| 1. |
- Sliz, E., et al.
(author)
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Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata
- 2023
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Journal article (peer-reviewed)abstract
- Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.
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| 2. |
- Mishra, A., et al.
(author)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Journal article (peer-reviewed)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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| 3. |
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| 4. |
- Taddei, C, et al.
(author)
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Repositioning of the global epicentre of non-optimal cholesterol
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 582:7810, s. 73-
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Journal article (peer-reviewed)abstract
- High blood cholesterol is typically considered a feature of wealthy western countries1,2. However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world3 and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health4,5. However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million individuals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol—which is a marker of cardiovascular risk—changed from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million–4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.
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| 5. |
- Tabassum, R, et al.
(author)
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Genetic architecture of human plasma lipidome and its link to cardiovascular disease
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4329-
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Journal article (peer-reviewed)abstract
- Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P <5 ×10−8), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and GALNT16 (false discovery rate<0.05). We identify loci for lipid species that are shown to predict CVD e.g., SPTLC3 for CER(d18:1/24:1). We show that lipoprotein lipase (LPL) may more efficiently hydrolyze medium length triacylglycerides (TAGs) than others. Polyunsaturated lipids have highest heritability and genetic correlations, suggesting considerable genetic regulation at fatty acids levels. We find low genetic correlations between traditional lipids and lipid species. Our results show that lipidomic profiles capture information beyond traditional lipids and identify genetic variants modifying lipid levels and risk of CVD.
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| 6. |
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| 7. |
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| 8. |
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| 9. |
- Kurki, MI, et al.
(author)
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FinnGen provides genetic insights from a well-phenotyped isolated population
- 2023
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 613:7944, s. 508-
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Journal article (peer-reviewed)abstract
- Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10–11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.
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| 10. |
- Lumbers, R. T., et al.
(author)
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The genomics of heart failure: design and rationale of the HERMES consortium
- 2021
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In: Esc Heart Failure. - : Wiley. - 2055-5822. ; 8:6, s. 5531-5541
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Journal article (peer-reviewed)abstract
- Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model. Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.
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| 11. |
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| 12. |
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| 13. |
- Brunner, Fabian J., et al.
(author)
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Application of non-HDL cholesterol for population-based cardiovascular risk stratification : results from the Multinational Cardiovascular Risk Consortium
- 2019
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In: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 394:10215, s. 2173-2183
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Journal article (peer-reviewed)abstract
- Background: The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment.Methods: In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol.Findings: Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7–59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0–20·1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol <2·6 mmol/L to 33·7% for ≥5·7 mmol/L in women and from 12·8% to 43·6% in men; p<0·0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0–1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6–2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0–1·3 to 2·3, 2·0–2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced.Interpretation: Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician–patient communication about primary prevention strategies.
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| 14. |
- Camen, S., et al.
(author)
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Temporal relations between atrial fibrillation and ischemic stroke and their prognostic impact on mortality
- 2018
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In: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 39, s. 204-205
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Journal article (other academic/artistic)abstract
- Introduction: Atrial fibrillation (AF) and stroke are common diseases and AF is a well-established risk factor for stroke. The physiological mechanism of atrial dysfunction, disturbed hemodynamics and arterial thromboembolism links the pathologies. However, limited evidence is available on the temporal relationship between stroke and AF and the impact of subsequent disease onset on mortality in the community.Methods and results: Across five prospective community cohorts (DanMONICA, FINRISK, Moli-Sani project, Northern Sweden MONICA study, The Tromsø Study) of the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE)-project we assessed baseline cardiovascular risk factors in 101164 individuals, median age 46.1 (25th, 75th percentile 35.8, 57.6) years, 48.4% men. We followed them for incident stroke and AF and determined the relation of subsequent disease diagnosis with overall mortality. Follow-up (FU) for stroke and AF was based upon linkage with national hospitalization registries or administrative registries for ambulatory visits to specialized hospitals.Over a median FU of 16.1 years N=4556 individuals were diagnosed solely with AF, N=2269 had a stroke but no AF diagnosed, and N=898 developed both stroke and AF during FU. Participants who developed either AF or stroke as the index event revealed a similar baseline risk factor profile. Temporal relations showed a peak of the diagnosis of both diseases within the years around the diagnosis of the other disease. The highest incidence rates of stroke were observed within a five-year interval prior to AF diagnosis. Cox regression showed an association of baseline stroke with diagnosis of AF during FU (hazard ratio (HR) 1.29; 95% confidence interval (CI) 1.11–1.50; p<0.001).In multivariable-adjusted Cox regression analyses with time-dependent covariates excluding individuals with diagnosis of both AF and stroke or death within 30 days, subsequent diagnosis of AF after stroke was associated with a higher overall mortality (HR, 3.51; 95% CI 1.87–6.59; p<0.001); subsequent stroke after the diagnosis of AF was associated with a HR of 2.39 (95% CI 1.59–3.60; p<0.001).Conclusions: Stroke and AF are common comorbidities in older adults with an overlapping risk factor profile. The temporal relations appear to be bidirectional, although uncertainty regarding disease onset remains due to the often paroxysmal and asymptomatic nature of AF. Stroke may precede detection of AF by years. The subsequent diagnosis of both diseases significantly increases mortality risk. Whether targeting modifiable risk factors or improved screening for AF after stroke would improve survival needs to be determined.
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| 15. |
- Csengeri, D., et al.
(author)
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Alcohol consumption and risk of atrial fibrillation - results from the BiomarCaRE Consortium
- 2018
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In: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 39, s. 902-903
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Journal article (other academic/artistic)abstract
- Background: Atrial fibrillation (AF) is an arrhythmia with high impact on public health. Among modifiable risk factors for the disease the role of alcohol consumption (AC) has remained inconsistent.Purpose: To assess the association between AC and incident AF across European cohorts.Methods: To study the association between self-reported AC and incident AF in N=107,845 community-based individuals from the BiomarCaRE consortium, 106,915 individuals free of AF at baseline were followed up for AF and stroke after AF. We assessed AC using validated questionnaires. Biomarkers N-terminal pro B-type natriuretic peptide (Nt-proBNP) and high sensitivity troponin I (hsTnI) were measured.Results: The median age of individuals was 47.8 years, 48.3% were men. The median of right-winsorized AC was 3 g/day. N=6,055 individuals developed AF (median follow-up time: 13.9 years). In a linear multivariable-adjusted Cox regression analyses, AC was linearly and positively associated with incident AF (Figure), hazard ratio (HR) per g/day 1.009, 95% confidence interval (CI) 1.007- 1.012, P<0.001. For one drink (12g) per day the HR was 1.15, CI 1.12–1.18, P<0.001. There was a high heterogeneity in associations across cohorts.No significant interactions of the association by Nt-proBNP and hsTnI were observed. AC was positively related to stroke risk after diagnosis of AF (HR 1.18, 95% CI 1.04–1.34, P=0.012).Conclusions: In contrast to other cardiovascular diseases, we did not observe a U-shaped association of alcohol with incident AF in the community, but a rather linearly increasing relation.
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| 16. |
- Shah, S, et al.
(author)
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Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
- 2020
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 163-
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Journal article (peer-reviewed)abstract
- Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.
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| 17. |
- Lahtinen, R., et al.
(author)
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New geochronological and Sm-Nd constraints across the Pajala shear zone of northern Fennoscandia : Reactivation of a Paleoproterozoic suture
- 2015
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In: Precambrian Research. - : Elsevier BV. - 0301-9268 .- 1872-7433. ; 256, s. 102-119
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Journal article (peer-reviewed)abstract
- Altogether 1130 U-Pb analyses on zircons from 25 samples across the Pajala shear zone in northern Fennoscandia were performed by LA-ICPMS methodology to study the origin of the zone. The samples were also analyzed for their Sm-Nd isotope systematics and geochemically. The new data is tested with existing geological information to elaborate the provenance and maximum depositional ages, the stratigraphic position of studied samples, and finally to assess the tectonic evolution in the Pajala shear zone area. Chromium-enriched metasedimentary rocks are found within and to the east and west of the N-S trending Pajala shear zone. No material originating from Proterozoic felsic igneous (zircons) or mafic (Sm-Nd) rocks was found in these rocks and thus, only Neoarchean or very early Paleoproterozoic ages of deposition are possible. Our new results indicate that the bimodal 1.99-1.97 Ga supracrustal rocks of the Rovaniemi Supersuite cover a large area east of the Pajala shear zone. Based on the absence of Archean zircons typical of the metasedimentary rocks covering the Archean basement, it seems that the basement and its sedimentary cover were not exposed at the time of deposition of the Rovaniemi Supersuite. The metasedimentary rocks of the Uusivirka Supersuite, located within the Pajala shear zone, vary from hornblende-bearing metasedimentary rocks, metapelite, and meta-arkose to orthoquartzite. Their characteristic features include a dominant Proterozoic zircon population (65-87%), with a high proportion of analyzed grains yielding ages between 1.96 Ga and 1.91 Ga, and maximum depositional ages of 1.92-1.91 Ga. We record at least three metamorphic events; at ca. 1.92-1.90 Ga, ca. 1.85 Ga and at 1.82-1.78 Ga, of which the youngest can possibly be separated into two events at 1.83-1.82 Ga and 1.79-1.77 Ga, respectively. We propose a tectonic model in which continental breakup occurred at 2.1-2.05 Ga, followed by the development of a magmatic arc (Kittila arc) at ca. 2.0 Ga above a subduction zone. Two Archean continental units (Norrbotten and Karelia) collided at ca. 1.92-1.91 Ga, the Kittila arc was obducted upon the Karelia continent as a foreland fold and thrust belt, and the metasedimentary rocks of the Uusivirka Supersuite were emplaced as foreland deposits. The proposed tectonic model is based on the absence of 2.44 Ga layered intrusions, and especially 2.06 Ga rocks and 1.99-1.97 Ga rocks of the Rovaniemi Supersuite that are found only east of the Pajala shear zone. In our model the Pajala shear zone originated as a divergent plate boundary, and was multiply reactivated after continental collision with both lateral and vertical movements.
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| 18. |
- Wain, Louise V., et al.
(author)
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Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney
- 2017
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In: Hypertension. - 0194-911X .- 1524-4563. ; 70:3, s. e4-e19
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Journal article (peer-reviewed)abstract
- 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.
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| 19. |
- Chadalavada, Sucharitha, et al.
(author)
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Diabetes and heart failure associations in women and men : Results from the MORGAM consortium
- 2023
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In: Frontiers in Cardiovascular Medicine. - 2297-055X. ; 10
-
Journal article (peer-reviewed)abstract
- Background: Diabetes and its cardiovascular complications are a growing concern worldwide. Recently, some studies have demonstrated that relative risk of heart failure (HF) is higher in women with type 1 diabetes (T1DM) than in men. This study aims to validate these findings in cohorts representing five countries across Europe.Methods: This study includes 88,559 (51.8% women) participants, 3,281 (46.3% women) of whom had diabetes at baseline. Survival analysis was performed with the outcomes of interest being death and HF with a follow-up time of 12 years. Sub-group analysis according to sex and type of diabetes was also performed for the HF outcome.Results: 6,460 deaths were recorded, of which 567 were amongst those with diabetes. Additionally, HF was diagnosed in 2,772 individuals (446 with diabetes). A multivariable Cox proportional hazard analysis showed that there was an increased risk of death and HF (hazard ratio (HR) of 1.73 [1.58–1.89] and 2.12 [1.91–2.36], respectively) when comparing those with diabetes and those without. The HR for HF was 6.72 [2.75–16.41] for women with T1DM vs. 5.80 [2.72–12.37] for men with T1DM, but the interaction term for sex differences was insignificant (p for interaction 0.45). There was no significant difference in the relative risk of HF between men and women when both types of diabetes were combined (HR 2.22 [1.93–2.54] vs. 1.99 [1.67–2.38] respectively, p for interaction 0.80).Conclusion: Diabetes is associated with increased risks of death and heart failure, and there was no difference in relative risk according to sex.
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| 20. |
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| 21. |
- Evangelou, Evangelos, et al.
(author)
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Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
- 2018
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:10, s. 1412-1425
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Journal article (peer-reviewed)abstract
- 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.
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| 22. |
- Gårdmark, Anna, et al.
(author)
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Biological ensemble modeling to evaluate potential futures of living marine resources
- 2013
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In: Ecological Applications. - : Wiley. - 1051-0761 .- 1939-5582. ; 23:4, s. 742-754
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Journal article (peer-reviewed)abstract
- Natural resource management requires approaches to understand and handle sources of uncertainty in future responses of complex systems to human activities. Here we present one such approach, the biological ensemble modeling approach,'' using the Eastern Baltic cod (Gadus morhua callarias) as an example. The core of the approach is to expose an ensemble of models with different ecological assumptions to climate forcing, using multiple realizations of each climate scenario. We simulated the long-term response of cod to future fishing and climate change in seven ecological models ranging from single-species to food web models. These models were analyzed using the biological ensemble modeling approach'' by which we (1) identified a key ecological mechanism explaining the differences in simulated cod responses between models, (2) disentangled the uncertainty caused by differences in ecological model assumptions from the statistical uncertainty of future climate, and (3) identified results common for the whole model ensemble. Species interactions greatly influenced the simulated response of cod to fishing and climate, as well as the degree to which the statistical uncertainty of climate trajectories carried through to uncertainty of cod responses. Models ignoring the feedback from prey on cod showed large interannual fluctuations in cod dynamics and were more sensitive to the underlying uncertainty of climate forcing than models accounting for such stabilizing predator-prey feedbacks. Yet in all models, intense fishing prevented recovery, and climate change further decreased the cod population. Our study demonstrates how the biological ensemble modeling approach makes it possible to evaluate the relative importance of different sources of uncertainty in future species responses, as well as to seek scientific conclusions and sustainable management solutions robust to uncertainty of food web processes in the face of climate change.
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| 23. |
- Kiiskinen, Tuomo, et al.
(author)
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Genetic predictors of lifelong medication-use patterns in cardiometabolic diseases
- 2023
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In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 29:1, s. 209-218
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Journal article (peer-reviewed)abstract
- Little is known about the genetic determinants of medication use in preventing cardiometabolic diseases. Using the Finnish nationwide drug purchase registry with follow-up since 1995, we performed genome-wide association analyses of longitudinal patterns of medication use in hyperlipidemia, hypertension and type 2 diabetes in up to 193,933 individuals (55% women) in the FinnGen study. In meta-analyses of up to 567,671 individuals combining FinnGen with the Estonian Biobank and the UK Biobank, we discovered 333 independent loci (P < 5 × 10–9) associated with medication use. Fine-mapping revealed 494 95% credible sets associated with the total number of medication purchases, changes in medication combinations or treatment discontinuation, including 46 credible sets in 40 loci not associated with the underlying treatment targets. The polygenic risk scores (PRS) for cardiometabolic risk factors were strongly associated with the medication-use behavior. A medication-use enhanced multitrait PRS for coronary artery disease matched the performance of a risk factor-based multitrait coronary artery disease PRS in an independent sample (UK Biobank, n = 343,676). In summary, we demonstrate medication-based strategies for identifying cardiometabolic risk loci and provide genome-wide tools for preventing cardiovascular diseases.
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| 24. |
- MacKenzie, Brian R., et al.
(author)
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Impact of Climate Change on Fish Population Dynamics in the Baltic Sea : A Dynamical Downscaling Investigation
- 2012
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In: Ambio. - : Springer Science and Business Media LLC. - 0044-7447 .- 1654-7209. ; 41:6, s. 626-636
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Journal article (peer-reviewed)abstract
- Understanding how climate change, exploitation and eutrophication will affect populations and ecosystems of the Baltic Sea can be facilitated with models which realistically combine these forcings into common frameworks. Here, we evaluate sensitivity of fish recruitment and population dynamics to past and future environmental forcings provided by three ocean-biogeochemical models of the Baltic Sea. Modeled temperature explained nearly as much variability in reproductive success of sprat (Sprattus sprattus; Clupeidae) as measured temperatures during 1973-2005, and both the spawner biomass and the temperature have influenced recruitment for at least 50 years. The three Baltic Sea models estimate relatively similar developments (increases) in biomass and fishery yield during twenty-first century climate change (ca. 28 % range among models). However, this uncertainty is exceeded by the one associated with the fish population model, and by the source of global climate data used by regional models. Knowledge of processes and biases could reduce these uncertainties.
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| 25. |
- Neumann, Johannes Tobias, et al.
(author)
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Prognostic value of cardiovascular biomarkers in the population
- 2024
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In: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 331:22, s. 1898-1909
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Journal article (peer-reviewed)abstract
- Importance: Identification of individuals at high risk for atherosclerotic cardiovascular disease within the population is important to inform primary prevention strategies.Objective: To evaluate the prognostic value of routinely available cardiovascular biomarkers when added to established risk factors.Design, Setting, and Participants: Individual-level analysis including data on cardiovascular biomarkers from 28 general population-based cohorts from 12 countries and 4 continents with assessments by participant age. The median follow-up was 11.8 years.Exposure: Measurement of high-sensitivity cardiac troponin I, high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, B-type natriuretic peptide, or high-sensitivity C-reactive protein.Main Outcomes and Measures: The primary outcome was incident atherosclerotic cardiovascular disease, which included all fatal and nonfatal events. The secondary outcomes were all-cause mortality, heart failure, ischemic stroke, and myocardial infarction. Subdistribution hazard ratios (HRs) for the association of biomarkers and outcomes were calculated after adjustment for established risk factors. The additional predictive value of the biomarkers was assessed using the C statistic and reclassification analyses.Results: The analyses included 164054 individuals (median age, 53.1 years [IQR, 42.7-62.9 years] and 52.4% were women). There were 17211 incident atherosclerotic cardiovascular disease events. All biomarkers were significantly associated with incident atherosclerotic cardiovascular disease (subdistribution HR per 1-SD change, 1.13 [95% CI, 1.11-1.16] for high-sensitivity cardiac troponin I; 1.18 [95% CI, 1.12-1.23] for high-sensitivity cardiac troponin T; 1.21 [95% CI, 1.18-1.24] for N-terminal pro-B-type natriuretic peptide; 1.14 [95% CI, 1.08-1.22] for B-type natriuretic peptide; and 1.14 [95% CI, 1.12-1.16] for high-sensitivity C-reactive protein) and all secondary outcomes. The addition of each single biomarker to a model that included established risk factors improved the C statistic. For 10-year incident atherosclerotic cardiovascular disease in younger people (aged <65 years), the combination of high-sensitivity cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein resulted in a C statistic improvement from 0.812 (95% CI, 0.8021-0.8208) to 0.8194 (95% CI, 0.8089-0.8277). The combination of these biomarkers also improved reclassification compared with the conventional model. Improvements in risk prediction were most pronounced for the secondary outcomes of heart failure and all-cause mortality. The incremental value of biomarkers was greater in people aged 65 years or older vs younger people.Conclusions and Relevance: Cardiovascular biomarkers were strongly associated with fatal and nonfatal cardiovascular events and mortality. The addition of biomarkers to established risk factors led to only a small improvement in risk prediction metrics for atherosclerotic cardiovascular disease, but was more favorable for heart failure and mortality..
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| 26. |
- Niiranen, Susa, et al.
(author)
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Combined effects of global climate change and regional ecosystem drivers on an exploited marine food web
- 2013
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In: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 19:11, s. 3327-3342
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Journal article (peer-reviewed)abstract
- Changes in climate, in combination with intensive exploitation of marine resources, have caused large-scale reorganizations in many of the world's marine ecosystems during the past decades. The Baltic Sea in Northern Europe is one of the systems most affected. In addition to being exposed to persistent eutrophication, intensive fishing, and one of the world's fastest rates of warming in the last two decades of the 20th century, accelerated climate change including atmospheric warming and changes in precipitation is projected for this region during the 21st century. Here, we used a new multi-model approach to project how the interaction of climate, nutrient loads and cod fishing may affect the future of the open Central Baltic Sea food web. Regionally downscaled global climate scenarios were, in combination with three nutrient load scenarios, used to drive an ensemble of three regional biogeochemical models (BGMs). An Ecopath with Ecosim food web model was then forced with the BGM results from different nutrient-climate scenarios in combination with two different cod fishing scenarios. The results showed that regional management is likely to play a major role in determining the future of the Baltic Sea ecosystem. By the end of the 21st century, for example, the combination of intensive cod fishing and high nutrient loads projected a strongly eutrophicated and sprat-dominated ecosystem, while low cod fishing in combination with low nutrient loads resulted in a cod-dominated ecosystem with eutrophication levels close to present. Also, non-linearities were observed in the sensitivity of different trophic groups to nutrient loads or fishing depending on the combination of the two. Finally, many climate variables and species biomasses were projected to levels unseen in the past. Hence, the risk for ecological surprises needs to be addressed, particularly when the results are discussed in the ecosystem-based management context.
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| 27. |
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| 28. |
- Niiranen, Susa, et al.
(author)
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Uncertainties in a Baltic Sea Food-Web Model Reveal Challenges for Future Projections
- 2012
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In: Ambio. - : Springer Science and Business Media LLC. - 0044-7447 .- 1654-7209. ; 41:6, s. 613-625
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Journal article (peer-reviewed)abstract
- Models that can project ecosystem dynamics under changing environmental conditions are in high demand. The application of such models, however, requires model validation together with analyses of model uncertainties, which are both often overlooked. We carried out a simplified model uncertainty and sensitivity analysis on an Ecopath with Ecosim food-web model of the Baltic Proper (BaltProWeb) and found the model sensitive to both variations in the input data of pre-identified key groups and environmental forcing. Model uncertainties grew particularly high in future climate change scenarios. For example, cod fishery recommendations that resulted in viable stocks in the original model failed after data uncertainties were introduced. In addition, addressing the trophic control dynamics produced by the food-web model proved as a useful tool for both model validation, and for studying the food-web function. These results indicate that presenting model uncertainties is necessary to alleviate ecological surprises in marine ecosystem management.
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| 29. |
- Otto, Saskia A., et al.
(author)
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Life Cycle Dynamics of a Key Marine Species Under Multiple Stressors
- 2020
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In: Frontiers in Marine Science. - : Frontiers Media SA. - 2296-7745. ; 7
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Journal article (peer-reviewed)abstract
- Identifying key indicator species, their life cycle dynamics and the multiple driving forces they are affected by is an important step in ecosystem-based management. Similarly important is understanding how environmental changes and trophic interactions shape future trajectories of key species with potential implications for ecosystem state and service provision. We here present a statistical modeling framework to assess and quantify cumulative effects on the long-term dynamics of the copepod Pseudocalanus acuspes, a key species in the Baltic Sea. Our model integrates linear and non-linear responses to changes in life stage density, climate and predation pressure as well as stochastic processes. We use the integrated life cycle model to simulate copepod dynamics under a combination of stressor scenarios and to identify conditions under which population responses are potentially mitigated or magnified. Our novel modeling approach reliably captures the historical P. acuspes population dynamics and allows us to identify females in spring and younger copepodites in summer as stages most sensitive to direct and indirect effects of the main environmental stressors, salinity and temperature. Our model simulations furthermore demonstrate that population responses to stressors are dampened through density effects. Multiple stressor interactions were mostly additive except when acting on the same life stage. Here, negative synergistic and positive dampening effects lead to a lower total population size than expected under additive interactions. As a consequence, we found that a favorable increase of oxygen and phosphate conditions together with a reduction in predation pressure by 50% each could counteract the negative effect of a 25% decrease in salinity by only 6%. Ultimately, our simulations suggest that P. acuspes will most certainly decline under a potential freshening of the Baltic Sea and increasing temperatures, which is conditional on the extent of the assumed climate change. Also the planned nutrient reduction strategy and fishery management plan will not necessarily benefit the temporal development of P. acuspes. Moving forward, there is a growing opportunity for using population modeling in cumulative effects assessments. Our modeling framework can help here as simple tool for species with a discrete life cycle to explore stressor interactions and the safe operating space under future climate change.
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| 30. |
- Pirinen, E., et al.
(author)
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Enhanced polyamine catabolism alters homeostatic control of white adipose tissue mass, energy expenditure, and glucose metabolism
- 2007
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In: Mol Cell Biol. - 0270-7306. ; 27:13, s. 4953-67
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Journal article (peer-reviewed)abstract
- Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) is an attractive candidate gene for type 2 diabetes, as genes of the oxidative phosphorylation (OXPHOS) pathway are coordinatively downregulated by reduced expression of PGC-1 alpha in skeletal muscle and adipose tissue of patients with type 2 diabetes. Here we demonstrate that transgenic mice with activated polyamine catabolism due to overexpression of spermidine/spermine N(1)-acetyltransferase (SSAT) had reduced white adipose tissue (WAT) mass, high basal metabolic rate, improved glucose tolerance, high insulin sensitivity, and enhanced expression of the OXPHOS genes, coordinated by increased levels of PGC-1 alpha and 5'-AMP-activated protein kinase (AMPK) in WAT. As accelerated polyamine flux caused by SSAT overexpression depleted the ATP pool in adipocytes of SSAT mice and N(1),N(11)-diethylnorspermine-treated wild-type fetal fibroblasts, we propose that low ATP levels lead to the induction of AMPK, which in turn activates PGC-1 alpha in WAT of SSAT mice. Our hypothesis is supported by the finding that the phenotype of SSAT mice was reversed when the accelerated polyamine flux was reduced by the inhibition of polyamine biosynthesis in WAT. The involvement of polyamine catabolism in the regulation of energy and glucose metabolism may offer a novel target for drug development for obesity and type 2 diabetes.
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| 31. |
- Tomczak, Maciej T., et al.
(author)
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Ecological Network Indicators of Ecosystem Status and Change in the Baltic Sea
- 2013
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:10
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Journal article (peer-reviewed)abstract
- Several marine ecosystems under anthropogenic pressure have experienced shifts from one ecological state to another. In the central Baltic Sea, the regime shift of the 1980s has been associated with food-web reorganization and redirection of energy flow pathways. These long-term dynamics from 1974 to 2006 have been simulated here using a food-web model forced by climate and fishing. Ecological network analysis was performed to calculate indices of ecosystem change. The model replicated the regime shift. The analyses of indicators suggested that the system's resilience was higher prior to 1988 and lower thereafter. The ecosystem topology also changed from a web-like structure to a linearized food-web.
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