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- Folkersen, Lasse, et al.
(författare)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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- van de Vegte, Yordi, et al.
(författare)
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Genetic insights into resting heart rate and its role in cardiovascular disease
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
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- Andersson, Åke, et al.
(författare)
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Status of the new injector for MAX-lab
- 2002
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Ingår i: 8th European Particle Accelerator Conference. ; , s. 772-774
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Konferensbidrag (refereegranskat)abstract
- The new injector for MAX-lab is built around two 125 MeV linacs [B. Anderberg, (2000)] equipped with SLED cavities [Z.D. Farkas, (1974)]. The electron beam is recirculated once to reach 500 MeV. A 2.3 MeV thermionic RF gun [B. Anderberg, (2000)] injects into the system. The RF-gun is put into operation and commissioning of the first linac is proceeding. Results from the thermionic RF-gun operation, linac commissioning and first beam operations are presented.
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- Andersson, Åke, et al.
(författare)
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The MAX IV facility
- 2004
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Ingår i: European Particle Accelerator Conference, EPAC2004, Lucerne, Switzerland.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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- Andréasson, Sven, et al.
(författare)
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Behandling av alkohol- och narkotikaproblem : En evidensbaserad kunskapssammanställning
- 2001
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Utvärderingens syfteMissbruk och beroende av alkohol är ett av de största folkhälsoproblemen. Narkotikamissbruk är mindre vanligt men har stora medicinska konsekvenser för de berörda. De sociala och juridiska aspekterna är betydande. En kritisk genomgång av litteraturen vad avser behandling av abstinens, protraherad abstinens, behandling i syfte att förhindra återfall, psykologiska och sociala behandlingar för att minska återfallsrisken, behandlingsprogram och institutionsvårdens roll, samt behandling av missbruk under graviditet. Dessutom en granskning av mini-intervention i primärvård och annan vård vars syfte är att minska konsumtionen hos högkonsumenter av alkohol. Nyligen gjorda meta-analyser inom området värderas och särskild vikt fästs vid interventioner som finns eller lätt kan introduceras i den svenska vårdorganisationen. Behandlingsprogram för patienter med samtidig annan psykisk störning värderas.Så kallat lågdosberoende av bensodiazepiner och andra lugnande medel eller sömnmedel behandlas inte. Inte heller belyses effekten av behandlingar vars primära mål är kroppsliga komplikationer av missbruket, och inte heller granskas metoder att minska tillgänglighet.TillvägagångssättStrukturerad översikt, kostnadsanalyser.Insamling av primärdataSystematisk sökning i relevanta databaser, litteraturlistor i påträffade studier samt i aktuella monografier. Ingen bakre tidsbegränsning och sökning i databaser till och med februari 1999.Utgångspunkt för urval av dataHuvudsakligen randomiserade, kontrollerade, dubbelblinda studier, samt metaanalyser som baseras på sådana studier. Vad gäller långtidsförlopp och ekonomiska analyser även kohortstudier och andra naturalistiska studier.Genomgång av publikationenSamtliga studier värderas med hjälp av en i gruppen utarbetad, och med övriga psykiatriprojekt gemensam, kvalitetsmall. Alla centrala studier läses av minst två i gruppen.Färdiga manuskript värderas av styrelse, expertgrupp samt externa granskare.
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- Broadaway, K Alaine, et al.
(författare)
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Loci for insulin processing and secretion provide insight into type 2 diabetes risk.
- 2023
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Ingår i: American Journal of Human Genetics. - : Elsevier. - 0002-9297 .- 1537-6605. ; 110:2, s. 284-299
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Tidskriftsartikel (refereegranskat)abstract
- Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.
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