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Karlsson, Torgny
Publications (10 of 15) Show all publications
Karlsson, T., Rask-Andersen, M., Pan, G., Höglund, J., Wadelius, C., Ek, W. E. & Johansson, Å. (2019). Contribution of genetics to visceral adiposity and its relation to cardiovascular and metabolic disease.. Nature Medicine, 25(9), 1390-1395
Open this publication in new window or tab >>Contribution of genetics to visceral adiposity and its relation to cardiovascular and metabolic disease.
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2019 (English)In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 25, no 9, p. 1390-1395Article in journal (Refereed) Published
Abstract [en]

Visceral adipose tissue (VAT)-fat stored around the internal organs-has been suggested as an independent risk factor for cardiovascular and metabolic disease1-3, as well as all-cause, cardiovascular-specific and cancer-specific mortality4,5. Yet, the contribution of genetics to VAT, as well as its disease-related effects, are largely unexplored due to the requirement for advanced imaging technologies to accurately measure VAT. Here, we develop sex-stratified, nonlinear prediction models (coefficient of determination = 0.76; typical 95% confidence interval (CI) = 0.74-0.78) for VAT mass using the UK Biobank cohort. We performed a genome-wide association study for predicted VAT mass and identified 102 novel visceral adiposity loci. Predicted VAT mass was associated with increased risk of hypertension, heart attack/angina, type 2 diabetes and hyperlipidemia, and Mendelian randomization analysis showed visceral fat to be a causal risk factor for all four diseases. In particular, a large difference in causal effect between the sexes was found for type 2 diabetes, with an odds ratio of 7.34 (95% CI = 4.48-12.0) in females and an odds ratio of 2.50 (95% CI = 1.98-3.14) in males. Our findings bolster the role of visceral adiposity as a potentially independent risk factor, in particular for type 2 diabetes in Caucasian females. Independent validation in other cohorts is necessary to determine whether the findings can translate to other ethnicities, or outside the UK.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-392977 (URN)10.1038/s41591-019-0563-7 (DOI)31501611 (PubMedID)
Available from: 2019-09-12 Created: 2019-09-12 Last updated: 2019-09-12
Johansson, Å., Rask-Andersen, M., Karlsson, T. & Ek, W. E. (2019). Genome-wide association analysis of 350 000 Caucasians from the UK Biobank identifies novel loci for asthma, hay fever and eczema.. Human Molecular Genetics, Article ID ddz175.
Open this publication in new window or tab >>Genome-wide association analysis of 350 000 Caucasians from the UK Biobank identifies novel loci for asthma, hay fever and eczema.
2019 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, article id ddz175Article in journal (Refereed) Epub ahead of print
Abstract [en]

Even though heritability estimates suggest that the risk of asthma, hay fever and eczema is largely due to genetic factors, previous studies have not explained a large part of the genetics behind these diseases. In this GWA study, we include 346 545 Caucasians from the UK Biobank to identify novel loci for asthma, hay fever and eczema and replicate novel loci in three independent cohorts. We further investigate if associated lead SNPs have a significantly larger effect for one disease compared to the other diseases, to highlight possible disease specific effects. We identified 141 loci, of which 41 are novel, to be associated (P ≤ 3x10-8) with asthma, hay fever or eczema, analysed separately or as disease phenotypes that includes the presence of different combinations of these diseases. The largest number of loci were associated with the combined phenotype (asthma/hay fever/eczema). However, as many as 20 loci had a significantly larger effect on hay fever/eczema-only compared to their effects on asthma, while 26 loci exhibited larger effects on asthma compared with their effects on hay fever/eczema. At four of the novel loci, TNFRSF8, MYRF, TSPAN8, and BHMG1, the lead SNPs were in LD (> 0.8) with potentially casual missense variants. Our study shows that a large amount of the genetic contribution is shared between the diseases. Nonetheless, a number of SNPs have a significantly larger effect on one of the phenotypes suggesting that part of the genetic contribution is more phenotype specific.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-392909 (URN)10.1093/hmg/ddz175 (DOI)31361310 (PubMedID)
Available from: 2019-09-11 Created: 2019-09-11 Last updated: 2019-09-12
Rask-Andersen, M., Karlsson, T., Ek, W. E. & Johansson, Å. (2019). Genome-wide association study of body fat distribution identifies adiposity loci and sex-specific genetic effects. Nature Communications, 10, Article ID 339.
Open this publication in new window or tab >>Genome-wide association study of body fat distribution identifies adiposity loci and sex-specific genetic effects
2019 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 339Article in journal (Refereed) Published
Abstract [en]

Body mass and body fat composition are of clinical interest due to their links to cardiovascular- and metabolic diseases. Fat stored in the trunk has been suggested to be more pathogenic compared to fat stored in other compartments. In this study, we perform genome-wide association studies (GWAS) for the proportion of body fat distributed to the arms, legs and trunk estimated from segmental bio-electrical impedance analysis (sBIA) for 362,499 individuals from the UK Biobank. 98 independent associations with body fat distribution are identified, 29 that have not previously been associated with anthropometric traits. A high degree of sex-heterogeneity is observed and the effects of 37 associated variants are stronger in females compared to males. Our findings also implicate that body fat distribution in females involves mesenchyme derived tissues and cell types, female endocrine tissues as well as extracellular matrix maintenance and remodeling.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-376829 (URN)10.1038/s41467-018-08000-4 (DOI)000456164400001 ()30664634 (PubMedID)
Funder
Swedish Society for Medical Research (SSMF)Göran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologySwedish Heart Lung FoundationÅke Wiberg Foundation
Available from: 2019-02-11 Created: 2019-02-11 Last updated: 2019-02-11Bibliographically approved
Rask-Andersen, M., Karlsson, T., Ek, W. E. & Johansson, Å. (2019). Genome-wide association study of body fat distribution identifies adiposity loci and sex-specific genetic effects. Nature Communications, 10, Article ID 339.
Open this publication in new window or tab >>Genome-wide association study of body fat distribution identifies adiposity loci and sex-specific genetic effects
2019 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 339Article in journal (Refereed) Published
Abstract [en]

Body mass and body fat composition are of clinical interest due to their links to cardiovascular- and metabolic diseases. Fat stored in the trunk has been suggested to be more pathogenic compared to fat stored in other compartments. In this study, we perform genome-wide association studies (GWAS) for the proportion of body fat distributed to the arms, legs and trunk estimated from segmental bio-electrical impedance analysis (sBIA) for 362,499 individuals from the UK Biobank. 98 independent associations with body fat distribution are identified, 29 that have not previously been associated with anthropometric traits. A high degree of sex-heterogeneity is observed and the effects of 37 associated variants are stronger in females compared to males. Our findings also implicate that body fat distribution in females involves mesenchyme derived tissues and cell types, female endocrine tissues as well as extracellular matrix maintenance and remodeling.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-392911 (URN)
Funder
Swedish Society for Medical Research (SSMF)Göran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologySwedish Heart Lung FoundationÅke Wiberg Foundation
Available from: 2019-09-11 Created: 2019-09-11 Last updated: 2019-09-11
Ek, W. E., Karlsson, T., Hernándes, C. A., Rask-Andersen, M. & Johansson, Å. (2018). Breast-feeding and risk of asthma, hay fever, and eczema [Letter to the editor]. Journal of Allergy and Clinical Immunology, 141(3), 1157-+
Open this publication in new window or tab >>Breast-feeding and risk of asthma, hay fever, and eczema
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2018 (English)In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 141, no 3, p. 1157-+Article in journal, Letter (Other academic) Published
National Category
Respiratory Medicine and Allergy Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-355831 (URN)10.1016/j.jaci.2017.10.022 (DOI)000426974800046 ()29132959 (PubMedID)
Available from: 2018-07-06 Created: 2018-07-06 Last updated: 2018-07-06Bibliographically approved
Ek, W. E., Rask-Andersen, M., Karlsson, T., Enroth, S., Gyllensten, U. B. & Johansson, Å. (2018). Genetic variants influencing phenotypic variance heterogeneity. Human Molecular Genetics, 27(5), 799-810
Open this publication in new window or tab >>Genetic variants influencing phenotypic variance heterogeneity
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2018 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 27, no 5, p. 799-810Article in journal (Refereed) Published
Abstract [en]

Most genetic studies identify genetic variants associated with disease risk or with the mean value of a quantitative trait. More rarely, genetic variants associated with variance heterogeneity are considered. In this study, we have identified such variance single-nucleotide polymorphisms (vSNPs) and examined if these represent biological gene x gene or gene x environment interactions or statistical artifacts caused by multiple linked genetic variants influencing the same phenotype. We have performed a genome-wide study, to identify vSNPs associated with variance heterogeneity in DNA methylation levels. Genotype data from over 10 million single-nucleotide polymorphisms (SNPs), and DNA methylation levels at over 430 000 CpG sites, were analyzed in 729 individuals. We identified vSNPs for 7195 CpG sites (P < 9.4 x 10(-11)). This is a relatively low number compared to 52 335 CpG sites for which SNPs were associated with mean DNA methylation levels. We further showed that variance heterogeneity between genotypes mainly represents additional, often rare, SNPs in linkage disequilibrium (LD) with the respective vSNP and for some vSNPs, multiple low frequency variants co-segregating with one of the vSNP alleles. Therefore, our results suggest that variance heterogeneity of DNA methylation mainly represents phenotypic effects by multiple SNPs, rather than biological interactions. Such effects may also be important for interpreting variance heterogeneity of more complex clinical phenotypes.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2018
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-350890 (URN)10.1093/hmg/ddx441 (DOI)000426838200003 ()29325024 (PubMedID)
Funder
Swedish Research Council, 2011-2354, 2015-03327Göran Gustafsson Foundation for Research in Natural Sciences and MedicineSwedish Society for Medical Research (SSMF)Åke Wiberg Foundation
Available from: 2018-05-28 Created: 2018-05-28 Last updated: 2018-07-06Bibliographically approved
Villarroel, B., Nyholm, A., Karlsson, T., Comeron, S., Korn, A., Sollerman, J. & Zackrisson, E. (2017). AGN luminosity and stellar age: two missing ingredients forAGN unification as seen with iPTF supernovae. Astrophysical Journal, 837(2), Article ID 110.
Open this publication in new window or tab >>AGN luminosity and stellar age: two missing ingredients forAGN unification as seen with iPTF supernovae
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2017 (English)In: Astrophysical Journal, ISSN 0004-637X, E-ISSN 1538-4357, Vol. 837, no 2, article id 110Article in journal (Refereed) Published
Abstract [en]

Active galactic nuclei (AGNs) are extremely powerful cosmic objects, driven by accretion of hot gas upon super-massive black holes. The zoo of AGN classes is divided into two major groups, with Type-1 AGNs displaying broad Balmer emission lines and Type-2 narrow ones. For a long time it was believed that a Type-2 AGN is a Type-1 AGN viewed through a dusty kiloparsec-sized torus, but an emerging body of observations suggests more than just the viewing angle matters. Here we report significant differences in supernova (SN) counts and classes in the first study to date of SNe near Type-1 and Type-2 AGN host galaxies, using data from the intermediate Palomar Transient Factory, the Sloan Digital Sky Survey Data Release 7, and Galaxy Zoo. We detect many more SNe in Type-2 AGN hosts (size of effect similar to 5.1 sigma) compared to Type-1 hosts, which shows that the two classes of AGN are located inside host galaxies with different properties. In addition, Type-1 and Type-2 AGNs that are dominated by star formation according to Wide-field Infrared Survey Explorer colors m(W1) - m(W2) < 0.5 and are matched in 22 mu m absolute magnitude differ by a factor of ten in L[O III] lambda 5007 luminosity, suggesting that when residing in similar types of host galaxies Type-1 AGNs are much more luminous. Our results demonstrate two more factors that play an important role in completing the current picture: the age of stellar populations and the AGN luminosity. This has immediate consequences for understanding the many AGN classes and galaxy evolution.

National Category
Astronomy, Astrophysics and Cosmology
Identifiers
urn:nbn:se:uu:diva-308356 (URN)10.3847/1538-4357/aa5d5a (DOI)000401172400008 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2016-11-24 Created: 2016-11-24 Last updated: 2017-06-15Bibliographically approved
Rask-Andersen, M., Karlsson, T., Ek, W. E. & Johansson, Å. (2017). Gene-environment interaction study for BMI reveals interactions between genetic factors and physical activity, alcohol consumption and socioeconomic status.. PLoS Genetics, 13(9), Article ID e1006977.
Open this publication in new window or tab >>Gene-environment interaction study for BMI reveals interactions between genetic factors and physical activity, alcohol consumption and socioeconomic status.
2017 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 9, article id e1006977Article in journal (Refereed) Published
Abstract [en]

Previous genome-wide association studies (GWAS) have identified hundreds of genetic loci to be associated with body mass index (BMI) and risk of obesity. Genetic effects can differ between individuals depending on lifestyle or environmental factors due to gene-environment interactions. In this study, we examine gene-environment interactions in 362,496 unrelated participants with Caucasian ancestry from the UK Biobank resource. A total of 94 BMI-associated SNPs, selected from a previous GWAS on BMI, were used to construct weighted genetic scores for BMI (GSBMI). Linear regression modeling was used to estimate the effect of gene-environment interactions on BMI for 131 lifestyle factors related to: dietary habits, smoking and alcohol consumption, physical activity, socioeconomic status, mental health, sleeping patterns, as well as female-specific factors such as menopause and childbirth. In total, 15 lifestyle factors were observed to interact with GSBMI, of which alcohol intake frequency, usual walking pace, and Townsend deprivation index, a measure of socioeconomic status, were all highly significant (p = 1.45*10-29, p = 3.83*10-26, p = 4.66*10-11, respectively). Interestingly, the frequency of alcohol consumption, rather than the total weekly amount resulted in a significant interaction. The FTO locus was the strongest single locus interacting with any of the lifestyle factors. However, 13 significant interactions were also observed after omitting the FTO locus from the genetic score. Our analyses indicate that many lifestyle factors modify the genetic effects on BMI with some groups of individuals having more than double the effect of the genetic score. However, the underlying causal mechanisms of gene-environmental interactions are difficult to deduce from cross-sectional data alone and controlled experiments are required to fully characterise the causal factors.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-332047 (URN)10.1371/journal.pgen.1006977 (DOI)000411976100011 ()28873402 (PubMedID)
Funder
Swedish Research Council, 2015-03327Göran Gustafsson Foundation for Research in Natural Sciences and MedicineSwedish Society for Medical Research (SSMF)Åke Wiberg FoundationSwedish National Infrastructure for Computing (SNIC), b2016021
Available from: 2017-10-23 Created: 2017-10-23 Last updated: 2018-07-06Bibliographically approved
Berghoff, B. A., Karlsson, T., Kallman, T., Wagner, G. E. H. & Grabherr, M. G. (2017). RNA-sequence data normalization through in silico prediction of reference genes: the bacterial response to DNA damage as case study. BioData Mining, 10, Article ID 30.
Open this publication in new window or tab >>RNA-sequence data normalization through in silico prediction of reference genes: the bacterial response to DNA damage as case study
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2017 (English)In: BioData Mining, ISSN 1756-0381, E-ISSN 1756-0381, Vol. 10, article id 30Article in journal (Refereed) Published
Abstract [en]

Background: Measuring how gene expression changes in the course of an experiment assesses how an organism responds on a molecular level. Sequencing of RNA molecules, and their subsequent quantification, aims to assess global gene expression changes on the RNA level (transcriptome). While advances in high-throughput RNA-sequencing (RNA-seq) technologies allow for inexpensive data generation, accurate post-processing and normalization across samples is required to eliminate any systematic noise introduced by the biochemical and/or technical processes. Existing methods thus either normalize on selected known reference genes that are invariant in expression across the experiment, assume that the majority of genes are invariant, or that the effects of up-and down-regulated genes cancel each other out during the normalization.

Results: Here, we present a novel method, moose(2), which predicts invariant genes in silico through a dynamic programming (DP) scheme and applies a quadratic normalization based on this subset. The method allows for specifying a set of known or experimentally validated invariant genes, which guides the DP. We experimentally verified the predictions of this method in the bacterium Escherichia coli, and show how moose(2) is able to (i) estimate the expression value distances between RNA-seq samples, (ii) reduce the variation of expression values across all samples, and (iii) to subsequently reveal new functional groups of genes during the late stages of DNA damage. We further applied the method to three eukaryotic data sets, on which its performance compares favourably to other methods. The software is implemented in C++ and is publicly available from http://grabherr.github.io/moose2/.

Conclusions: The proposed RNA-seq normalization method, moose(2), is a valuable alternative to existing methods, with two major advantages: (i) in silico prediction of invariant genes provides a list of potential reference genes for downstream analyses, and (ii) non-linear artefacts in RNA-seq data are handled adequately to minimize variations between replicates.

Keywords
RNA-seq, Transcriptomics, Normalization, Gene expression, DNA damage, Stress response
National Category
Microbiology
Identifiers
urn:nbn:se:uu:diva-334397 (URN)10.1186/s13040-017-0150-8 (DOI)000409118300001 ()28878825 (PubMedID)
Funder
Swedish Research Council FormasSwedish Research Council, 621-2010-5233
Available from: 2017-12-08 Created: 2017-12-08 Last updated: 2018-05-25Bibliographically approved
Ek, W. E., Tobi, E. W., Ahsan, M., Lampa, E., Ponzi, E., Kyrtopoulos, S. A., . . . Johansson, Å. (2017). Tea and coffee consumption in relation to DNA methylation in four European cohorts. Human Molecular Genetics, 26(16), pp. 3221-3231
Open this publication in new window or tab >>Tea and coffee consumption in relation to DNA methylation in four European cohorts
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2017 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 26, no 16, p. 3221-3231Article in journal, News item (Refereed) Published
Abstract [en]

Lifestyle factors, such as food choices and exposure to chemicals, can alter DNA methylation and lead to changes in gene activity. Two such exposures with pharmacologically active components are coffee and tea consumption. Both coffee and tea have been suggested to play an important role in modulating disease-risk in humans by suppressing tumour progression, decreasing inflammation and influencing estrogen metabolism. These mechanisms may be mediated by changes in DNA methylation. To investigate if DNA methylation in blood is associated with coffee and tea consumption, we performed a genome-wide DNA methylation study for coffee and tea consumption in four European cohorts (N = 3,096). DNA methylation was measured from whole blood at 421,695 CpG sites distributed throughout the genome and analysed in men and women both separately and together in each cohort. Meta-analyses of the results and additional regional-level analyses were performed. After adjusting for multiple testing, the meta-analysis revealed that two individual CpG-sites, mapping to DNAJC16 and TTC17, were differentially methylated in relation to tea consumption in women. No individual sites were associated with men or with the sex-combined analysis for tea or coffee. The regional analysis revealed that 28 regions were differentially methylated in relation to tea consumption in women. These regions contained genes known to interact with estradiol metabolism and cancer. No significant regions were found in the sex-combined and male-only analysis for either tea or coffee consumption.

Place, publisher, year, edition, pages
Oxford University Press, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-332048 (URN)10.1093/hmg/ddx194 (DOI)000406794000017 ()28535255 (PubMedID)
Available from: 2017-10-23 Created: 2017-10-23 Last updated: 2018-07-06Bibliographically approved
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