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Tikkanen, E., Gustafsson, S., Knowles, J. W., Perez, M., Burgess, S. & Ingelsson, E. (2019). Body composition and atrial fibrillation: a Mendelian randomization study. European Heart Journal, 40(16), 1277-1282
Open this publication in new window or tab >>Body composition and atrial fibrillation: a Mendelian randomization study
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2019 (English)In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 40, no 16, p. 1277-1282Article in journal (Refereed) Published
Abstract [en]

Aims

Increases in fat-free mass and fat mass have been associated with higher risk of atrial fibrillation (AF) in observational studies. It is not known whether these associations reflect independent causal processes. Our aim was to evaluate independent causal roles of fat-free mass and fat mass on AF.

Methods and results

We conducted a large observational study to estimate the associations between fat-free mass and fat mass on incident AF in the UK Biobank (N = 487 404, N events = 10 365). Genome-wide association analysis was performed to obtain genetic instruments for Mendelian randomization (MR). We evaluated the causal effects of fat-free mass and fat mass on AF with two-sample method by using genetic associations from AFGen consortium as outcome. Finally, we evaluated independent causal effects of fat-free mass and fat mass with multivariate MR. Both fat-free mass and fat mass had observational associations with incident AF [hazard ratio (HR) = 1.77, 95% confidence interval (CI) 1.72-1.83; HR = 1.40, 95% CI 1.37-1.43 per standard deviation increase in fat-free and fat mass, respectively]. The causal effects using the inverse-variance weighted method were 1.55 (95% CI 1.38-1.75) for fat-free mass and 1.30 (95% CI 1.17-1.45) for fat mass. Weighted median, Egger regression, and penalized methods showed similar estimates. The multivariate MR analysis suggested that the causal effects of fat-free and fat mass were independent of each other (causal risk ratios: 1.37, 95% CI 1.06-1.75; 1.28, 95% CI 1.03-1.58).

Conclusion

Genetically programmed increases in fat-free mass and fat mass independently cause an increased risk of AF.

Keywords
Fat-free mass, Fat mass, Bioimpedance, Genetics, Atrial fibrillation, Causal effect
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-396561 (URN)10.1093/eurheartj/ehz003 (DOI)000490013700010 ()30721963 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation, 2013.0126
Available from: 2019-11-06 Created: 2019-11-06 Last updated: 2019-11-06Bibliographically approved
Dörr, M., Hamburg, N. M., Müller, C., Smith, N. L., Gustafsson, S., Lehtimäki, T., . . . Schnabel, R. B. (2019). Common Genetic Variation in Relation to Brachial Vascular Dimensions and Flow-Mediated Vasodilation [Letter to the editor]. CIRCULATION-GENOMIC AND PRECISION MEDICINE, 12(2), Article ID e002409.
Open this publication in new window or tab >>Common Genetic Variation in Relation to Brachial Vascular Dimensions and Flow-Mediated Vasodilation
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2019 (English)In: CIRCULATION-GENOMIC AND PRECISION MEDICINE, ISSN 2574-8300, Vol. 12, no 2, article id e002409Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2019
Keywords
brachial artery, dilation, epidemiology, genetics, genome-wide association study, insulin-like growth factor binding protein 3
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-379085 (URN)10.1161/CIRCGEN.118.002409 (DOI)000458995600002 ()30779634 (PubMedID)
Funder
EU, European Research Council, 648131EU, European Research Council, 742927
Available from: 2019-03-12 Created: 2019-03-12 Last updated: 2019-03-12Bibliographically approved
Zanetti, D., Rao, A., Gustafsson, S., Assimes, T. L., Montgomery, S. B. & Ingelsson, E. (2019). Identification of 22 novel loci associated with urinary biomarkers of albumin, sodium, and potassium excretion. Kidney International, 95(5), 1197-1208
Open this publication in new window or tab >>Identification of 22 novel loci associated with urinary biomarkers of albumin, sodium, and potassium excretion
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2019 (English)In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 95, no 5, p. 1197-1208Article in journal (Refereed) Published
Abstract [en]

Urine biomarkers reflecting kidney function and handling of dietary sodium and potassium are strongly associated with several common diseases including chronic kidney disease, cardiovascular disease, and diabetes mellitus. Knowledge about the genetic determinants of these biomarkers may shed light on pathophysiological mechanisms underlying the development of these diseases. We performed genome-wide association studies of urinary albumin: creatinine ratio (UACR), urinary potassium: creatinine ratio (UK/UCr), urinary sodium: creatinine ratio (UNa/UCr) and urinary sodium: potassium ratio (UNa/UK) in up to 218,450 (discovery) and 109,166 (replication) unrelated individuals of European ancestry from the UK Biobank. Further, we explored genetic correlations, tissue-specific gene expression, and possible genes implicated in the regulation of these biomarkers. After replication, we identified 19 genome-wide significant independent loci associated with UACR, 6 each with UK/UCr and UNa/UCr, and 4 with UNa/UK. In addition to 22 novel associations, we confirmed several established associations, including between the CUBN locus and microalbuminuria. We detected high pairwise genetic correlation across the urinary biomarkers, and between their levels and several physiological measurements. We highlight GIPR, a potential diabetes drug target, as possibly implicated in the genetic control of urinary potassium excretion, and NRBP1, a locus associated with gout, as plausibly involved in sodium and albumin excretion. Overall, we identified 22 novel genome-wide significant associations with urinary biomarkers and confirmed several previously established associations, providing new insights into the genetic basis of these traits and their connection to chronic diseases.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE INC, 2019
Keywords
chronic kidney disease, genetics, microalbuminuria, urinary biomarkers
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-383153 (URN)10.1016/j.kint.2018.12.017 (DOI)000465213400023 ()30910378 (PubMedID)
Available from: 2019-05-10 Created: 2019-05-10 Last updated: 2019-05-10Bibliographically approved
Helle, E., Cordova-Palomera, A., Ojala, T., Saha, P., Potiny, P., Gustafsson, S., . . . Priest, J. R. (2019). Loss of function, missense, and intronic variants in NOTCH1 confer different risks for left ventricular outflow tract obstructive heart defects in two European cohorts. Genetic Epidemiology, 43(2), 215-226
Open this publication in new window or tab >>Loss of function, missense, and intronic variants in NOTCH1 confer different risks for left ventricular outflow tract obstructive heart defects in two European cohorts
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2019 (English)In: Genetic Epidemiology, ISSN 0741-0395, E-ISSN 1098-2272, Vol. 43, no 2, p. 215-226Article in journal (Refereed) Published
Abstract [en]

Loss of function variants in NOTCH1 cause left ventricular outflow tract obstructive defects (LVOTO). However, the risk conferred by rare and noncoding variants in NOTCH1 for LVOTO remains largely uncharacterized. In a cohort of 49 families affected by hypoplastic left heart syndrome, a severe form of LVOTO, we discovered predicted loss of function NOTCH1 variants in 6% of individuals. Rare or low-frequency missense variants were found in 16% of families. To make a quantitative estimate of the genetic risk posed by variants in NOTCH1 for LVOTO, we studied associations of 400 coding and noncoding variants in NOTCH1 in 1,085 cases and 332,788 controls from the UK Biobank. Two rare intronic variants in strong linkage disequilibrium displayed significant association with risk for LVOTO amongst European-ancestry individuals. This result was replicated in an independent analysis of 210 cases and 68,762 controls of non-European and mixed ancestry. In conclusion, carrying rare predicted loss of function variants in NOTCH1 confer significant risk for LVOTO. In addition, the two intronic variants seem to be associated with an increased risk for these defects. Our approach demonstrates the utility of population-based data sets in quantifying the specific risk of individual variants for disease-related phenotypes.

Keywords
congenital heart defects, left ventricular outflow tract obstruction (LVOTO), NOTCH1, UK Biobank
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-381089 (URN)10.1002/gepi.22176 (DOI)000462061900008 ()30511478 (PubMedID)
Available from: 2019-04-23 Created: 2019-04-23 Last updated: 2019-04-23Bibliographically approved
Harati, H., Zanetti, D., Rao, A., Gustafsson, S., Perez, M., Ingelsson, E. & Knowles, J. W. (2019). No evidence of a causal association of type 2 diabetes and glucose metabolism with atrial fibrillation. Diabetologia, 62(5), 800-804
Open this publication in new window or tab >>No evidence of a causal association of type 2 diabetes and glucose metabolism with atrial fibrillation
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2019 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 62, no 5, p. 800-804Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis

Several epidemiological studies have shown an increased risk of atrial fibrillation in individuals with type 2 diabetes or milder forms of dysglycaemia. We aimed to assess whether this relation is causal using a Mendelian randomisation approach.

Methods

Two-sample Mendelian randomisation was used to obtain estimates of the influence of type 2 diabetes, fasting blood glucose (FBG), and HbA(1c) on the risk of atrial fibrillation. Instrumental variables were constructed using available summary statistics from meta-analyses of genome-wide association studies (GWAS) for type 2 diabetes and associated phenotypes. Pleiotropic SNPs were excluded from the analyses. The most recent GWAS meta-analysis summary statistics for atrial fibrillation, which included over 1 million individuals (approximately 60,000 individuals with atrial fibrillation) was used for outcome analysis.

Results

Neither type 2 diabetes (OR 1.01 [95% CI 0.98, 1.03]; p=0.37), nor FBG (OR 0.95 [95% CI 0.82, 1.09] per mmol/l; p=0.49) or HbA(1c) (OR 1.01 [95% CI, 0.85, 1.17] per mmol/mol [%]; p=0.88) were associated with atrial fibrillation in Mendelian randomisation analyses. We had >80% statistical power to detect ORs of 1.08, 1.06 and 1.09 or larger for type 2 diabetes, FBG and HbA(1c), respectively, for associations with atrial fibrillation.

Conclusions/interpretation

This Mendelian randomisation analysis does not support a causal role of clinical significance between genetically programmed type 2 diabetes, FBG or HbA(1c) and development of atrial fibrillation. These data suggest that drug treatment to reduce dysglycaemia is unlikely to be an effective strategy for atrial fibrillation prevention.

Place, publisher, year, edition, pages
SPRINGER, 2019
Keywords
Atrial fibrillation, Genome-wide association, Mendelian randomisation, Type 2 diabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-382548 (URN)10.1007/s00125-019-4836-y (DOI)000463795300008 ()30810766 (PubMedID)
Available from: 2019-05-10 Created: 2019-05-10 Last updated: 2019-05-10Bibliographically approved
Schmidt, A. F., Holmes, M. V., Preiss, D., Swerdlow, D. I., Denaxas, S., Fatemifar, G., . . . Hingorani, A. D. (2019). Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9. BMC Cardiovascular Disorders, 19(1), Article ID 240.
Open this publication in new window or tab >>Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9
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2019 (English)In: BMC Cardiovascular Disorders, ISSN 1471-2261, E-ISSN 1471-2261, Vol. 19, no 1, article id 240Article in journal (Refereed) Published
Abstract [en]

Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

Place, publisher, year, edition, pages
BMC, 2019
Keywords
Genetic association studies, Mendelian randomisation, LDL-cholesterol, Phenome-wide association scan
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-401186 (URN)10.1186/s12872-019-1187-z (DOI)000503475600002 ()31664920 (PubMedID)
Available from: 2020-01-07 Created: 2020-01-07 Last updated: 2020-01-07Bibliographically approved
Justice, A. E., Giedraitis, V., Gustafsson, S., Ingelsson, E., Lind, L., Wallentin, L. & Lindgren, C. M. (2019). Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution. Nature Genetics, 51(3), 452-469
Open this publication in new window or tab >>Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
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2019 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, no 3, p. 452-469Article in journal (Refereed) Published
Abstract [en]

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-379344 (URN)10.1038/s41588-018-0334-2 (DOI)000459947200014 ()30778226 (PubMedID)
Funder
NIH (National Institute of Health), 1K99HL130580NIH (National Institute of Health), R01-DK089256NIH (National Institute of Health), 2R01HD057194NIH (National Institute of Health), U01HG007416NIH (National Institute of Health), R01DK101855NIH (National Institute of Health), T32 HL007055NIH (National Institute of Health), KL2TR001109
Note

For complete list of authors see http://dx.doi.org/10.1038/s41588-018-0334-2

Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-03-15Bibliographically approved
Yi-Ting, L., Fall, T., Hammar, U., Gustafsson, S., Ingelsson, E., Ärnlöv, J., . . . Sundström, J. (2019). Proteomic Analysis of Longitudinal Changes in Blood Pressure. JOURNAL OF CLINICAL MEDICINE, 8(10), Article ID 1585.
Open this publication in new window or tab >>Proteomic Analysis of Longitudinal Changes in Blood Pressure
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2019 (English)In: JOURNAL OF CLINICAL MEDICINE, ISSN 2077-0383, Vol. 8, no 10, article id 1585Article in journal (Refereed) Published
Abstract [en]

Hypertension is the leading risk factor for premature death worldwide. The identification of modifiable causes of hypertension remains an imperative task. We aimed to investigate associations between 79 proteins implicated in cardiovascular disease and longitudinal blood pressure (BP) changes in three Swedish prospective cohorts. In a discovery phase, we investigated associations between baseline circulating protein levels assessed with a proximity extension assay and BP stage progression at follow-up 5 years later among persons without BP-lowering drugs at baseline in two independent community-based cohorts from the Prospective Investigation of the Vasculature in Uppsala Seniors study (PIVUS) and the Uppsala Longitudinal Study of Adult Men (ULSAM). We used an independent cohort, the Malmo Diet and Cancer Study (MDC), for replication. The primary outcome of BP stage progression was defined as per the 2017 AHA/ACC (American Heart Association/American College of Cardiology) Guideline BP categories. We also investigated associations of protein levels with changes in BP on a continuous scale, and meta-analyzed all three cohorts. Levels of renin were associated with BP stage progression with a 5% false discovery rate (FDR) in the ULSAM (n = 238) and PIVUS (n = 566) cohorts, but we could not replicate this association in the MDC cohort (n = 2659). The association in the discovery cohorts was modest, with an odds ratio for BP stage progression over 5 years of 1.33 (95% confidence interval 1.14 to 1.56) per standard deviation of baseline renin. In conclusion, we could not find any novel robust associations with longitudinal BP increase in a proximity extension assay-based proteomics investigation in three cohorts.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
proteomics, blood pressure, hypertension, prospective cohort
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-400097 (URN)10.3390/jcm8101585 (DOI)000498398500083 ()31581667 (PubMedID)
Funder
Swedish Heart Lung Foundation, 20041151
Available from: 2020-01-07 Created: 2020-01-07 Last updated: 2020-01-07Bibliographically approved
Liu, C., Marioni, R. E., Hedman, Å. K., Pfeiffer, L., Tsai, P.-C., Reynolds, L. M., . . . Levy, D. (2018). A DNA methylation biomarker of alcohol consumption.. Molecular Psychiatry, 23, 422-433
Open this publication in new window or tab >>A DNA methylation biomarker of alcohol consumption.
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2018 (English)In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 23, p. 422-433Article in journal (Refereed) Published
Abstract [en]

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10(-7). Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10(-7). In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.

National Category
Other Basic Medicine
Identifiers
urn:nbn:se:uu:diva-319698 (URN)10.1038/mp.2016.192 (DOI)000423441700028 ()27843151 (PubMedID)
Note

De tio första författarna delar på förstaförfattarskapet. De sex sista författarna delar på sistaförfattarskapet.

Available from: 2017-04-06 Created: 2017-04-06 Last updated: 2018-03-19Bibliographically approved
Chen, X., Gustafsson, S., Whitington, T., Borne, Y., Lorentzen, E., Sun, J., . . . Magnusson, P. K. E. (2018). A genome-wide association study of IgM antibody against phosphorylcholine: shared genetics and phenotypic relationship to chronic lymphocytic leukemia. Human Molecular Genetics, 27(10), 1809-1818
Open this publication in new window or tab >>A genome-wide association study of IgM antibody against phosphorylcholine: shared genetics and phenotypic relationship to chronic lymphocytic leukemia
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2018 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 27, no 10, p. 1809-1818Article in journal (Refereed) Published
Abstract [en]

Phosphorylcholine (PC) is an epitope on oxidized low-density lipoprotein (oxLDL), apoptotic cells and several pathogens like Streptococcus pneumoniae. Immunoglobulin M against PC (IgM anti-PC) has the ability to inhibit uptake of oxLDL by macrophages and increase clearance of apoptotic cells. From our genome-wide association studies (GWASs) in four European-ancestry cohorts, six single nucleotide polymorphisms (SNPs) in 11q24.1 were discovered (in 3002 individuals) and replicated (in 646 individuals) to be associated with serum level of IgM anti-PC (the leading SNP rs35923643-G, combined beta = 0.19, 95% confidence interval 0.13-0.24, P = 4.3 x 10(-11)). The haplotype tagged by rs35923643-G (or its proxy SNP rs735665-A) is also known as the top risk allele for chronic lymphocytic leukemia (CLL), and a main increasing allele for general IgM. By using summary GWAS results of IgM anti-PC and CLL in the polygenic risk score (PRS) analysis, PRS on the basis of IgM anti-PC risk alleles positively associated with CLL risk (explained 0.6% of CLL variance, P = 1.2 x 10(-15)). Functional prediction suggested that rs35923643-G might impede the binding of Runt-related transcription factor 3, a tumor suppressor playing a central role in the immune regulation of cancers. Contrary to the expectations from the shared genetics between IgM anti-PC and CLL, an inverse relationship at the phenotypic level was found in a nested case-control study (30 CLL cases with 90 age-and sex-matched controls), potentially reflecting reverse causation. The suggested function of the top variant as well as the phenotypic association between IgM anti-PC and CLL risk needs replication and motivates further studies.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-356866 (URN)10.1093/hmg/ddy094 (DOI)000431886200012 ()29547969 (PubMedID)
Funder
Swedish Research Council, 2017-00641Swedish Heart Lung Foundation, 20070481
Available from: 2018-08-15 Created: 2018-08-15 Last updated: 2018-08-15Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-5894-0351

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