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Shah, S., Henry, A., Roselli, C., Lin, H., Sveinbjornsson, G., Fatemifar, G., . . . Ye, B. (2020). Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure. Nature Communications, 11(1), Article ID 163.
Open this publication in new window or tab >>Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
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2020 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 11, no 1, article id 163Article in journal (Refereed) Published
Abstract [en]

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2020
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-407649 (URN)10.1038/s41467-019-13690-5 (DOI)000511898900014 ()31919418 (PubMedID)
Funder
AstraZenecaNovo Nordisk
Available from: 2020-03-30 Created: 2020-03-30 Last updated: 2020-03-30Bibliographically approved
Wuttke, M., Li, Y., Li, M., Sieber, K. B., Feitosa, M. F., Gorski, M., . . . Pattaro, C. (2019). A catalog of genetic loci associated with kidney function from analyses of a million individuals. Nature Genetics, 51(6), 957-972
Open this publication in new window or tab >>A catalog of genetic loci associated with kidney function from analyses of a million individuals
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 6, p. 957-972Article in journal (Refereed) Published
Abstract [en]

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-387933 (URN)10.1038/s41588-019-0407-x (DOI)000469996900008 ()31152163 (PubMedID)
Funder
AstraZenecaNovo NordiskNIH (National Institute of Health)
Note

Group Authors: Lifelines COHort Study

Available from: 2019-06-26 Created: 2019-06-26 Last updated: 2019-06-26Bibliographically approved
Tikkanen, E., Gustafsson, S., Knowles, J. W., Perez, M., Burgess, S. & Ingelsson, E. (2019). Body composition and atrial fibrillation: a Mendelian randomization study. European Heart Journal, 40(16), 1277-1282
Open this publication in new window or tab >>Body composition and atrial fibrillation: a Mendelian randomization study
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2019 (English)In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 40, no 16, p. 1277-1282Article in journal (Refereed) Published
Abstract [en]

Aims

Increases in fat-free mass and fat mass have been associated with higher risk of atrial fibrillation (AF) in observational studies. It is not known whether these associations reflect independent causal processes. Our aim was to evaluate independent causal roles of fat-free mass and fat mass on AF.

Methods and results

We conducted a large observational study to estimate the associations between fat-free mass and fat mass on incident AF in the UK Biobank (N = 487 404, N events = 10 365). Genome-wide association analysis was performed to obtain genetic instruments for Mendelian randomization (MR). We evaluated the causal effects of fat-free mass and fat mass on AF with two-sample method by using genetic associations from AFGen consortium as outcome. Finally, we evaluated independent causal effects of fat-free mass and fat mass with multivariate MR. Both fat-free mass and fat mass had observational associations with incident AF [hazard ratio (HR) = 1.77, 95% confidence interval (CI) 1.72-1.83; HR = 1.40, 95% CI 1.37-1.43 per standard deviation increase in fat-free and fat mass, respectively]. The causal effects using the inverse-variance weighted method were 1.55 (95% CI 1.38-1.75) for fat-free mass and 1.30 (95% CI 1.17-1.45) for fat mass. Weighted median, Egger regression, and penalized methods showed similar estimates. The multivariate MR analysis suggested that the causal effects of fat-free and fat mass were independent of each other (causal risk ratios: 1.37, 95% CI 1.06-1.75; 1.28, 95% CI 1.03-1.58).

Conclusion

Genetically programmed increases in fat-free mass and fat mass independently cause an increased risk of AF.

Keywords
Fat-free mass, Fat mass, Bioimpedance, Genetics, Atrial fibrillation, Causal effect
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-396561 (URN)10.1093/eurheartj/ehz003 (DOI)000490013700010 ()30721963 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation, 2013.0126
Available from: 2019-11-06 Created: 2019-11-06 Last updated: 2019-11-06Bibliographically approved
Lind, L., Elmstahl, S. & Ingelsson, E. (2019). Cardiometabolic Proteins Associated with Metabolic Syndrome. Metabolic Syndrome and Related Disorders, 17(5), 272-279
Open this publication in new window or tab >>Cardiometabolic Proteins Associated with Metabolic Syndrome
2019 (English)In: Metabolic Syndrome and Related Disorders, ISSN 1540-4196, E-ISSN 1557-8518, Vol. 17, no 5, p. 272-279Article in journal (Refereed) Published
Abstract [en]

Background: Although metabolic syndrome (MetS) was described in the late 80s, the molecular mechanisms underlying clustering of risk factors in certain individuals are not fully understood. The present study used targeted proteomics to establish cardiometabolic proteins related to all MetS components, thereby providing new hypotheses regarding pathways involved in the pathogenesis of MetS.

Methods: In the EpiHealth study, 249 cardiometabolic proteins were measured by proximity extension assay (PEA) and related to the five MetS components [consensus-modified National Cholesterol Education Program (NCEP) criteria] in 2,444 participants aged 45-75 years (50% women).

Results: Thirty-one proteins were associated with systolic blood pressure following adjustment for age and sex (P < 0.000040, taking multiple testing into account). The corresponding number of proteins significantly associated with fasting glucose, waist circumference, high-density lipoprotein cholesterol, and serum triglycerides were 58, 132, 127, and 148. Twenty-two proteins were significantly related to all 5 MetS components, and of those, 20 were with MetS as a binary outcome (n = 600, 24% of the sample) following adjustment for age, sex, fat mass, and lifestyle factors (alcohol intake, smoking, education, and exercise habits).

Conclusion: Using targeted proteomics, we identified 20 proteins reflecting a range of pathways, such as immunomodulation at different levels; regulation of adipocyte differentiation; lipid, carbohydrate, and amino acid metabolism; or insulin-like growth factor signaling, to be strongly associated with MetS independently of fat mass and lifestyle factors. Whether some of these proteins are causally involved in the pathogenesis of clustering of multiple risk factors in the same individual remains to be investigated.

Keywords
metabolic syndrome, proteomics, epidemiology
National Category
Other Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-380437 (URN)10.1089/met.2018.0123 (DOI)000461504000001 ()30883260 (PubMedID)
Available from: 2019-03-28 Created: 2019-03-28 Last updated: 2019-12-18Bibliographically approved
Dörr, M., Hamburg, N. M., Müller, C., Smith, N. L., Gustafsson, S., Lehtimäki, T., . . . Schnabel, R. B. (2019). Common Genetic Variation in Relation to Brachial Vascular Dimensions and Flow-Mediated Vasodilation [Letter to the editor]. CIRCULATION-GENOMIC AND PRECISION MEDICINE, 12(2), Article ID e002409.
Open this publication in new window or tab >>Common Genetic Variation in Relation to Brachial Vascular Dimensions and Flow-Mediated Vasodilation
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2019 (English)In: CIRCULATION-GENOMIC AND PRECISION MEDICINE, ISSN 2574-8300, Vol. 12, no 2, article id e002409Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2019
Keywords
brachial artery, dilation, epidemiology, genetics, genome-wide association study, insulin-like growth factor binding protein 3
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-379085 (URN)10.1161/CIRCGEN.118.002409 (DOI)000458995600002 ()30779634 (PubMedID)
Funder
EU, European Research Council, 648131EU, European Research Council, 742927
Available from: 2019-03-12 Created: 2019-03-12 Last updated: 2019-03-12Bibliographically approved
Cook, N. L., Pjanic, M., Emmerich, A. G., Rao, A. S., Hetty, S., Knowles, J. W., . . . Ingelsson, E. (2019). CRISPR-Cas9-mediated knockout of SPRY2 in human hepatocytes leads to increased glucose uptake and lipid droplet accumulation. BMC Endocrine Disorders, 19, Article ID 115.
Open this publication in new window or tab >>CRISPR-Cas9-mediated knockout of SPRY2 in human hepatocytes leads to increased glucose uptake and lipid droplet accumulation
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2019 (English)In: BMC Endocrine Disorders, ISSN 1472-6823, E-ISSN 1472-6823, Vol. 19, article id 115Article in journal (Refereed) Published
Abstract [en]

Background

The prevalence of obesity and its comorbidities, including type 2 diabetes mellitus (T2DM), is dramatically increasing throughout the world; however, the underlying aetiology is incompletely understood. Genome-wide association studies (GWAS) have identified hundreds of genec susceptibility loci for obesity and T2DM, although the causal genes and mechanisms are largely unknown. SPRY2 is a candidate gene identified in GWAS of body fat percentage and T2DM, and has recently been linked to insulin production in pancreatic β-cells. In the present study, we aimed to further understand SPRY2 via functional characterisation in HepG2 cells, an in vitro model of human hepatocytes widely used to investigate T2DM and insulin resistance.

Methods

CRISPR-Cas9 genome editing was used to target SPRY2 in HepG2 cells, and the functional consequences of SPRY2 knockout (KO) and overexpression subsequently assessed using glucose uptake and lipid droplet assays, measurement of protein kinase phosphorylation and RNA sequencing.

Results

The major functional consequence of SPRY2 KO was a significant increase in glucose uptake, along with elevated lipid droplet accumulation. These changes were attenuated, but not reversed, in cells overexpressing SPRY2. Phosphorylation of protein kinases across key signalling pathways (including Akt and mitogen activated protein kinases) was not altered after SPRY2 KO. Transcriptome profiling in SPRY2 KO and mock (control) cells revealed a number of differentially expressed genes related to cholesterol biosynthesis, cell cycle regulation and cellular signalling pathways. Phospholipase A2 group IIA (PLA2G2A) mRNA level was subsequently validated as significantly upregulated following SPRY2 KO, highlighting this as a potential mediator downstream of SPRY2.

Conclusion

These findings suggest a role for SPRY2 in glucose and lipid metabolism in hepatocytes and contribute to clarifying the function of this gene in the context of metabolic diseases.

Keywords
CRISPR-Cas9, Glucose metabolism, Hepatocytes, Lipid metabolism, Obesity, SPRY2, Type 2 diabetes mellitus
National Category
Cell and Molecular Biology Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-400155 (URN)10.1186/s12902-019-0442-8 (DOI)000506837800004 ()31664995 (PubMedID)
Funder
Swedish Heart Lung Foundation, 20140422Swedish Research Council, 2015-02907Knut and Alice Wallenberg Foundation, 2013.0126NIH (National Institute of Health), 1R01 DK106236-01A1NIH (National Institute of Health), R01DK107437
Note

De 2 sista författarna delar sistaförfattarskapet

Available from: 2019-12-18 Created: 2019-12-18 Last updated: 2020-03-24Bibliographically approved
Castillejo-Lopez, C., Pjanic, M., Pirona, A. C., Hetty, S., Wabitsch, M., Wadelius, C., . . . Ingelsson, E. (2019). Detailed Functional Characterization of a Waist-Hip Ratio Locus in 7p15.2 Defines an Enhancer Controlling Adipocyte Differentiation. ISCIENCE, 20, 42-59
Open this publication in new window or tab >>Detailed Functional Characterization of a Waist-Hip Ratio Locus in 7p15.2 Defines an Enhancer Controlling Adipocyte Differentiation
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2019 (English)In: ISCIENCE, ISSN 2589-0042, Vol. 20, p. 42-59Article in journal (Refereed) Published
Abstract [en]

We combined CAGE sequencing in human adipocytes during differentiation with data from genome-wide association studies to identify an enhancer in the SNX10 locus on chromosome 7, presumably involved in body fat distribution. Using reporter assays and CRISPR-Cas9 gene editing in human cell lines, we characterized the role of the enhancer in adipogenesis. The enhancer was active during adipogenesis and responded strongly to insulin and isoprenaline. The allele associated with increased waist-hip ratio in human genetic studies was associated with higher enhancer activity. Mutations of the enhancer resulted in less adipocyte differentiation. RNA sequencing of cells with disrupted enhancer showed reduced expression of established adipocyte markers, such as ADIPOQ and LPL, and identified CHI3L1 on chromosome 1 as a potential gene involved in adipocyte differentiation. In conclusion, we identified and characterized an enhancer in the SNX10 locus and outlined its plausible mechanisms of action and downstream targets.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-397133 (URN)10.1016/j.isci.2019.09.006 (DOI)000493388000004 ()31557715 (PubMedID)
Funder
Swedish Research Council, 2015-02907Knut and Alice Wallenberg Foundation, 2013.0126NIH (National Institute of Health), R01DK106236EXODIAB - Excellence of Diabetes Research in Sweden
Available from: 2019-11-28 Created: 2019-11-28 Last updated: 2019-11-28Bibliographically approved
Mubanga, M., Byberg, L., Egenvall, A., Sundström, J., Magnusson, P. K., Ingelsson, E. & Fall, T. (2019). Dog ownership and Cardiovascular Risk Factors: a nationwide prospective register-based cohort study. BMJ Open, 9, Article ID 23447.
Open this publication in new window or tab >>Dog ownership and Cardiovascular Risk Factors: a nationwide prospective register-based cohort study
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2019 (English)In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 9, article id 23447Article in journal (Refereed) Published
Abstract [en]

Objective To study the association between dog ownership and cardiovascular risk factors.

Design A nationwide register–based cohort study and a cross-sectional study in a subset.

Setting A cohort of 2 026 865 participants was identified from the Register of the Total Population and linked to national registers for information on dog ownership, prescribed medication, hospital admissions, education level, income and country of birth. Participants were followed from 1 October, 2006, to the end of the study on 31 December, 2012, assessing medication for a cardiovascular risk factor, emigration and death. Cross-sectional associations were further assessed in 10 110 individuals from the TwinGene study with additional adjustment for professional level, employment status, Charlson comorbidity index, disability and tobacco use.

Participants All Swedish residents aged 45–80 years on 1 October, 2006.

Main outcome measures Initiation of medication for hypertension, dyslipidaemia and diabetes mellitus.

Results After adjustment for confounders, the results indicated slightly higher likelihood of initiating antihypertensive (HR, 1.02; 95% CI, 1.01 to 1.03) and lipid-lowering treatment (HR, 1.02; 95% CI, 1.01 to 1.04) in dog owners than in non-owners, particularly among those aged 45–60 years and in those owning mixed breed or companion/toy breed dogs. No association of dog ownership with initiation of treatment for diabetes was found in the overall analysis (HR, 0.98; 95% CI, 0.95 to 1.01). Sensitivity analyses in the TwinGene cohort indicated confounding of the association between dog ownership and prevalent treatment for hypertension, dyslipidaemia and diabetes mellitus, respectively, from factors not available in the national cohort, such as employment status and non cardiovascularchronic disease status.

Conclusions In this large cohort study, dog ownership was associated with a minimally higher risk of initiation of treatment for hypertension and dyslipidaemia implying that the previously reported lower risk of cardiovascular mortality among dog owners in this cohort is not explained by reduced hypertension and dyslipidaemia. These observations may suffer from residual confounding despite access to multiple important covariates, and future studies may add valuable information.

Keywords
cardiovascular risk, hypertension, dog ownership, diabetes, registers
National Category
Cardiac and Cardiovascular Systems Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-357625 (URN)10.1136/bmjopen-2018-023447 (DOI)000471144900063 ()30850401 (PubMedID)
Funder
Swedish Research Council, 2017-00641Swedish Research Council Formas, 2013-1673Göran Gustafsson Foundation for Research in Natural Sciences and Medicine
Available from: 2018-08-19 Created: 2018-08-19 Last updated: 2019-12-18Bibliographically approved
Mubanga, M., Byberg, L., Egenvall, A., Ingelsson, E. & Fall, T. (2019). Dog Ownership and Survival After a Major Cardiovascular Event: A Register-Based Prospective Study. Circulation. Cardiovascular Quality and Outcomes, 12(10), Article ID e005342.
Open this publication in new window or tab >>Dog Ownership and Survival After a Major Cardiovascular Event: A Register-Based Prospective Study
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2019 (English)In: Circulation. Cardiovascular Quality and Outcomes, ISSN 1941-7713, E-ISSN 1941-7705, Vol. 12, no 10, article id e005342Article in journal (Refereed) Published
Abstract [en]

Background: Dog ownership is associated with increased physical activity levels and increased social support, both of which could improve the outcome after a major cardiovascular event. Dog ownership may be particularly important in single-occupancy households where ownership provides substitutive companionship and motivation for physical activity.

Methods and Results: We used the Swedish National Patient Register to identify all patients aged 40 to 85 presenting with an acute myocardial infarction (n=181 696; 5.7% dog ownership) or ischemic stroke (n=154 617; 4.8% dog ownership) between January 1, 2001 and December 31, 2012. Individual information was linked across registers for cause of death, sociodemographic, and dog ownership data. We evaluated all-cause mortality and risk of recurrent hospitalization for the same cause until December 31, 2012. Models were adjusted for socioeconomic, health, and demographic factors at study inclusion such as age, marital status, the presence of children in the home, area of residence, and income, as well as all registered comorbidities and hospitalization for cardiovascular disease in the past 5 years. Dog owners had a lower risk of death after hospitalization for acute myocardial infarction during the full follow-up period of 804 137 person-years, with an adjusted hazard ratio (HR) of 0.67 (95% CI, 0.61 to 0.75) for those who lived alone, and HR of 0.85 (95% CI, 0.80 to 0.90) for those living with a partner or a child. Similarly, after an ischemic stroke, dog owners were at lower risk of death during the full follow-up of 638 219 person-years adjusted HR of 0.73 (95% CI, 0.66 to 0.80) for those who lived alone and HR of 0.88 (95% CI, 0.83 to 0.93) for those living with a partner or a child. We further found an association of dog ownership with reduced risk of hospitalization for recurrent myocardial infarction (HR, 0.93; 95% CI, 0.87 to 0.99).

Conclusions: We found evidence of an association of dog ownership with a better outcome after a major cardiovascular event. Although our models are adjusted for many potential confounders, there are also unmeasured confounders such as smoking that prevent us from drawing conclusions regarding a possible causal effect.

Keywords
cardiovascular diseases, dog ownership, motivation, myocardial infarction
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-396741 (URN)10.1161/CIRCOUTCOMES.118.005342 (DOI)000490295200002 ()31592725 (PubMedID)
Funder
Swedish Research Council Formas, 2013-1673EU, European Research CouncilGöran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of Technology
Available from: 2019-11-19 Created: 2019-11-19 Last updated: 2019-11-19Bibliographically approved
Spracklen, C. N., Karaderi, T., Yaghootkar, H., Schurmann, C., Fine, R. S., Kutalik, Z., . . . Mohlke, K. L. (2019). Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology. American Journal of Human Genetics, 105(1), 15-28
Open this publication in new window or tab >>Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology
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2019 (English)In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 105, no 1, p. 15-28Article in journal (Refereed) Published
Abstract [en]

Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 x 10(-7)). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r(2) > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 x 10(-4)) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.

Place, publisher, year, edition, pages
CELL PRESS, 2019
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-391019 (URN)10.1016/j.ajhg.2019.05.002 (DOI)000473723000003 ()31178129 (PubMedID)
Funder
EU, European Research Council, 323195: GLUCOSEGENES-FP7-IDEAS-ERCNovo Nordisk, NNF17OC0027594Novo Nordisk, NNF14CC0001Academy of Finland, 285380Wellcome trust, WT083442AIA
Available from: 2019-08-20 Created: 2019-08-20 Last updated: 2019-08-20Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2256-6972

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