| 1. |
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| 2. |
- Clark, DW, et al.
(författare)
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Associations of autozygosity with a broad range of human phenotypes
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
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Tidskriftsartikel (refereegranskat)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
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| 3. |
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| 4. |
- Joshi, PK, et al.
(författare)
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Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity
- 2017
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8:1, s. 910-
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Tidskriftsartikel (refereegranskat)abstract
- Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents’ survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.
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| 5. |
- Postmus, I., et al.
(författare)
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Meta-analysis of genome-wide association studies of HDL cholesterol response to statins
- 2016
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 53:12, s. 835-45
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Tidskriftsartikel (refereegranskat)abstract
- Background In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Interindividual variation in HDL-C response to statins may be partially explained by genetic variation. Methods and results We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1x10(-4) from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5x10(-8)) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment. Conclusions Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.
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| 6. |
- Ashar, Foram N., et al.
(författare)
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A comprehensive evaluation of the genetic architecture of sudden cardiac arrest
- 2018
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Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 39:44, s. 3961-
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Sudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA.Methods and results: We carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk.Conclusions: Our findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.
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| 7. |
- Joshi, Peter K, et al.
(författare)
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Directional dominance on stature and cognition in diverse human populations
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
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Tidskriftsartikel (refereegranskat)abstract
- Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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| 8. |
- Grahn, T., et al.
(författare)
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Excited states and reduced transition probabilities in Os-168
- 2016
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Ingår i: PHYSICAL REVIEW C. - : American Physical Society. - 2469-9985. ; 94:4
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Tidskriftsartikel (refereegranskat)abstract
- The level scheme of the neutron-deficient nuclide Os-168 has been extended and mean lifetimes of excited states have been measured by the recoil distance Doppler-shift method using the JUROGAM gamma-ray spectrometer in conjunction with the IKP Koln plunger device. The 168Os. rays were measured in delayed coincidence with recoiling fusion-evaporation residues detected at the focal plane of the RITU gas-filled separator. The ratio of reduced transition probabilities B(E2; 4(1)(+)-> 2(1)(+))/B(E2; 2(1)(+)-> 0(1)(+)) is measured to be 0.34(18), which is very unusual for collective band structures and cannot be reproduced by interacting boson model (IBM-2) calculations based on the SkM* energy-density functional.
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| 9. |
- Postmus, Iris, et al.
(författare)
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Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.
- 2014
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
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| 12. |
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| 13. |
- Köttgen, Anna, et al.
(författare)
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New loci associated with kidney function and chronic kidney disease
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:5, s. 376-384
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m2; n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide–significant loci (P < 5 × 10−8) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.
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| 14. |
- Lange, Leslie A, et al.
(författare)
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Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol.
- 2014
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 94:2, s. 233-245
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Tidskriftsartikel (refereegranskat)abstract
- Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.
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| 15. |
- Pinto, Ana Margarida, et al.
(författare)
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Emotion regulation and the salience network : a hypothetical integrative model of fibromyalgia
- 2023
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Ingår i: Nature Reviews Rheumatology. - : Springer Nature. - 1759-4790 .- 1759-4804. ; 19:1, s. 44-60
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Tidskriftsartikel (refereegranskat)abstract
- Fibromyalgia is characterized by widespread pain, fatigue, sleep disturbances and other symptoms, and has a substantial socioeconomic impact. Current biomedical and psychosocial treatments are unsatisfactory for many patients, and treatment progress has been hindered by the lack of a clear understanding of the pathogenesis of fibromyalgia. We present here a model of fibromyalgia that integrates current psychosocial and neurophysiological observations. We propose that an imbalance in emotion regulation, reflected by an overactive 'threat' system and underactive 'soothing' system, might keep the 'salience network' (also known as the midcingulo-insular network) in continuous alert mode, and this hyperactivation, in conjunction with other mechanisms, contributes to fibromyalgia. This proposed integrative model, which we term the Fibromyalgia: Imbalance of Threat and Soothing Systems (FITSS) model, should be viewed as a working hypothesis with limited supporting evidence available. We hope, however, that this model will shed new light on existing psychosocial and biological observations, and inspire future research to address the many gaps in our knowledge about fibromyalgia, ultimately stimulating the development of novel therapeutic interventions.
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| 16. |
- Pinto, Ana Margarida, et al.
(författare)
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Neurophysiological and psychosocial mechanisms of fibromyalgia : A comprehensive review and call for an integrative model
- 2023
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Ingår i: Neuroscience and Biobehavioral Reviews. - : Elsevier. - 0149-7634 .- 1873-7528. ; 151
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Forskningsöversikt (refereegranskat)abstract
- Research into the neurobiological and psychosocial mechanisms involved in fibromyalgia has progressed remarkably in recent years. Despite this, current accounts of fibromyalgia fail to capture the complex, dynamic, and mutual crosstalk between neurophysiological and psychosocial domains. We conducted a comprehensive review of the existing literature in order to: a) synthesize current knowledge on fibromyalgia; b) explore and highlight multi-level links and pathways between different systems; and c) build bridges connecting disparate perspectives. An extensive panel of international experts in neurophysiological and psychosocial aspects of fi-bromyalgia discussed the collected evidence and progressively refined and conceptualized its interpretation. This work constitutes an essential step towards the development of a model capable of integrating the main factors implicated in fibromyalgia into a single, unified construct which appears indispensable to foster the under-standing, assessment, and intervention for fibromyalgia.
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| 17. |
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| 18. |
- Procter, M. G., et al.
(författare)
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Anomalous transition strength in the proton-unbound nucleus (109)(53)I56
- 2011
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Ingår i: Physics Letters B. - : Elsevier BV. - 0370-2693 .- 1873-2445. ; 704:3, s. 118-122
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Tidskriftsartikel (refereegranskat)abstract
- A lifetime measurement has been made for the first excited 11/2(+) state in the proton-unbound nucleus (109)(53)I56 using the recoil-distance Doppler-shift method in conjunction with recoil-proton tagging. The experimental reduced transition probability is considerably smaller than the prediction of theoretical shell-model calculations using the CD-Bonn nucleon-nucleon potential. The discrepancy between the theoretical and experimental reduced transition strengths in this work most likely arises from the inability of the current shell-model calculations to accurately account for the behavior of the unbound nuclear states.
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| 19. |
- Procter, M. G., et al.
(författare)
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Lifetime measurement in the proton-unbound nucleus 109I
- 2011
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Ingår i: AIP Conf. Proc.. - : AIP. - 9780735409835 ; , s. 105-110
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Konferensbidrag (refereegranskat)abstract
- The Recoil-Distance Doppler-shift method has been combined with Recoil-Decay Tagging for the first time to measure a lifetime in the proton-unbound nucleus 109I. The lifetime value was determined using the Differential Decay-Curve method in singles mode. The result has been compared to theoretical shell-model calculations in order to better understand the nature of unbound valence nucleons at the proton drip line.
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| 20. |
- Tang, Wenbo, et al.
(författare)
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Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:7, s. e100776-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. Methods: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. Results: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P = 5.71 x 10(-7)). In addition, meta-analysis using the five cohorts with >= 3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P = 2.18 x 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. Conclusions: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.
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| 21. |
- Wang, X., et al.
(författare)
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Collective structures up to spin ∼ 65h in the N 90 isotones 158Er and 157Ho
- 2012
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Ingår i: Journal of Physics: Conference Series. - : IOP Publishing. - 1742-6588 .- 1742-6596. ; 381:1
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Tidskriftsartikel (refereegranskat)abstract
- A new collective band with high dynamic moment of inertia in 158Er at spins beyond band termination has been found in addition to the two previously reported ones. The measured transition quadrupole moments (Qt) of these three bands are very similar. These three bands have been suggested to possess a triaxial strongly deformed shape, based on comparisons with calculations using the cranked Nilsson-Strutinsky model and with tilted axis cranking calculations using the Skyrme-Hartree-Fock model. In addition, three collective bands with similar high dynamic moments of inertia, tentatively assigned to 157Ho, have been observed. Thus, it is suggested that all these structures share a common underlying character and that they are most likely associated with triaxial strongly deformed minima which are predicted to be close to the yrast line at spin 50 - 70h.
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| 22. |
- Wang, X., et al.
(författare)
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Quadrupole moments of collective structures up to spin similar to 65(h)over-bar in Er-157 and Er-158: A challenge for understanding triaxiality in nuclei
- 2011
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Ingår i: Physics Letters. Section B: Nuclear, Elementary Particle and High-Energy Physics. - : Elsevier BV. - 0370-2693. ; 702:2-3, s. 127-130
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Tidskriftsartikel (refereegranskat)abstract
- The transition quadrupole moments. Q(t), of four weakly populated collective bands up to spin similar to 65h in Er-157,Er-158 have been measured to be similar to II eb demonstrating that these sequences are associated with large deformations. However, the data are inconsistent with calculated values from cranked Nilsson-Strutinsky calculations that predict the lowest energy triaxial shape to be associated with rotation about the short principal axis. The data appear to favor either a stable triaxial shape rotating about the intermediate axis or, alternatively, a triaxial shape with larger deformation rotating about the short axis. These new results challenge the present understanding of triaxiality in nuclei. (C) 2011 Elsevier B.V. All rights reserved.
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