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Jiang, J., Thalamuthu, A., Ho, J. E., Mahajan, A., Ek, W. E., Brown, D. A., . . . Mather, K. A. (2018). A Meta-Analysis of Genome-Wide Association Studies of Growth Differentiation Factor-15 Concentration in Blood. Frontiers in Genetics, 9, Article ID 97.
Open this publication in new window or tab >>A Meta-Analysis of Genome-Wide Association Studies of Growth Differentiation Factor-15 Concentration in Blood
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2018 (English)In: Frontiers in Genetics, ISSN 1664-8021, E-ISSN 1664-8021, Vol. 9, article id 97Article in journal (Refereed) Published
Abstract [en]

Blood levels of growth differentiation factor-15 (GDF-15), also known as macrophage inhibitory cytokine-1 (MIC-1), have been associated with various pathological processes and diseases, including cardiovascular disease and cancer. Prior studies suggest genetic factors play a role in regulating blood MIC-1/GDF-15 concentration. In the current study, we conducted the largest genome-wide association study (GWAS) to date using a sample of similar to 5,400 community-based Caucasian participants, to determine the genetic variants associated with MIC-1/GDF-15 blood concentration. Conditional and joint (COJO), gene-based association, and gene-set enrichment analyses were also carried out to identify novel loci, genes, and pathways. Consistent with prior results, a locus on chromosome 19, which includes nine single nucleotide polymorphisms (SNPs) (top SNP, rs888663, p = 1.690 x 10(-35)), was significantly associated with blood MIC-1/GDF-15 concentration, and explained 21.47% of its variance. COJO analysis showed evidence for two independent signals within this locus. Gene-based analysis confirmed the chromosome 19 locus association and in addition, a putative locus on chromosome 1. Gene-set enrichment analyses showed that the "COPI-mediated anterograde transport" gene-set was associated with MIC-1/GDF15 blood concentration with marginal significance after FDR correction (p = 0.067). In conclusion, a locus on chromosome 19 was associated with MIC-1/GDF-15 blood concentration with genome-wide significance, with evidence for a new locus (chromosome 1). Future studies using independent cohorts are needed to confirm the observed associations especially for the chromosomes 1 locus, and to further investigate and identify the causal SNPs that contribute to MIC-1/GDF-15 levels.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2018
Keywords
genome-wide association study, growth differentiation factor-15, macrophage inhibitory cytokine-1, community-based individuals, chromosome 19
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-354354 (URN)10.3389/fgene.2018.00097 (DOI)000428198300001 ()
Funder
Knut and Alice Wallenberg FoundationEU, European Research CouncilSwedish Research Council, 2012-1397Swedish Research Council, 2012-1727Swedish Research Council, 2012-2215Swedish Research Council, 80576801Swedish Research Council, 70374401Swedish Foundation for Strategic Research Australian Research Council, DP0774213Australian Research Council, DP0773584Australian Research Council, LP0669645
Available from: 2018-08-08 Created: 2018-08-08 Last updated: 2018-08-08Bibliographically 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
Enroth, S., Maturi, V., Berggrund, M., Bosdotter Enroth, S., Moustakas, A., Johansson, Å. & Gyllensten, U. B. (2018). Systemic and specific effects of antihypertensive and lipid-lowering medication on plasma protein biomarkers for cardiovascular diseases. Scientific Reports, 8, Article ID 5531.
Open this publication in new window or tab >>Systemic and specific effects of antihypertensive and lipid-lowering medication on plasma protein biomarkers for cardiovascular diseases
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 5531Article in journal (Refereed) Published
Abstract [en]

A large fraction of the adult population is on lifelong medication for cardiovascular disorders, but the metabolic consequences are largely unknown. This study determines the effects of common anti-hypertensive and lipid lowering drugs on circulating plasma protein biomarkers. We studied 425 proteins in plasma together with anthropometric and lifestyle variables, and the genetic profile in a cross-sectional cohort. We found 8406 covariate-protein associations, and a two-stage GWAS identified 17253 SNPs to be associated with 109 proteins. By computationally removing variation due to lifestyle and genetic factors, we could determine that medication, per se, affected the abundance levels of 35.7% of the plasma proteins. Medication either affected a single, a few, or a large number of protein, and were found to have a negative or positive influence on known disease pathways and biomarkers. Anti-hypertensive or lipid lowering drugs affected 33.1% of the proteins. Angiotensin-converting enzyme inhibitors showed the strongest lowering effect by decreasing plasma levels of myostatin. Cell-culture experiments showed that angiotensin-converting enzyme inhibitors reducted myostatin RNA levels. Thus, understanding the effects of lifelong medication on the plasma proteome is important both for sharpening the diagnostic precision of protein biomarkers and in disease management.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-351628 (URN)10.1038/s41598-018-23860-y (DOI)000428999200067 ()29615742 (PubMedID)
Funder
Swedish Foundation for Strategic Research Swedish National Infrastructure for Computing (SNIC), b2011203; b2014145
Available from: 2018-06-07 Created: 2018-06-07 Last updated: 2018-07-06Bibliographically 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
Warren, H. R., Evangelou, E., Cabrera, C. P., Gao, H., Ren, M., Mifsud, B., . . . Morris, A. P. (2017). Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk. Nature Genetics, 49(3), 403-415
Open this publication in new window or tab >>Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk
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2017 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 49, no 3, p. 403-415Article in journal (Refereed) Published
Abstract [en]

Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-318933 (URN)10.1038/ng.3768 (DOI)000394917800014 ()28135244 (PubMedID)
Available from: 2017-04-10 Created: 2017-04-10 Last updated: 2018-07-06Bibliographically approved
Graff, M., Scott, R. A., Justice, A. E., Young, K. L., Feitosa, M. F., Barata, L., . . . Kilpeläinen, T. O. (2017). Genome-wide physical activity interactions in adiposity: A meta-analysis of 200,452 adults.. PLoS Genetics, 13(4), Article ID e1006528.
Open this publication in new window or tab >>Genome-wide physical activity interactions in adiposity: A meta-analysis of 200,452 adults.
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2017 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 4, article id e1006528Article in journal (Refereed) Published
Abstract [en]

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2017
Keywords
BODY-MASS INDEX; REACTIVE PROTEIN-LEVELS; GENE-EXPRESSION; IDENTICAL-TWINS; ADIPOCYTE DIFFERENTIATION; ASSOCIATION METAANALYSIS; ACTIVITY QUESTIONNAIRES; FAT DISTRIBUTION; BINDING PROTEIN; FOOD-INTAKE
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-321624 (URN)10.1371/journal.pgen.1006528 (DOI)000402549200002 ()28448500 (PubMedID)
Available from: 2017-05-09 Created: 2017-05-09 Last updated: 2018-07-06Bibliographically approved
Folkersen, L., Fauman, E., Sabater-Lleal, M., Strawbridge, R. J., Frånberg, M., Sennblad, B., . . . Mälarstig, A. (2017). Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease. PLoS Genetics, 13(4), Article ID e1006706.
Open this publication in new window or tab >>Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease
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2017 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 4, article id e1006706Article in journal (Refereed) Published
Abstract [en]

Recent advances in highly multiplexed immunoassays have allowed systematic large-scale measurement of hundreds of plasma proteins in large cohort studies. In combination with genotyping, such studies offer the prospect to 1) identify mechanisms involved with regulation of protein expression in plasma, and 2) determine whether the plasma proteins are likely to be causally implicated in disease. We report here the results of genome-wide association (GWA) studies of 83 proteins considered relevant to cardiovascular disease (CVD), measured in 3,394 individuals with multiple CVD risk factors. We identified 79 genome-wide significant (p<5e-8) association signals, 55 of which replicated at P<0.0007 in separate validation studies (n = 2,639 individuals). Using automated text mining, manual curation, and network-based methods incorporating information on expression quantitative trait loci (eQTL), we propose plausible causal mechanisms for 25 trans-acting loci, including a potential post-translational regulation of stem cell factor by matrix metalloproteinase 9 and receptor-ligand pairs such as RANK-RANK ligand. Using public GWA study data, we further evaluate all 79 loci for their causal effect on coronary artery disease, and highlight several potentially causal associations. Overall, a majority of the plasma proteins studied showed evidence of regulation at the genetic level. Our results enable future studies of the causal architecture of human disease, which in turn should aid discovery of new drug targets.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2017
Keywords
GENOME-WIDE ASSOCIATION; INTIMA-MEDIA THICKNESS; GENETIC-VARIANTS; MENDELIAN RANDOMIZATION; EXPRESSION; RISK; POPULATION; CELLS; GWAS; LIFE
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-319845 (URN)10.1371/journal.pgen.1006706 (DOI)000402549200023 ()28369058 (PubMedID)
Available from: 2017-04-10 Created: 2017-04-10 Last updated: 2018-01-03Bibliographically approved
Wain, L. V., Vaez, A., Jansen, R., Joehanes, R., van der Most, P. J., Erzurumluoglu, A. M., . . . Xiao, L. (2017). Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney. Hypertension, 70(3), E4-e19
Open this publication in new window or tab >>Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney
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2017 (English)In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 70, no 3, p. E4-e19Article in journal (Refereed) Published
Abstract [en]

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

Keywords
blood pressure, cardiovascular risk, complex traits, eSNP, GWAS, hypertension
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-334925 (URN)10.1161/HYPERTENSIONAHA.117.09438 (DOI)000407241500001 ()
Funder
NIH (National Institute of Health), R01-DK062370; ZIA-HG000024; R01D0042157-01A; MH081802; 1RC2 MH089951; 1RC2 MH089995Swedish Research Council, K2007-66X-20270-01-3; 2011-5252; 2012-2884; 2011-2354; 2015-03327EU, FP7, Seventh Framework Programme, FP7 313010EU, European Research CouncilSwedish Heart Lung Foundation, 20120197Torsten Söderbergs stiftelseKnut and Alice Wallenberg FoundationSwedish Research Council, 2012-1397; M-2005-1112; 2009-2298Swedish Diabetes Association, 2013-024Swedish Society for Medical Research (SSMF)
Available from: 2017-11-29 Created: 2017-11-29 Last updated: 2018-07-06Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-2915-4498

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