| 1. |
- Ntalla, Ioanna, et al.
(författare)
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Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
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| 2. |
- 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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| 3. |
- Young, William J., et al.
(författare)
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Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways
- 2022
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease. The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.
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| 4. |
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| 5. |
- Lahrouchi, Najim, et al.
(författare)
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Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome
- 2020
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Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 142:4, s. 324-338
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Tidskriftsartikel (refereegranskat)abstract
- Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P<5x10(-8)) nearNOS1AP,KCNQ1, andKLF12, and 1 missense variant inKCNE1(p.Asp85Asn) at the suggestive threshold (P<10(-6)). Heritability analyses showed that approximate to 15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r(g)=0.40;P=3.2x10(-3)). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P<0.005). Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.
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| 6. |
- Bastard, Paul, et al.
(författare)
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Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1.
- 2021
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Ingår i: The Journal of experimental medicine. - 1540-9538. ; 218:7
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Tidskriftsartikel (refereegranskat)abstract
- Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti-IFN-β and another anti-IFN-ε, but none had anti-IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.
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| 7. |
- Belay, Mulugeta, et al.
(författare)
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Detection of Mycobacterium tuberculosis complex DNA in CD34-positive peripheral blood mononuclear cells of asymptomatic tuberculosis contacts : an observational study
- 2021
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Ingår i: The Lancet Microbe. - 2666-5247. ; 2:6, s. 267-275
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Tidskriftsartikel (refereegranskat)abstract
- Background: Haematopoietic stem cells expressing the CD34 surface marker have been posited as a niche for Mycobacterium tuberculosis complex bacilli during latent tuberculosis infection. Our aim was to determine whether M tuberculosis complex DNA is detectable in CD34-positive peripheral blood mononuclear cells (PBMCs) isolated from asymptomatic adults living in a setting with a high tuberculosis burden. Methods: We did a cross-sectional study in Ethiopia between Nov 22, 2017, and Jan 10, 2019. Digital PCR (dPCR) was used to determine whether M tuberculosis complex DNA was detectable in PBMCs isolated from 100 mL blood taken from asymptomatic adults with HIV infection or a history of recent household or occupational exposure to an index case of human or bovine tuberculosis. Participants were recruited from HIV clinics, tuberculosis clinics, and cattle farms in and around Addis Ababa. A nested prospective study was done in a subset of HIV-infected individuals to evaluate whether administration of isoniazid preventive therapy was effective in clearing M tuberculosis complex DNA from PBMCs. Follow-up was done between July 20, 2018, and Feb 13, 2019. QuantiFERON-TB Gold assays were also done on all baseline and follow-up samples. Findings: Valid dPCR data (ie, droplet counts >10 000 per well) were available for paired CD34-positive and CD34-negative PBMC fractions from 197 (70%) of 284 participants who contributed data to cross-sectional analyses. M tuberculosis complex DNA was detected in PBMCs of 156 of 197 participants with valid dPCR data (79%, 95% CI 74–85). It was more commonly present in CD34-positive than in CD34-negative fractions (154 [73%] of 197 vs 46 [23%] of 197; p<0·0001). Prevalence of dPCR-detected M tuberculosis complex DNA did not differ between QuantiFERON-negative and QuantiFERON-positive participants (77 [78%] of 99 vs 79 [81%] of 98; p=0·73), but it was higher in HIV-infected than in HIV-uninfected participants (67 [89%] of 75 vs 89 [73%] of 122, p=0·0065). By contrast, the proportion of QuantiFERON-positive participants was lower in HIV-infected than in HIV-uninfected participants (25 [33%] of 75 vs 73 [60%] of 122; p<0·0001). Administration of isoniazid preventive therapy reduced the prevalence of dPCR-detected M tuberculosis complex DNA from 41 (95%) of 43 HIV-infected individuals at baseline to 23 (53%) of 43 after treatment (p<0·0001), but it did not affect the prevalence of QuantiFERON positivity (17 [40%] of 43 at baseline vs 13 [30%] of 43 after treatment; p=0·13). Interpretation: We report a novel molecular microbiological biomarker of latent tuberculosis infection with properties that are distinct from those of a commercial interferon-γ release assay. Our findings implicate the bone marrow as a niche for M tuberculosis in latently infected individuals. Detection of M tuberculosis complex DNA in PBMCs has potential applications in the diagnosis of latent tuberculosis infection, in monitoring response to preventive therapy, and as an outcome measure in clinical trials of interventions to prevent or treat latent tuberculosis infection. Funding: UK Medical Research Council.
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| 8. |
- Berg, Ingrid L., et al.
(författare)
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MutS alpha deficiency increases tolerance to DNA damage in yeast lacking postreplication repair
- 2020
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Ingår i: DNA Repair. - : Elsevier BV. - 1568-7864 .- 1568-7856. ; 91-92
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Tidskriftsartikel (refereegranskat)abstract
- By combining mutations in DNA repair genes, important and unexpected interactions between different repair pathways can be discovered. In this study, we identified a novel link between mismatch repair (MMR) genes and postreplication repair (PRR) in Saccharomyces cerevisiae. Strains lacking Rad5 (HLTF in mammals), a protein important for restarting stalled replication forks in the error-free PRR pathway, were supersensitive to the DNA methylating agent methyl methanesulfonate (MMS). Deletion of the mismatch repair genes, MSH2 or MSH6, which together constitutes the MutS alpha complex, partially suppressed the MMS super-sensitivity of the rad5 Delta, strain. Deletion of MSH2 also suppressed the MMS sensitivity of mms2 Delta, which acts together with Rad5 in error-free PRR. However, inactivating the mismatch repair genes MSH3 and MLH1 did not suppress rad5 Delta, showing that the suppression was specific for disabling MutS alpha. The partial suppression did not require translesion DNA synthesis (REV1, REV3 or RAD30), base excision repair (MAGI) or homologous recombination (RAD51). Instead, the underlying mechanism was dependent on RAD52 while independent of established pathways involving RAD52, like single-strand annealing and break-induced replication. We propose a Rad5- and Rad51-independent template switch pathway, capable of compensating for the loss of the error-free template-switch subpathway of postreplication repair, triggered by the loss of MutS alpha.
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| 9. |
- Berg, Lotta, et al.
(författare)
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Djurskydd inom grisuppfödning
- 2020
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- I Sverige tillåts idag generellt avvänjning av smågrisar i praktiken vid en individuell ålder om tidigast 28 dagar. Detta skiljer från EUs grisdirektiv där avvänjning tillåts från 21 dagars ålder. En digivningsperiod på 21 dagar ger en högre produktion eftersom medeltalet kullar per sugga och år teoretiskt då kan öka med 4,5 % (från 2,2 till 2,3 kullar per år). Det har även föreslagits att en kortare digivningsperiod skulle innebära mindre påfrestningar på suggorna, och därigenom medföra förbättrad välfärd för dessa. Rådet finner att det finns mycket få studier som jämför avvänjning vid just 21 och 28 dagar. De vetenskapliga studier som studerar detta mer i detalj är i de flesta fall genomförda i alternativa system, så som grupphållnings-system eller så kallade ”getaway pens” där suggan kan gå ifrån sina smågrisar. Resultat från dessa studier går därmed inte att generalisera till konventionella system där suggor med smågrisar hålls individuellt med små möjligheter för suggan att reglera t.ex. digivning eller födosöksbeteende. Trots bristen på vetenskapligt granskade rapporter konstaterades att en avvänjning vid 28 dagars ålder var att föredra sett ur smågrisens perspektiv, eftersom matsmältningsapparat och immunsystem är mer utvecklade den fjärde levnadsveckan. Det förefaller dock finnas en ganska tydlig skillnad i fysiologisk mognad mellan grisar som är yngre (<19-21 dagar) respektive äldre (28 dagar), men där grisar som är 25 dagar och äldre skiljer sig mindre från grisar som är 28 dagar gamla än grisar som är 23 dagar och yngre. Diperiodens belastning på den domesticerade suggan i modern grisproduktion överstiger den hos frilevande suggor eftersom antalet överlevande kultingar är högre, samt att suggan inte heller genom att styra digivningen kan skydda sig från kullens ökande krav på att dia. De ökande kullstorlekarna kan teoretiskt innebära påfrestningar på suggan, och tidig avvänjning skulle därmed kunna bidra till att minska påfrestningarna på suggan. Det finns dock inga vetenskapliga studier som stödjer en sådan slutsats. Det kan dock konstateras att en svensk sugga under slutet av diperioden i medeltal ger di till 13 kultingar som vardera väger cirka 10 kg, vilka tillsammans dagligen kräver 108 MJ omsättbar energi (25 800 kcal) varav huvuddelen kommer från suggans mjölk. I dagens svenska grisproduktion med omgångsuppfödning kan det skilja 4-7 dagar mellan de först födda och de sist födda i gruppen. För att samla sugg-gruppen inför nästa grisning avvänjs alla suggor samma dag och vid en lägsta individuell avvänjningsålder av 28 dagar blir medelåldern vid avvänjning därför i praktiken cirka 32 dagar. Om lantbruken fortsätter att fokusera på avvänjning så nära 28 dagars ålder som möjligt kommer ”manöverutrymmet” för att synkronisera suggorna vid avvänjning att försvinna. Suggor med fysiologiskt längre dräktighet än genomsnittet riskerar då att förskjutas i grisningstid jämfört med medelsuggorna. Vid en förlängning med tre dagar mellan två grisningstillfällen kan en sugga redan som tredjegrisare vara så pass avvikande vad gäller grisningsdag att hon kommer att slås ut (slaktas) i förtid om det inte ges möjlighet att synkronisera gruppen vid avvänjning. Vid en bedömning av lämpligaste dagen för avvänjning bör såväl smågrisens som suggans situation beaktas. Det vetenskapliga underlaget för detta är mycket begränsat, men det ska beaktas att inhysning och skötsel har större betydelse för såväl smågrisars som suggors hälsa och välfärd än den exakta avvänjningsåldern. Vid en samlad bedömning ansågs därför att en avvänjning vid 28 dagar i genomsnitt förefaller acceptabel, under förutsättning att avvänjningsåldern i inget enskilt fall understiger 25 dagar.
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| 10. |
- Berg, Martin, 1977-, et al.
(författare)
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Automated Welfare Futures : Interrogating Automated Decision-Making in the Nordics
- 2022
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- How can we, as social scientists, make sense of the promises and implications of automated and data-driven systems that are becoming increasingly ubiquitous and essential for the Nordic welfare states? What are the theoretical and methodological tensions and possibilities that these systems pose to research when they assemble and disassemble existing structures, organisational logics and dependencies?Over the last few years, critical social science research has established that data harvesting and digital tracking, in particular, pose a general societal challenge that risks undermining Nordic values of autonomy and equity and the overall welfare of people. At the same time, the welfare state and welfare provision are increasingly characterised by processes of datafication, promoting uses of data analytics and automated decision-making (ADM). Researchers have flagged datafication as a specific concern for the public sector in relation to questions of ADM systems, and other forms of data-driven optimization. Despite the burgeoning literature on various concerns and the ethical guidelines and regulatory initiatives that try to respond to them, however, we have engaged so far with a limited range of theoretical and methodological approaches to explore the social dynamics at play in concrete contexts of ADM.This roundtable brings together key scholars that engage critically with the social aims and implications of datafication to address how ADM is imagined, practised and experienced in different empirical contexts and across various organisational levels in the Nordics. The roundtable will open with short ’provocations’ through which the speakers present and contextualise concepts they have used or would like to promote in the study of emerging automated and data-driven systems. The provocations are followed by a joint discussion about how these concepts can support sociological research that studies the promises and implications of automated and data-driven systems as part of the myths and realities of the Nordic welfare states, now and in the future.
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