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Gorski, M., van der Most, P. J., Teumer, A., Chu, A. Y., Li, M., Mijatovic, V., . . . Fuchsberger, C. (2017). 1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function.. Scientific Reports, 7, Article ID 45040.
Open this publication in new window or tab >>1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function.
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 45040Article in journal (Refereed) Published
Abstract [en]

HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10(-8) previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-321625 (URN)10.1038/srep45040 (DOI)000400432700001 ()28452372 (PubMedID)
Available from: 2017-05-09 Created: 2017-05-09 Last updated: 2017-07-06
Aschard, H., Tobin, M. D., Hancock, D. B., Skurnik, D., Sood, A., James, A., . . . Kraft, P. (2017). Evidence for large-scale gene-by-smoking interaction effects on pulmonary function. International Journal of Epidemiology, 46(3), 894-904
Open this publication in new window or tab >>Evidence for large-scale gene-by-smoking interaction effects on pulmonary function
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2017 (English)In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 46, no 3, p. 894-904Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Smoking is the strongest environmental risk factor for reduced pulmonary function. The genetic component of various pulmonary traits has also been demonstrated, and at least 26 loci have been reproducibly associated with either FEV1 (forced expiratory volume in 1 second) or FEV1/FVC (FEV1/forced vital capacity). Although the main effects of smoking and genetic loci are well established, the question of potential gene-by-smoking interaction effect remains unanswered. The aim of the present study was to assess, using a genetic risk score approach, whether the effect of these 26 loci on pulmonary function is influenced by smoking.

METHODS: We evaluated the interaction between smoking exposure, considered as either ever vs never or pack-years, and a 26-single nucleotide polymorphisms (SNPs) genetic risk score in relation to FEV1 or FEV1/FVC in 50 047 participants of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and SpiroMeta consortia.

RESULTS: We identified an interaction (βint = -0.036, 95% confidence interval, -0.040 to -0.032, P = 0.00057) between an unweighted 26 SNP genetic risk score and smoking status (ever/never) on the FEV1/FVC ratio. In interpreting this interaction, we showed that the genetic risk of falling below the FEV 1: /FVC threshold used to diagnose chronic obstructive pulmonary disease is higher among ever smokers than among never smokers. A replication analysis in two independent datasets, although not statistically significant, showed a similar trend in the interaction effect.

CONCLUSIONS: This study highlights the benefit of using genetic risk scores for identifying interactions missed when studying individual SNPs and shows, for the first time, that persons with the highest genetic risk for low FEV1/FVC may be more susceptible to the deleterious effects of smoking.

Keyword
FEV1/FVC, genetic risk score, gene–environment interaction, smoking
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-317998 (URN)10.1093/ije/dyw318 (DOI)000406242600023 ()28082375 (PubMedID)
Available from: 2017-03-23 Created: 2017-03-23 Last updated: 2017-10-30Bibliographically approved
Wain, L. V., Shrine, N., Artigas, M. S., Erzurumluoglu, A. M., Noyvert, B., Bossini-Castillo, L., . . . Tobin, M. D. (2017). Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets.. Nature Genetics, 49(3), 416-425
Open this publication in new window or tab >>Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets.
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2017 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 49, no 3, p. 416-425Article in journal (Refereed) Published
Abstract [en]

Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (∼6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10(-49)), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-317994 (URN)10.1038/ng.3787 (DOI)000394917800015 ()28166213 (PubMedID)
Available from: 2017-03-23 Created: 2017-03-23 Last updated: 2017-11-29Bibliographically 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: 2017-11-29Bibliographically 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
Keyword
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.

Keyword
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: 2017-11-29Bibliographically approved
Pan, G., Ameur, A., Enroth, S., Bysani, M., Nord, H., Cavalli, M., . . . Wadelius, C. (2017). PATZ1 down-regulates FADS1 by binding to rs174557 and is opposed by SP1/SREBP1c. Nucleic Acids Research, 45(5), 2408-2422
Open this publication in new window or tab >>PATZ1 down-regulates FADS1 by binding to rs174557 and is opposed by SP1/SREBP1c
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2017 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 45, no 5, p. 2408-2422Article in journal (Refereed) Published
Abstract [en]

The FADS1 and FADS2 genes in the FADS cluster encode the rate-limiting enzymes in the synthesis of long-chain polyunsaturated fatty acids (LC-PUFAs). Genetic variation in this region has been associated with a large number of diseases and traits many of them correlated to differences in metabolism of PUFAs. However, the causative variants leading to these associations have not been identified. Here we find that the multiallelic rs174557 located in an AluYe5 element in intron 1 of FADS1 is functional and lies within a PATZ1 binding site. The derived allele of rs174557, which is the common variant in most populations, diminishes binding of PATZ1, a transcription factor conferring allele-specific downregulation of FADS1 The PATZ1 binding site overlaps with a SP1 site. The competitive binding between the suppressive PATZ1 and the activating complex of SP1 and SREBP1c determines the enhancer activity of this region, which regulates expression of FADS1.

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-317999 (URN)10.1093/nar/gkw1186 (DOI)000397286600024 ()27932482 (PubMedID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish Research Council, 521-2010-3505 6212011-6052 521-2012-2884Swedish Diabetes AssociationSwedish Cancer Society, 15 0878
Available from: 2017-03-23 Created: 2017-03-23 Last updated: 2017-04-18Bibliographically approved
Björkesten, J., Enroth, S., Shen, Q., Wik, L., Hougaard, D., Cohen, A., . . . Landegren, U. (2017). Stability of Proteins in Dried Blood Spot Biobanks.. Molecular & Cellular Proteomics, 16(7), 1286-1296
Open this publication in new window or tab >>Stability of Proteins in Dried Blood Spot Biobanks.
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2017 (English)In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 16, no 7, p. 1286-1296Article in journal (Refereed) Published
Abstract [en]

An important motivation for the construction of biobanks is to discover biomarkers that identify diseases at early, potentially curable stages. This will require biobanks from large numbers of individuals, preferably sampled repeatedly, where the samples are collected and stored under conditions that preserve potential biomarkers. Dried blood samples are attractive for biobanking because of the ease and low cost of collection and storage. Here we have investigated their suitability for protein measurements. 92 proteins with relevance for oncology were analyzed using multiplex proximity extension assays (PEA) in dried blood spots collected on paper and stored for up to 30 years at either +4&deg;C or -24&deg;C.</p> <p>Our main findings were that 1) the act of drying only slightly influenced detection of blood proteins (average correlation of 0.970), and in a reproducible manner (correlation of 0.999), 2) detection of some proteins was not significantly affected by storage over the full range of three decades (34% and 76% of the analyzed proteins at +4&deg;C and -24&deg;C, respectively), while levels of others decreased slowly during storage with half-lives in the range of 10 to 50 years, and 3) detectability of proteins was less affected in dried samples stored at -24&deg;C compared to at +4&deg;C, as the median protein abundance had decreased to 80% and 93% of starting levels after 10 years of storage at +4&deg;C or -24&deg;C, respectively. The results of our study are encouraging as they suggest an inexpensive means to collect large numbers of blood samples, even by the donors themselves, and to transport, and store biobanked samples as spots of whole blood dried on paper. Combined with emerging means to measure hundreds or thousands of protein, such biobanks could prove of great medical value by greatly enhancing discovery as well as routine analysis of blood biomarkers.

Keyword
Absolute quantification, Affinity proteomics, Biobanking, Bioinformatics splicing, Biomarkers, Blood*, DBS, Diagnostic, Dried Blood Spot, Multiplex protein detection, PCR, Plasma or serum analysis, Predictive markers*, Protein Stability, Proximity Extension Assay
National Category
Clinical Laboratory Medicine
Identifiers
urn:nbn:se:uu:diva-322568 (URN)10.1074/mcp.RA117.000015 (DOI)000404597500009 ()28501802 (PubMedID)
Funder
Swedish Research CouncilEU, FP7, Seventh Framework Programme, 294409Novo Nordisk
Available from: 2017-05-25 Created: 2017-05-25 Last updated: 2017-11-29Bibliographically approved
Ahsan, M., Ek, W. E., Rask-Andersen, M., Karlsson, T., Lind-Thomsen, A., Enroth, S., . . . Johansson, Å. (2017). The relative contribution of DNA methylation and genetic variants on protein biomarkers for human diseases.. PLoS Genetics, 13(9), Article ID e1007005.
Open this publication in new window or tab >>The relative contribution of DNA methylation and genetic variants on protein biomarkers for human diseases.
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2017 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 9, article id e1007005Article in journal (Refereed) Published
Abstract [en]

Associations between epigenetic alterations and disease status have been identified for many diseases. However, there is no strong evidence that epigenetic alterations are directly causal for disease pathogenesis. In this study, we combined SNP and DNA methylation data with measurements of protein biomarkers for cancer, inflammation or cardiovascular disease, to investigate the relative contribution of genetic and epigenetic variation on biomarker levels. A total of 121 protein biomarkers were measured and analyzed in relation to DNA methylation at 470,000 genomic positions and to over 10 million SNPs. We performed epigenome-wide association study (EWAS) and genome-wide association study (GWAS) analyses, and integrated biomarker, DNA methylation and SNP data using between 698 and 1033 samples depending on data availability for the different analyses. We identified 124 and 45 loci (Bonferroni adjusted P < 0.05) with effect sizes up to 0.22 standard units' change per 1% change in DNA methylation levels and up to four standard units' change per copy of the effective allele in the EWAS and GWAS respectively. Most GWAS loci were cis-regulatory whereas most EWAS loci were located in trans. Eleven EWAS loci were associated with multiple biomarkers, including one in NLRC5 associated with CXCL11, CXCL9, IL-12, and IL-18 levels. All EWAS signals that overlapped with a GWAS locus were driven by underlying genetic variants and three EWAS signals were confounded by smoking. While some cis-regulatory SNPs for biomarkers appeared to have an effect also on DNA methylation levels, cis-regulatory SNPs for DNA methylation were not observed to affect biomarker levels. We present associations between protein biomarker and DNA methylation levels at numerous loci in the genome. The associations are likely to reflect the underlying pattern of genetic variants, specific environmental exposures, or represent secondary effects to the pathogenesis of disease.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-332046 (URN)10.1371/journal.pgen.1007005 (DOI)000411976100027 ()28915241 (PubMedID)
Funder
Swedish Research Council, K2007-66X-20270-01-3, 2011-2354, 2015-03327Swedish Foundation for Strategic Research Göran Gustafsson Foundation for Research in Natural Sciences and MedicineSwedish Society for Medical Research (SSMF)Åke Wiberg Foundation
Available from: 2017-10-23 Created: 2017-10-23 Last updated: 2017-12-19Bibliographically approved
Enroth, S., Hallmans, G., Grankvist, K. & Gyllensten, U. (2016). Effects of Long-Term Storage Time and Original Sampling Month on Biobank Plasma Protein Concentrations. EBioMedicine, 12, 309-314
Open this publication in new window or tab >>Effects of Long-Term Storage Time and Original Sampling Month on Biobank Plasma Protein Concentrations
2016 (English)In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 12, p. 309-314Article in journal (Refereed) Published
Abstract [en]

The quality of clinical biobank samples is crucial to their value for life sciences research. A number of factors related to the collection and storage of samples may affect the biomolecular composition. We have studied the effect of long-time freezer storage, chronological age at sampling, season and month of the year and on the abundance levels of 108 proteins in 380 plasma samples collected from 106 Swedish women. Storage time affected 18 proteins and explained 4.8-34.9% of the observed variance. Chronological age at sample collection after adjustment for storage-time affected 70 proteins and explained 1.1-33.5% of the variance. Seasonal variation had an effect on 15 proteins and month (number of sun hours) affected 36 proteins and explained up to 4.5% of the variance after adjustment for storage-time and age. The results show that freezer storage time and collection date (month and season) exerted similar effect sizes as age on the protein abundance levels. This implies that information on the sample handling history, in particular storage time, should be regarded as equally prominent covariates as age or gender and need to be included in epidemiological studies involving protein levels.

Keyword
Plasma proteins, Biobank, Covariate, Storage time, Sampling month, Proximity extension assay
National Category
General Practice
Identifiers
urn:nbn:se:uu:diva-310022 (URN)10.1016/j.ebiom.2016.08.038 (DOI)000386878500048 ()27596149 (PubMedID)
Available from: 2016-12-12 Created: 2016-12-09 Last updated: 2018-01-13Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-5056-9137

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