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Rask-Andersen, Mathias
Publications (10 of 38) 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
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
Attwood, M. M., Rask-Andersen, M. & Schiöth, H. B. (2018). Orphan Drugs and Their Impact on Pharmaceutical Development. TIPS - Trends in Pharmacological Sciences, 39(6), 525-535
Open this publication in new window or tab >>Orphan Drugs and Their Impact on Pharmaceutical Development
2018 (English)In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 39, no 6, p. 525-535Article, review/survey (Refereed) Published
Abstract [en]

High levels of productivity, with an increasing number of approvals for new molecular entities (NMEs) by the FDA during the past decade, have coincided with the emergence of innovative drugs for treatments of rare diseases that have utilized the FDA orphan drug program. Since 2000, NMEs with orphan designation encompass a significant portion of approved drugs and constitute about 80% of the approved drugs that have established novel human genome-encoded products in recent years. Biological approvals are also expanding, with 40% of the approved biological agents having orphan designation. This trend illustrates a pivot within the pharmaceutical industry: from research programs that focus on canonical blockbuster indications and targets, towards the establishment of new treatments for rare and difficult to treat diseases.

National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-358124 (URN)10.1016/j.tips.2018.03.003 (DOI)000432349900001 ()29779531 (PubMedID)
Available from: 2018-08-24 Created: 2018-08-24 Last updated: 2019-03-15Bibliographically approved
Wiemerslage, L., Islam, R., van der Kamp, C., Cao, H., Olivo, G., Ence-Eriksson, F., . . . Schiöth, H. B. (2017). A DNA methylation site within the KLF13 gene is associated with orexigenic processes based on neural responses and ghrelin levels. International Journal of Obesity, 41(6), 990-994
Open this publication in new window or tab >>A DNA methylation site within the KLF13 gene is associated with orexigenic processes based on neural responses and ghrelin levels
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2017 (English)In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 41, no 6, p. 990-994Article in journal (Refereed) Published
Abstract [en]

We investigated five methylation markers recently linked to body-mass index, for their role in the neuropathology of obesity. In neuroimaging experiments, our analysis involving 23 participants showed that methylation levels for the cg07814318 site, which lies within the KLF13 gene, correlated with brain activity in the claustrum, putamen, cingulate gyrus, and frontal gyri, some of which have been previously associated to food signaling, obesity, or reward. Methylation levels at cg07814318 also positively correlated with ghrelin levels. Moreover, expression of KLF13 was augmented in the brains of obese and starved mice. Our results suggest the cg07814318 site could be involved in orexigenic processes, and also implicate KLF13 in obesity. Our findings are the first to associate methylation levels in blood with brain activity in obesity-related regions, and further support previous findings between ghrelin, brain activity, and genetic differences.

National Category
Neurosciences Endocrinology and Diabetes Nutrition and Dietetics
Identifiers
urn:nbn:se:uu:diva-315855 (URN)10.1038/ijo.2017.43 (DOI)000402735900024 ()28194012 (PubMedID)
Funder
Swedish Research CouncilThe Swedish Brain Foundation
Available from: 2017-02-21 Created: 2017-02-21 Last updated: 2018-02-21Bibliographically approved
Solstrand Dahlberg, L., Wiemerslage, L., Swenne, I., Larsen, A., Stark, J., Rask-Andersen, M., . . . Brooks, S. J. (2017). Adolescents newly diagnosed with eating disorders have structural differences in brain regions linked with eating disorder symptoms. Nordic Journal of Psychiatry, 71(3), 188-196
Open this publication in new window or tab >>Adolescents newly diagnosed with eating disorders have structural differences in brain regions linked with eating disorder symptoms
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2017 (English)In: Nordic Journal of Psychiatry, ISSN 0803-9488, E-ISSN 1502-4725, Vol. 71, no 3, p. 188-196Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Adults with eating disorders (ED) show brain volume reductions in the frontal, insular, cingulate, and parietal cortices, as well as differences in subcortical regions associated with reward processing. However, little is known about the structural differences in adolescents with behavioural indications of early stage ED.

AIM: This is the first study to investigate structural brain changes in adolescents newly diagnosed with ED compared to healthy controls (HC), and to study whether ED cognitions correlate with structural changes in adolescents with ED of short duration.

METHODS: Fifteen adolescent females recently diagnosed with ED, and 28 age-matched HC individuals, were scanned with structural magnetic resonance imaging (MRI). Whole-brain and region-of-interest analyses were conducted using voxel-based morphometry (VBM). ED cognitions were measured with self-report questionnaires and working memory performance was measured with a neuropsychological computerized test.

RESULTS AND CONCLUSIONS: The left superior temporal gyrus had a smaller volume in adolescents with ED than in HC, which correlated with ED cognitions (concerns about eating, weight, and shape). Working memory reaction time correlated positively with insula volumes in ED participants, but not HC. In ED, measurements of restraint and obsession was negatively correlated with temporal gyrus volumes, and positively correlated with cerebellar and striatal volumes. Thus, adolescents with a recent diagnosis of ED had volumetric variations in brain areas linked to ED cognitions, obsessions, and working memory. The findings emphasize the importance of early identification of illness, before potential long-term effects on structure and behaviour occur.

Keywords
Eating disorders, adolescents, MRI, eating disorders not otherwise specified, anorexia nervosa
National Category
Psychiatry
Identifiers
urn:nbn:se:uu:diva-311299 (URN)10.1080/08039488.2016.1250948 (DOI)000399501200004 ()27844498 (PubMedID)
Funder
The Swedish Brain FoundationSwedish Research Council Formas
Available from: 2016-12-22 Created: 2016-12-22 Last updated: 2017-05-30Bibliographically approved
Ek, W. E., Ahsan, M., Rask-Andersen, M., Liang, L., Moffatt, M. F., Gyllensten, U. & Johansson, Å. (2017). Epigenome-wide DNA methylation study of IgE concentration in relation to self-reported allergies. Epigenomics, 9(4), 407-418
Open this publication in new window or tab >>Epigenome-wide DNA methylation study of IgE concentration in relation to self-reported allergies
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2017 (English)In: Epigenomics, ISSN 1750-1911, Vol. 9, no 4, p. 407-418Article in journal (Refereed) Published
Abstract [en]

AIM: Epigenetic mechanisms are critical for normal immune development and epigenetic alterations might therefore be possible contributors to immune diseases. To investigate if DNA methylation in whole blood is associated with total and allergen-specific IgE levels.

METHODS: We performed an epigenome-wide association study to investigate the association between DNA methylation and IgE level, allergen-specific IgE and self-reported immune diseases and allergies in 728 individuals.

RESULTS: We identified and replicated 15 CpG sites associated with IgE, mapping to biologically relevant genes, including ACOT7, ILR5A, KCNH2, PRG2 and EPX. A total of 331 loci were associated with allergen-specific IgE, but none of these CpG sites were associated with self-reported allergies and immune diseases.

CONCLUSION: This study shows that IgE levels are associated with DNA methylation levels at numerous CpG sites, which might provide new leads for investigating the links between IgE and allergic inflammation.

Keywords
DNA methylation, Fx5, IgE, Phadiatop, allergy, immune diseases
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-318034 (URN)10.2217/epi-2016-0158 (DOI)000399344700006 ()28322575 (PubMedID)
Funder
Swedish Society of Medicine, 2011-2354 K2007-66X-20270-01-3Göran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologySwedish Foundation for Strategic Research EU, European Research CouncilScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2017-03-23 Created: 2017-03-23 Last updated: 2018-07-06Bibliographically 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
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