| 1. |
- Wang, Z., et al.
(författare)
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Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention
- 2022
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 54:9, s. 1332-1344
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Tidskriftsartikel (refereegranskat)abstract
- Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention. Multi-ancestry meta-analyses of genome-wide association studies for self-reported physical activity during leisure time, leisure screen time, sedentary commuting and sedentary behavior at work identify 99 loci associated with at least one of these traits.
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| 2. |
- Johansson, J., et al.
(författare)
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Gustavson syndrome is caused by an in-frame deletion in RBMX associated with potentially disturbed SH3 domain interactions
- 2024
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Ingår i: European Journal of Human Genetics. - : SPRINGERNATURE. - 1018-4813 .- 1476-5438. ; 32:3, s. 333-341
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Tidskriftsartikel (refereegranskat)abstract
- RNA binding motif protein X-linked (RBMX) encodes the heterogeneous nuclear ribonucleoprotein G (hnRNP G) that regulates splicing, sister chromatid cohesion and genome stability. RBMX knock down experiments in various model organisms highlight the gene's importance for brain development. Deletion of the RGG/RG motif in hnRNP G has previously been associated with Shashi syndrome, however involvement of other hnRNP G domains in intellectual disability remain unknown. In the current study, we present the underlying genetic and molecular cause of Gustavson syndrome. Gustavson syndrome was first reported in 1993 in a large Swedish five-generation family presented with profound X-linked intellectual disability and an early death. Extensive genomic analyses of the family revealed hemizygosity for a novel in-frame deletion in RBMX in affected individuals (NM_002139.4; c.484_486del, p.(Pro162del)). Carrier females were asymptomatic and presented with skewed X-chromosome inactivation, indicating silencing of the pathogenic allele. Affected individuals presented minor phenotypic overlap with Shashi syndrome, indicating a different disease-causing mechanism. Investigation of the variant effect in a neuronal cell line (SH-SY5Y) revealed differentially expressed genes enriched for transcription factors involved in RNA polymerase II transcription. Prediction tools and a fluorescence polarization assay imply a novel SH3-binding motif of hnRNP G, and potentially a reduced affinity to SH3 domains caused by the deletion. In conclusion, we present a novel in-frame deletion in RBMX segregating with Gustavson syndrome, leading to disturbed RNA polymerase II transcription, and potentially reduced SH3 binding. The results indicate that disruption of different protein domains affects the severity of RBMX-associated intellectual disabilities.
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| 3. |
- Pinese, Mark, et al.
(författare)
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The Medical Genome Reference Bank contains whole genome and phenotype data of 2570 healthy elderly
- 2020
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Population health research is increasingly focused on the genetic determinants of healthy ageing, but there is no public resource of whole genome sequences and phenotype data from healthy elderly individuals. Here we describe the first release of the Medical Genome Reference Bank (MGRB), comprising whole genome sequence and phenotype of 2570 elderly Australians depleted for cancer, cardiovascular disease, and dementia. We analyse the MGRB for single-nucleotide, indel and structural variation in the nuclear and mitochondrial genomes. MGRB individuals have fewer disease-associated common and rare germline variants, relative to both cancer cases and the gnomAD and UK Biobank cohorts, consistent with risk depletion. Age-related somatic changes are correlated with grip strength in men, suggesting blood-derived whole genomes may also provide a biologic measure of age-related functional deterioration. The MGRB provides a broadly applicable reference cohort for clinical genetics and genomic association studies, and for understanding the genetics of healthy ageing. Healthspan and healthy aging are areas of research with potential socioeconomic impact. Here, the authors present the Medical Genome Reference Bank (MGRB) which consist of over 4,000 individuals aged 70 years and older without a history of the major age-related diseases and report on results from whole-genome sequencing and association analyses.
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| 4. |
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| 5. |
- Dumanski, Jan P., et al.
(författare)
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Immune cells lacking Y chromosome show dysregulation of autosomal gene expression
- 2021
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Ingår i: Cellular and Molecular Life Sciences (CMLS). - : Springer. - 1420-682X .- 1420-9071. ; 78:8, s. 4019-4033
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiological investigations show that mosaic loss of chromosome Y (LOY) in leukocytes is associated with earlier mortality and morbidity from many diseases in men. LOY is the most common acquired mutation and is associated with aberrant clonal expansion of cells, yet it remains unclear whether this mosaicism exerts a direct physiological effect. We studied DNA and RNA from leukocytes in sorted- and single-cells in vivo and in vitro. DNA analyses of sorted cells showed that men diagnosed with Alzheimer’s disease was primarily affected with LOY in NK cells whereas prostate cancer patients more frequently displayed LOY in CD4 + T cells and granulocytes. Moreover, bulk and single-cell RNA sequencing in leukocytes allowed scoring of LOY from mRNA data and confirmed considerable variation in the rate of LOY across individuals and cell types. LOY-associated transcriptional effect (LATE) was observed in ~ 500 autosomal genes showing dysregulation in leukocytes with LOY. The fraction of LATE genes within specific cell types was substantially larger than the fraction of LATE genes shared between different subsets of leukocytes, suggesting that LOY might have pleiotropic effects. LATE genes are involved in immune functions but also encode proteins with roles in other diverse biological processes. Our findings highlight a surprisingly broad role for chromosome Y, challenging the view of it as a “genetic wasteland”, and support the hypothesis that altered immune function in leukocytes could be a mechanism linking LOY to increased risk for disease.
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| 6. |
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| 7. |
- Mattisson, Jonas, 1994-
(författare)
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The role of hematopoietic chromosome Y loss in health and disease
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Mosaic loss of chromosome Y (mLOY) is the most common somatic mutation, and affected men have increased risk for all major causes of death, including cardiovascular diseases and cancer. As a male specific mutation, it helps explain why men live shorter lives than women. However, the causality is debated, and contrasting models have been proposed to explain how Y loss in blood could be linked with disease in other organs. In this thesis, I provide results contributing to this debate.In Paper I, we identify 156 loci associated with genetic susceptibility for mLOY. Enrichment of loci involved in processes such as cell-cycle regulation and cancer susceptibility suggest that mLOY could be viewed as a barometer of genomic instability. In Paper II, we used the mLOY-associated variants identified in Paper I to calculate a PRS for mLOY in an independent cohort. We found that men with high PRS displayed a five-fold increased risk in an age dependent manner.In Paper III, we showed that mLOY and CHIP driving SNVs often co-occur in leukocytes. Considering that they share clinical manifestations, further studies are necessary to elucidate how these mutations contributes to disease risk. In Paper IV, we studied transcriptional effects of mLOY in leukocytes and identified almost 500 dysregulated autosomal genes, varying between cell types. We also report that mLOY in specific leukocytes might be linked with different types of disease. In Paper V, regulatory T cells are shown to be affected with Y loss to a greater extent than other CD4+ T lymphocytes. We propose that mLOY might drive T lymphocytes towards the regulatory phenotype, known to exhibit immunosuppressive functions. In Paper VI, we used CITE-seq to show that expression and cell surface abundance of the immunoprotein CD99 is lower in leukocytes with Y loss. This finding provides a possible explanation how mLOY could influence normal immune response, since CD99 is essential is for the mobility and cell-to-cell interactions of leukocytes. In Paper VII, it is shown that hematological mLOY cause disease directly in other organs. Mice with mLOY was shown to have a reduced survival, increased fibrosis and cardiac dysfunction, while men in UK biobank with mLOY in blood was found to die from diseases of the circulatory system in a dose dependent manner. Treatment with TGFβ1-inhibitors could restore cardiac function in mLOY-mice. Together, the presented results show that mLOY both reflect genomic instability overall, while also causing disease directly.
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| 8. |
- Najjari, Afef, et al.
(författare)
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Physiological and genomic insights into abiotic stress of halophilic archaeon Natrinema altunense 4.1R isolated from a saline ecosystem of Tunisian desert
- 2023
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Ingår i: Genetica. - : Springer Science and Business Media LLC. - 1573-6857 .- 0016-6707. ; 151:2, s. 133-152
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Tidskriftsartikel (refereegranskat)abstract
- Halophilic archaea are polyextremophiles with the ability to withstand fluctuations in salinity, high levels of ultraviolet radiation, and oxidative stress, allowing them to survive in a wide range of environments and making them an excellent model for astrobiological research. Natrinema altunense 4.1R is a halophilic archaeon isolated from the endorheic saline lake systems, Sebkhas, located in arid and semi-arid regions of Tunisia. It is an ecosystem characterized by periodic flooding from subsurface groundwater and fluctuating salinities. Here, we assess the physiological responses and genomic characterization of N. altunense 4.1R to UV-C radiation, as well as osmotic and oxidative stresses. Results showed that the 4.1R strain is able to survive up to 36% of salinity, up to 180 J/m2 to UV-C radiation, and at 50 mM of H2O2, a resistance profile similar to Halobacterium salinarum, a strain often used as UV-C resistant model. In order to understand the genetic determinants of N. altunense 4.1R survival strategy, we sequenced and analyzed its genome. Results showed multiple gene copies of osmotic stress, oxidative stress, and DNA repair response mechanisms supporting its survivability at extreme salinities and radiations. Indeed, the 3D molecular structures of seven proteins related to responses to UV-C radiation (excinucleases UvrA, UvrB, and UvrC, and photolyase), saline stress (trehalose-6-phosphate synthase OtsA and trehalose-phosphatase OtsB), and oxidative stress (superoxide dismutase SOD) were constructed by homology modeling. This study extends the abiotic stress range for the species N. altunense and adds to the repertoire of UV and oxidative stress resistance genes generally known from haloarchaeon.
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| 9. |
- Riaz, Moeen, et al.
(författare)
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A polygenic risk score predicts mosaic loss of chromosome Y in circulating blood cells
- 2021
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Ingår i: Cell & Bioscience. - : Springer Nature. - 2045-3701. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Mosaic loss of Y chromosome (LOY) is the most common somatic change that occurs in circulating white blood cells of older men. LOY in leukocytes is associated with increased risk for all-cause mortality and a range of common disease such as hematological and non-hematological cancer, Alzheimer’s disease, and cardiovascular events. Recent genome-wide association studies identified up to 156 germline variants associated with risk of LOY. The objective of this study was to use these variants to calculate a novel polygenic risk score (PRS) for LOY, and to assess the predictive performance of this score in a large independent population of older men.Results: We calculated a PRS for LOY in 5131 men aged 70 years and older. Levels of LOY were estimated using microarrays and validated by whole genome sequencing. After adjusting for covariates, the PRS was a significant predictor of LOY (odds ratio [OR] = 1.74 per standard deviation of the PRS, 95% confidence intervals [CI] 1.62–1.86, p < 0.001). Men in the highest quintile of the PRS distribution had > fivefold higher risk of LOY than the lowest (OR = 5.05, 95% CI 4.05–6.32, p < 0.001). Adding the PRS to a LOY prediction model comprised of age, smoking and alcohol consumption significantly improved prediction (AUC = 0.628 [CI 0.61–0.64] to 0.695 [CI 0.67–0.71], p < 0.001).Conclusions: Our results suggest that a PRS for LOY could become a useful tool for risk prediction and targeted intervention for common disease in men.
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