin pairs and in majority of tissues
- 2022
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Ingår i: Epigenomics. - : Future Medicine Ltd. - 1750-192X .- 1750-1911. ; 14:18, s. 1105-1124
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Tidskriftsartikel (refereegranskat)abstract
- Aims & methods: The aim of this study was to characterize the methylation level of a polymorphically imprinted gene, VTRNA2-1/ nc886, in human populations and somatic tissues.48 datasets, consisting of more than 30 tissues and >30,000 individuals, were used. Results: nc886 methylation status is associated with twin status and ethnic background, but the variation between populations is limited. Monozygotic twin pairs present concordant methylation, whereas ∼30% of dizygotic twin pairs present discordant methylation in the nc886 locus. The methylation levels of nc886 are uniform across somatic tissues, except in cerebellum and skeletal muscle. Conclusion: The nc886 imprint may be established in the oocyte, and, after implantation, the methylation status is stable, excluding a few specific tissues.
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- Undorf, Sabine, et al.
(författare)
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Learning from the 2018 heatwave in the context of climate change : are high-temperature extremes important for adaptation in Scotland?
- 2020
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Ingår i: Environmental Research Letters. - : IOP Publishing. - 1748-9326. ; 15:3
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Tidskriftsartikel (refereegranskat)abstract
- To understand whether high temperatures and temperature extremes are important for climate change adaptation in Scotland, we place the 2018 heatwave in the context of past, present, and future climate, and provide a rapid but comprehensive impact analysis. The observed hottest day (d), 5 d, and 30 d period of 2018 and the 5 d period with the warmest nights had return periods of 5-15 years for 1950-2018. The warmest night and the maximum 30 d average nighttime temperature were more unusual with return periods of >30 years. Anthropogenic climate change since 1850 has made all these high-temperature extremes more likely. Higher risk ratios are found for experiments from the CMIP6-generation global climate model HadGEM3-GA6 compared to those from the very-large ensemble system weather@home. Between them, the best estimates of the risk ratios for daytime extremes range between 1.2-2.4, 1.2-2.3, and 1.4-4.0 for the 1, 5, and 30 d averages. For the corresponding nighttime extremes, the values are higher and the ranges wider (1.5- >50, 1.5-5.5, and 1.6- >50). The short-period nighttime extremes were more likely in 2018 than in 2017, suggesting a contribution from year-to-year climate variability to the risk enhancement of extreme temperatures due to anthropogenic effects. Climate projections suggest further substantial increases in the likelihood of 2018 temperatures between now and 2050, and that towards the end of the century every summer might be as hot as 2018. Major negative impacts occurred, especially on rural sectors, while transport and water infrastructure alleviated most impacts by implementing costly special measures. Overall, Scotland could cope with the impacts of the 2018 heatwave. However, given the likelihood increase of high-temperature extremes, uncertainty about consequences of even higher temperatures and/or repeated heatwaves, and substantial costs of preventing negative impacts, we conclude that despite its cool climate, high-temperature extremes are important to consider for climate change adaptation in Scotland.
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