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Wang, Z., Davey Smith, G., Loos, R. J. F. & den Hoed, M. (2023). Distilling causality between physical activity traits and obesity via Mendelian randomization. Communications Medicine, 3(1), Article ID 173.
Open this publication in new window or tab >>Distilling causality between physical activity traits and obesity via Mendelian randomization
2023 (English)In: Communications Medicine, E-ISSN 2730-664X, Vol. 3, no 1, article id 173Article in journal (Refereed) Published
Abstract [en]

Background

Whether obesity is a cause or consequence of low physical activity levels and more sedentary time has not yet been fully elucidated. Better instrumental variables and a more thorough consideration of potential confounding variables that may influence the causal inference between physical activity and obesity are needed.

Methods

Leveraging results from our recent genome-wide association study for leisure time moderate-to-vigorous intensity (MV) physical activity and screen time, we here disentangle the causal relationships between physical activity, sedentary behavior, education—defined by years of schooling—and body mass index (BMI), using multiple univariable and multivariable Mendelian Randomization (MR) approaches.

Results

Univariable MR analyses suggest bidirectional causal effects of physical activity and sedentary behavior with BMI. However, multivariable MR analyses that take years of schooling into account suggest that more MV physical activity causes a lower BMI, and a higher BMI causes more screen time, but not vice versa. In addition, more years of schooling causes higher levels of MV physical activity, less screen time, and lower BMI.

Conclusions

In conclusion, our results highlight the beneficial effect of education on improved health and suggest that a more physically active lifestyle leads to lower BMI, while sedentary behavior is a consequence of higher BMI.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-519525 (URN)10.1038/s43856-023-00407-5 (DOI)001118401700001 ()38036650 (PubMedID)
Funder
Swedish Research Council, 201901417Uppsala University
Available from: 2024-01-08 Created: 2024-01-08 Last updated: 2024-01-10Bibliographically approved
van de Vegte, Y., Eppinga, R. P., van der Ende, M. Y., Hagemeijer, Y., Mahendran, Y. V., Salfati, E. Y., . . . van der Harst, P. (2023). Genetic insights into resting heart rate and its role in cardiovascular disease. Nature Communications, 14(1), Article ID 4646.
Open this publication in new window or tab >>Genetic insights into resting heart rate and its role in cardiovascular disease
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2023 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 14, no 1, article id 4646Article in journal (Refereed) Published
Abstract [en]

The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Cardiac and Cardiovascular Systems Medical Genetics
Identifiers
urn:nbn:se:uu:diva-511622 (URN)10.1038/s41467-023-39521-2 (DOI)001042222000014 ()37532724 (PubMedID)
Funder
Wellcome trust, 202802/Z/16/Z
Available from: 2023-09-15 Created: 2023-09-15 Last updated: 2023-10-03Bibliographically approved
Mathieson, I., Day, F. R., Barban, N., Tropf, F. C., Brazel, D. M., Vaez, A., . . . Perry, J. R. B. (2023). Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus. Nature Human Behaviour, 7(5), 790-801
Open this publication in new window or tab >>Genome-wide analysis identifies genetic effects on reproductive success and ongoing natural selection at the FADS locus
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2023 (English)In: Nature Human Behaviour, E-ISSN 2397-3374, Vol. 7, no 5, p. 790-801Article in journal (Refereed) Published
Abstract [en]

Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Genetics Medical Genetics Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-512810 (URN)10.1038/s41562-023-01528-6 (DOI)000955741600006 ()36864135 (PubMedID)
Funder
EU, European Research Council, 835079EU, European Research Council, 865356EU, European Research Council, 615603
Available from: 2023-09-29 Created: 2023-09-29 Last updated: 2023-09-29Bibliographically approved
Lagou, V., Jiang, L., Ulrich, A., Zudina, L., Gonzalez, K. S., Balkhiyarova, Z., . . . Prokopenko, I. (2023). GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification. Nature Genetics, 55(9), 1448-+
Open this publication in new window or tab >>GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification
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2023 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 55, no 9, p. 1448-+Article in journal (Refereed) Published
Abstract [en]

Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on 'around the clock' glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification. Genome-wide association analyses of blood glucose measurements under nonstandardized conditions provide insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Endocrinology and Diabetes Medical Genetics
Identifiers
urn:nbn:se:uu:diva-515676 (URN)10.1038/s41588-023-01462-3 (DOI)001064048700005 ()37679419 (PubMedID)
Funder
Swedish Research Council, 2017-02688Swedish Research Council, 2020-02191Swedish Research Council, 2019-01417Swedish Heart Lung Foundation, 20200781Swedish Heart Lung Foundation, 20200602EU, Horizon 2020, H2020-SC1-2019-874739European Foundation for the Study of DiabetesWorld Cancer Research Fund International, 2017/1641
Available from: 2023-11-16 Created: 2023-11-16 Last updated: 2023-11-16Bibliographically approved
Mujica, E. & den Hoed, M. (2023). Investigating the role of lipid genes in liver disease using models of steatotic liver disease in zebrafish (Danio rerio). Liver international, 43(11), 2348-2350
Open this publication in new window or tab >>Investigating the role of lipid genes in liver disease using models of steatotic liver disease in zebrafish (Danio rerio)
2023 (English)In: Liver international, ISSN 1478-3223, E-ISSN 1478-3231, Vol. 43, no 11, p. 2348-2350Article in journal, Editorial material (Other academic) Published
Place, publisher, year, edition, pages
John Wiley & Sons, 2023
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-519534 (URN)10.1111/liv.15752 (DOI)
Funder
Swedish Research Council, 201901417
Available from: 2024-01-08 Created: 2024-01-08 Last updated: 2024-01-23Bibliographically approved
Mattis, K. K., Krentz, N. A., Metzendorf, C., Abaitua, F., Spigelman, A. F., Sun, H., . . . Gloyn, A. L. (2023). Loss of RREB1 in pancreatic beta cells reduces cellular insulin content and affects endocrine cell gene expression. Diabetologia, 66(4), 674-694
Open this publication in new window or tab >>Loss of RREB1 in pancreatic beta cells reduces cellular insulin content and affects endocrine cell gene expression
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2023 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 66, no 4, p. 674-694Article in journal (Refereed) Published
Abstract [en]

AIMS/HYPOTHESIS: Genome-wide studies have uncovered multiple independent signals at the RREB1 locus associated with altered type 2 diabetes risk and related glycaemic traits. However, little is known about the function of the zinc finger transcription factor Ras-responsive element binding protein 1 (RREB1) in glucose homeostasis or how changes in its expression and/or function influence diabetes risk.

METHODS: A zebrafish model lacking rreb1a and rreb1b was used to study the effect of RREB1 loss in vivo. Using transcriptomic and cellular phenotyping of a human beta cell model (EndoC-βH1) and human induced pluripotent stem cell (hiPSC)-derived beta-like cells, we investigated how loss of RREB1 expression and activity affects pancreatic endocrine cell development and function. Ex vivo measurements of human islet function were performed in donor islets from carriers of RREB1 type 2 diabetes risk alleles.

RESULTS: CRISPR/Cas9-mediated loss of rreb1a and rreb1b function in zebrafish supports an in vivo role for the transcription factor in beta cell mass, beta cell insulin expression and glucose levels. Loss of RREB1 also reduced insulin gene expression and cellular insulin content in EndoC-βH1 cells and impaired insulin secretion under prolonged stimulation. Transcriptomic analysis of RREB1 knockdown and knockout EndoC-βH1 cells supports RREB1 as a novel regulator of genes involved in insulin secretion. In vitro differentiation of RREB1KO/KO hiPSCs revealed dysregulation of pro-endocrine cell genes, including RFX family members, suggesting that RREB1 also regulates genes involved in endocrine cell development. Human donor islets from carriers of type 2 diabetes risk alleles in RREB1 have altered glucose-stimulated insulin secretion ex vivo, consistent with a role for RREB1 in regulating islet cell function.

CONCLUSIONS/INTERPRETATION: Together, our results indicate that RREB1 regulates beta cell function by transcriptionally regulating the expression of genes involved in beta cell development and function.

Place, publisher, year, edition, pages
Springer Nature, 2023
Keywords
Beta cell, CRISPR/Cas9, Diabetes, Differentiation, Human genetics, Pancreatic islet, RREB1, Stem cell, Transcription factor, Zebrafish
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-495953 (URN)10.1007/s00125-022-05856-6 (DOI)000912974300001 ()36633628 (PubMedID)
Available from: 2023-02-05 Created: 2023-02-05 Last updated: 2023-05-29Bibliographically approved
Höijer, I., Emmanouilidou, A., Östlund, R., van Schendel, R., Bozorgpana, S., Tijsterman, M., . . . Ameur, A. (2022). CRISPR-Cas9 induces large structural variants at on-target and off-target sites in vivo that segregate across generations. Nature Communications, 13, Article ID 627.
Open this publication in new window or tab >>CRISPR-Cas9 induces large structural variants at on-target and off-target sites in vivo that segregate across generations
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2022 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 13, article id 627Article in journal (Refereed) Published
Abstract [en]

CRISPR-Cas9 genome editing has potential to cure diseases without current treatments, but therapies must be safe. Here we show that CRISPR-Cas9 editing can introduce unintended mutations in vivo, which are passed on to the next generation. By editing fertilized zebrafish eggs using four guide RNAs selected for off-target activity in vitro, followed by long-read sequencing of DNA from >1100 larvae, juvenile and adult fish across two generations, we find that structural variants (SVs), i.e., insertions and deletions >= 50 bp, represent 6% of editing outcomes in founder larvae. These SVs occur both at on-target and off-target sites. Our results also illustrate that adult founder zebrafish are mosaic in their germ cells, and that 26% of their offspring carries an off-target mutation and 9% an SV. Hence, pre-testing for off-target activity and SVs using patient material is advisable in clinical applications, to reduce the risk of unanticipated effects with potentially large implications.

Place, publisher, year, edition, pages
Springer NatureSpringer Nature, 2022
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-468369 (URN)10.1038/s41467-022-28244-5 (DOI)000752241200003 ()35110541 (PubMedID)
Available from: 2022-03-01 Created: 2022-03-01 Last updated: 2024-01-15Bibliographically approved
Pellegrinelli, V., Rodriguez-Cuenca, S., Rouault, C., Figueroa-Juarez, E., Schilbert, H., Virtue, S., . . . Vidal-Puig, A. (2022). Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance. Nature Metabolism, 4(4), 476-+
Open this publication in new window or tab >>Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance
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2022 (English)In: Nature Metabolism, E-ISSN 2522-5812, Vol. 4, no 4, p. 476-+Article in journal (Refereed) Published
Abstract [en]

Resulting from impaired collagen turnover, fibrosis is a hallmark of adipose tissue (AT) dysfunction and obesity-associated insulin resistance (IR). Prolidase, also known as peptidase D (PEPD), plays a vital role in collagen turnover by degrading proline-containing dipeptides but its specific functional relevance in AT is unknown. Here we show that in human and mouse obesity, PEPD expression and activity decrease in AT, and PEPD is released into the systemic circulation, which promotes fibrosis and AT IR. Loss of the enzymatic function of PEPD by genetic ablation or pharmacological inhibition causes AT fibrosis in mice. In addition to its intracellular enzymatic role, secreted extracellular PEPD protein enhances macrophage and adipocyte fibro-inflammatory responses via EGFR signalling, thereby promoting AT fibrosis and IR. We further show that decreased prolidase activity is coupled with increased systemic levels of PEPD that act as a pathogenic trigger of AT fibrosis and IR. Thus, PEPD produced by macrophages might serve as a biomarker of AT fibro-inflammation and could represent a therapeutic target for AT fibrosis and obesity-associated IR and type 2 diabetes. Obesity-associated AT fibro-inflammation and metabolic disturbances are linked to PEPD activity and PEPD extracellular levels.

Place, publisher, year, edition, pages
Springer NatureSpringer Nature, 2022
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-474446 (URN)10.1038/s42255-022-00561-5 (DOI)000788415800012 ()35478031 (PubMedID)
Funder
EU, Horizon 2020, 634413EU, Horizon 2020, 634413EU, European Research Council, 669879Swedish Heart Lung Foundation, 20170872Swedish Heart Lung Foundation, 20140543Swedish Heart Lung Foundation, 20170678Swedish Heart Lung Foundation, 20180706Swedish Research Council, 2015-03657Swedish Research Council, 2019-01417
Available from: 2022-05-16 Created: 2022-05-16 Last updated: 2024-01-15Bibliographically approved
Wang, Z., Emmerich, A., Pillon, N. J., Moore, T., Hemerich, D., Cornelis, M. C., . . . den Hoed, M. (2022). Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention. Nature Genetics, 54(9), 1332-1344
Open this publication in new window or tab >>Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention
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2022 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 54, no 9, p. 1332-1344Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Springer Nature, 2022
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-489990 (URN)10.1038/s41588-022-01165-1 (DOI)000852469800001 ()36071172 (PubMedID)
Funder
Uppsala University
Available from: 2022-12-06 Created: 2022-12-06 Last updated: 2023-02-13Bibliographically approved
Huang, L. O., Rauch, A., Mazzaferro, E., Preuss, M., Carobbio, S., Bayrak, C. S., . . . Loos, R. J. F. (2021). Genome-wide discovery of genetic loci that uncouple excess adiposity from its comorbidities. Nature Metabolism, 3(2), 228-243
Open this publication in new window or tab >>Genome-wide discovery of genetic loci that uncouple excess adiposity from its comorbidities
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2021 (English)In: Nature Metabolism, E-ISSN 2522-5812, Vol. 3, no 2, p. 228-243Article in journal (Refereed) Published
Abstract [en]

Obesity is a major risk factor for cardiometabolic diseases. Nevertheless, a substantial proportion of individuals with obesity do not suffer cardiometabolic comorbidities. The mechanisms that uncouple adiposity from its cardiometabolic complications are not fully understood. Here, we identify 62 loci of which the same allele is significantly associated with both higher adiposity and lower cardiometabolic risk. Functional analyses show that the 62 loci are enriched for genes expressed in adipose tissue, and for regulatory variants that influence nearby genes that affect adipocyte differentiation. Genes prioritized in each locus support a key role of fat distribution (FAM13A, IRS1 and PPARG) and adipocyte function (ALDH2, CCDC92, DNAH10, ESR1, FAM13A, MTOR, PIK3R1 and VEGFB). Several additional mechanisms are involved as well, such as insulin-glucose signalling (ADCY5, ARAP1, CREBBP, FAM13A, MTOR, PEPD, RAC1 and SH2B3), energy expenditure and fatty acid oxidation (IGF2BP2), browning of white adipose tissue (CSK, VEGFA, VEGFB and SLC22A3) and inflammation (SH2B3, DAGLB and ADCY9). Some of these genes may represent therapeutic targets to reduce cardiometabolic risk linked to excess adiposity.

Place, publisher, year, edition, pages
Springer NatureNATURE RESEARCH, 2021
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-440458 (URN)10.1038/s42255-021-00346-2 (DOI)000621880500011 ()33619380 (PubMedID)
Available from: 2021-04-19 Created: 2021-04-19 Last updated: 2024-01-15Bibliographically approved
Projects
Identifying targets and compounds for the therapeutic intervention of coronary heart disease using a zebrafish model system [2015-03657_VR]; Uppsala UniversityIdentifying novel therapeutic strategies for coronary artery disease using CRISPR-Cas9 aided, image-based screens of candidate genes for triglyceride levels and atherosclerosis in zebrafish model systems [20180706_HLF]; Uppsala UniversityIdentifying and characterising new targets, drugs, and small molecules for prevention and treatment of coronary artery disease [2019-01417_VR]; Uppsala UniversityIdentifying and characterising new targets, drugs, and small molecules for prevention and treatment of coronary artery disease [20200602_HLF]; Uppsala UniversityIdentifying and characterising new targets, drugs, and small molecules for prevention and treatment of coronary artery disease [20200781_HLF]; Uppsala UniversityIn vivo perturbation and imaging to characterise causal genes and therapeutic targets for fatty liver disease [2023-02556_VR]; Uppsala University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-8081-428X

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