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Clark, D. W., Karlsson, T., Sennblad, B., Gyllensten, U. B., Johansson, Å. & Wilson, J. F. (2019). Associations of autozygosity with a broad range of human phenotypes. Nature Communications, 10, Article ID 4957.
Open this publication in new window or tab >>Associations of autozygosity with a broad range of human phenotypes
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2019 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 4957Article in journal (Refereed) Published
Abstract [en]

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F-ROH) for >1.4 million individuals, we show that F-ROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F-ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F-ROH are confirmed within full-sibling pairs, where the variation in F-ROH is independent of all environmental confounding.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-397418 (URN)10.1038/s41467-019-12283-6 (DOI)000493438700005 ()31673082 (PubMedID)
Note

For complete list of authors see http://dx.doi.org/10.1038/s41467-019-12283-6

Available from: 2019-11-20 Created: 2019-11-20 Last updated: 2019-11-20Bibliographically approved
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 Genetics
Identifiers
urn:nbn:se:uu:diva-392977 (URN)10.1038/s41591-019-0563-7 (DOI)000484832800021 ()31501611 (PubMedID)
Funder
Swedish National Infrastructure for Computing (SNIC), b2016021Swedish National Infrastructure for Computing (SNIC), sens2017538Swedish Society for Medical Research (SSMF)Swedish Research Council, 2015-03327Göran Gustafsson Foundation for Research in Natural Sciences and MedicineÅke Wiberg Foundation, M16-0210Swedish Heart Lung Foundation, 20170484Swedish Diabetes AssociationScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2019-09-12 Created: 2019-09-12 Last updated: 2019-11-20Bibliographically approved
Imboden, M., Wielscher, M., Rezwan, F. I., Amaral, A. F., Schaffner, E., Jeong, A., . . . Probst-Hensch, N. M. (2019). Epigenome-wide association study of lung function level and its change. European Respiratory Journal, 54(1), Article ID 1900457.
Open this publication in new window or tab >>Epigenome-wide association study of lung function level and its change
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2019 (English)In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 54, no 1, article id 1900457Article in journal (Refereed) Published
Abstract [en]

Previous reports link differential DNA methylation (DNAme) to environmental exposures that are associated with lung function. Direct evidence on lung function DNAme is, however, limited. We undertook an agnostic epigenome-wide association study (EWAS) on pre-bronchodilation lung function and its change in adults.In a discovery-replication EWAS design, DNAme in blood and spirometry were measured twice, 6-15 years apart, in the same participants of three adult population-based discovery cohorts (n=2043). Associated DNAme markers (p<5×10-7) were tested in seven replication cohorts (adult: n=3327; childhood: n=420). Technical bias-adjusted residuals of a regression of the normalised absolute β-values on control probe-derived principle components were regressed on level and change of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and their ratio (FEV1/FVC) in the covariate-adjusted discovery EWAS. Inverse-variance-weighted meta-analyses were performed on results from discovery and replication samples in all participants and never-smokers.EWAS signals were enriched for smoking-related DNAme. We replicated 57 lung function DNAme markers in adult, but not childhood samples, all previously associated with smoking. Markers not previously associated with smoking failed replication. cg05575921 (AHRR (aryl hydrocarbon receptor repressor)) showed the statistically most significant association with cross-sectional lung function (FEV1/FVC: pdiscovery=3.96×10-21 and pcombined=7.22×10-50). A score combining 10 DNAme markers previously reported to mediate the effect of smoking on lung function was associated with lung function (FEV1/FVC: p=2.65×10-20).Our results reveal that lung function-associated methylation signals in adults are predominantly smoking related, and possibly of clinical utility in identifying poor lung function and accelerated decline. Larger studies with more repeat time-points are needed to identify lung function DNAme in never-smokers and in children.

Place, publisher, year, edition, pages
European Respiratory Society, 2019
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:uu:diva-392910 (URN)10.1183/13993003.00457-2019 (DOI)000486537500022 ()31073081 (PubMedID)
Funder
EU, Horizon 2020, 633212
Available from: 2019-09-11 Created: 2019-09-11 Last updated: 2019-10-30Bibliographically approved
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, 28(23), 4022-4041
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, Vol. 28, no 23, p. 4022-4041Article in journal (Refereed) Published
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
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-392909 (URN)10.1093/hmg/ddz175 (DOI)000509925500009 ()31361310 (PubMedID)
Available from: 2019-09-11 Created: 2019-09-11 Last updated: 2020-03-24Bibliographically 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-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: 2019-11-20Bibliographically approved
Höglund, J., Rafati, N., Rask-Andersen, M., Enroth, S., Karlsson, T., Ek, W. E. & Johansson, Å. (2019). Improved power and precision with whole genome sequencing data in genome-wide association studies of inflammatory biomarkers. Scientific Reports, 9, Article ID 16844.
Open this publication in new window or tab >>Improved power and precision with whole genome sequencing data in genome-wide association studies of inflammatory biomarkers
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 16844Article in journal (Refereed) Published
Abstract [en]

Genome-wide association studies (GWAS) have identified associations between thousands of common genetic variants and human traits. However, common variants usually explain a limited fraction of the heritability of a trait. A powerful resource for identifying trait-associated variants is whole genome sequencing (WGS) data in cohorts comprised of families or individuals from a limited geographical area. To evaluate the power of WGS compared to imputations, we performed GWAS on WGS data for 72 inflammatory biomarkers, in a kinship-structured cohort. When using WGS data, we identified 18 novel associations that were not detected when analyzing the same biomarkers with genotyped or imputed SNPs. Five of the novel top variants were low frequency variants with a minor allele frequency (MAF) of <5%. Our results suggest that, even when applying a GWAS approach, we gain power and precision using WGS data, presumably due to more accurate determination of genotypes. The lack of a comparable dataset for replication of our results is a limitation in our study. However, this further highlights that there is a need for more genetic epidemiological studies based on WGS data.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-397948 (URN)10.1038/s41598-019-53111-7 (DOI)000496416000054 ()31727947 (PubMedID)
Funder
Swedish National Infrastructure for Computing (SNIC), sens2016007Swedish Heart Lung Foundation
Available from: 2020-01-02 Created: 2020-01-02 Last updated: 2020-01-02Bibliographically approved
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: 2019-11-20Bibliographically approved
Evangelou, E., Warren, H. R., Mosen-Ansorena, D., Mifsud, B., Pazoki, R., Gao, H., . . . Caulfield, M. J. (2018). Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.. Nature Genetics, 50(10), 1412-1425
Open this publication in new window or tab >>Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
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2018 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 50, no 10, p. 1412-1425Article in journal (Refereed) Published
Abstract [en]

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-367084 (URN)10.1038/s41588-018-0205-x (DOI)000446047000013 ()30224653 (PubMedID)
Funder
EU, European Research CouncilNovo Nordisk, NNF15CC0018486EU, FP7, Seventh Framework Programme, HEALTH-F2-2013-601456Wellcome trust, RE/13/1/30181Wellcome trust, WT098051
Available from: 2018-11-28 Created: 2018-11-28 Last updated: 2018-12-05Bibliographically 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: 2019-11-20Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-2915-4498

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