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  • Adams, Hieab H. H., et al. (författare)
  • Novel genetic loci underlying human intracranial volume identified through genome-wide association
  • 2016
  • Ingår i: Nature Neuroscience. - 1097-6256 .- 1546-1726. ; 19:12, s. 1569-1582
  • Tidskriftsartikel (refereegranskat)abstract
    • Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (rho(genetic) = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N-combined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.
  • Fritzell, Peter, et al. (författare)
  • Bacteria : back pain, leg pain and Modic sign—a surgical multicentre comparative study
  • 2019
  • Ingår i: European spine journal. - : Springer. - 0940-6719 .- 1432-0932. ; 28:12, s. 2981-2989
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: To compare bacterial findings in pain-generating degenerated discs in adults operated on for lumbar disc herniation (LDH), and mostly also suffering from low back pain (LBP), with findings in adolescent patients with non-degenerated non-pain-generating discs operated on for scoliosis, and to evaluate associations with Modic signs on magnetic resonance imaging (MRI). Cutibacterium acnes (Propionibacterium acnes) has been found in painful degenerated discs, why it has been suggested treating patients with LDH/LBP with antibiotics. As multidrug-resistant bacteria are a worldwide concern, new indications for using antibiotics should be based on solid scientific evidence.Methods: Between 2015 and 2017, 40 adults with LDH/LBP (median age 43, IQR 33–49) and 20 control patients with scoliosis (median age 17, IQR 15–20) underwent surgery at seven Swedish hospitals. Samples were cultured from skin, surgical wound, discs and vertebrae. Genetic relatedness of C. acnes isolates was investigated using single-nucleotide polymorphism analysis. DNA samples collected from discs/vertebrae were analysed using 16S rRNA-based PCR sequencing. MRI findings were assessed for Modic changes.Results: No bacterial growth was found in 6/40 (15%) LDH patients, compared with 3/20 (15%) scoliosis patients. Most positive samples in both groups were isolated from the skin and then from subcutis or deep within the wound. Of the four disc and vertebral samples from each of the 60 patients, 235/240 (98%) were DNA negative by bacterial PCR. A single species, C. acnes, was found exclusively in the disc/vertebra from one patient in each group. In the LDH group, 29/40 (72%) patients had at least one sample with growth of C. acnes, compared to 14/20 (70%) in the scoliosis group. Bacterial findings and Modic changes were not associated.Conclusions: Cutibacterium acnes found in discs and vertebrae during surgery for disc herniation in adults with degenerated discs may be caused by contamination, as findings in this group were similar to findings in a control group of young patients with scoliosis and non-degenerated discs. Furthermore, such findings were almost always combined with bacterial findings on the skin and/or in the wound. There was no association between preoperative Modic changes and bacterial findings. Antibiotic treatment of lumbar disc herniation with sciatica and/or low back pain, without signs of clinical discitis/spondylitis, should be seriously questioned. 
  • Grut, V., et al. (författare)
  • Cytomegalovirus seropositivity is associated with reduced risk of multiple sclerosis-a presymptomatic case-control study
  • 2021
  • Ingår i: European Journal of Neurology. - : Wiley-Blackwell. - 1351-5101 .- 1468-1331. ; 28:9, s. 3072-3079
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and purpose Epstein-Barr virus (EBV) and human herpesvirus 6A (HHV-6A) are associated with increased risk of multiple sclerosis (MS). Conversely, infection with cytomegalovirus (CMV) has been suggested to reduce the risk of MS but supporting data from presymptomatic studies are lacking. Here, it was sought to increase the understanding of CMV in MS aetiology. Methods A nested case-control study was performed with presymptomatically collected blood samples identified through crosslinkage of MS registries and Swedish biobanks. Serological antibody response against CMV, EBV and HHV-6A was determined using a bead-based multiplex assay. Odds ratio (OR) with 95% confidence interval (CI) for CMV seropositivity as a risk factor for MS was calculated by conditional logistic regression and adjusted for EBV and HHV-6A seropositivity. Potential interactions on the additive scale were analysed by calculating the attributable proportion due to interaction (AP). Results Serum samples from 670 pairs of matched cases and controls were included. CMV seropositivity was associated with a reduced risk for MS (OR = 0.70, 95% CI 0.56-0.88, p = 0.003). Statistical interactions on the additive scale were observed between seronegativity for CMV and seropositivity against HHV-6A (AP 0.34, 95% CI 0.06-0.61) and EBV antigen EBNA-1 (amino acid 385-420) at age 20-39 years (AP 0.37, 95% CI 0.09-0.65). Conclusions Cytomegalovirus seropositivity is associated with a decreased risk for MS. The protective role for CMV infection in MS aetiology is further supported by the interactions between CMV seronegativity and EBV and HHV-6A seropositivity.
  • Lund, Lars H, et al. (författare)
  • Association between enrolment in a heart failure quality registry and subsequent mortality-a nationwide cohort study.
  • 2017
  • Ingår i: European Journal of Heart Failure. - : John Wiley & Sons. - 1388-9842 .- 1879-0844.
  • Tidskriftsartikel (refereegranskat)abstract
    • AIMS: Heart failure (HF) quality registries report quality of care but it is unknown whether they improve outcomes. The aims were to assess predictors of enrolment in a HF registry, test the hypothesis that enrolment in a HF registry is associated with reduced mortality, and assess potential explanatory factors for this reduction in mortality, if present.METHODS AND RESULTS: We conducted a nationwide prospective cohort study of patients with new-onset HF registered in the Swedish National Patient Registry (NPR, a mandatory registry of ICD-code diagnoses) with or without concurrent registration in the Swedish Heart Failure Registry (SwedeHF, a voluntary quality reporting registry) 2006-2013. The association between demographics, co-morbidities and medications, and enrolment in the SwedeHF, was assessed using multivariable logistic regression. The association between enrolment in the SwedeHF and all-cause mortality was assessed using multivariable Cox regression, with adjustment for demographics, co-morbidities and medications. A total of 231 437 patients were included, of which 21 888 (9.5%) were in the SwedeHF [age (mean ± standard deviation) 74 ± 13 years; 41% women; 68% inpatients] and 209 549 (90.5%) were not (age 78 ± 12 years, 50% women; 79% inpatients). Selected variables independently associated with enrolment in the SwedeHF were male sex, younger age, higher education, absent co-morbidities and co-morbidity-related medications, and use of HF and cardiovascular medications. Over a median (interquartile range) follow-up of 874 (247-1667) days, there were 13.0 vs. 20.8 deaths per 100 patient-years (P < 0.001). The hazard ratio (95% confidence interval) for death for the SwedeHF yes vs. no was 0.65 (0.63-0.66) crude, and increased to 0.80 (0.78-0.81) after adding demographics, to 0.82 (0.80-0.84) after adding co-morbidities and co-morbidity-related medications, to 0.95 (0.93-0.97) after adding cardiovascular medications, and to 1.04 (1.02-1.07) after adding HF-specific medications.CONCLUSION: Heart failure patients of male sex, younger age, and higher education were more likely to be enrolled in a HF quality registry. Enrolment was associated with reduced all-cause mortality that was explained by demographic differences and better utilization of cardiovascular and HF medications.
  • Lövdén, Martin, et al. (författare)
  • The dimensionality of between-person differences in white matter microstructure in old age
  • 2013
  • Ingår i: Human Brain Mapping. - : Wiley-Blackwell. - 1065-9471 .- 1097-0193. ; 34:6, s. 1386-1398
  • Tidskriftsartikel (refereegranskat)abstract
    • Between-person differences in white matter microstructure may partly generalize across the brain and partly play out differently for distinct tracts. We used diffusion-tensor imaging and structural equation modeling to investigate this issue in a sample of 260 adults aged 60–87 years. Mean fractional anisotropy and mean diffusivity of seven white matter tracts in each hemisphere were quantified. Results showed good fit of a model positing that individual differences in white matter microstructure are structured according to tracts. A general factor, although accounting for variance in the measures, did not adequately represent the individual differences. This indicates the presence of a substantial amount of tract-specific individual differences in white matter microstructure. In addition, individual differences are to a varying degree shared between tracts, indicating that general factors also affect white matter microstructure. Age-related differences in white matter microstructure were present for all tracts. Correlations among tract factors did not generally increase as a function of age, suggesting that aging is not a process with homogenous effects on white matter microstructure across the brain. These findings highlight the need for future research to examine whether relations between white matter microstructure and diverse outcomes are specific or general. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc.
  • Matilla-Santander, N., et al. (författare)
  • COVID-19 and Precarious Employment : Consequences of the Evolving Crisis
  • 2021
  • Ingår i: International Journal of Health Services. - : Sage Publications. - 0020-7314 .- 1541-4469.
  • Tidskriftsartikel (refereegranskat)abstract
    • The world of work is facing an ongoing pandemic and an economic downturn with severe effects worldwide. Workers trapped in precarious employment (PE), both formal and informal, are among those most affected by the COVID-19 pandemic. Here we call attention to at least 5 critical ways that the consequences of the crisis among workers in PE will be felt globally: (a) PE will increase, (b) workers in PE will become more precarious, (c) workers in PE will face unemployment without being officially laid off, (d) workers in PE will be exposed to serious stressors and dramatic life changes that may lead to a rise in diseases of despair, and (e) PE might be a factor in deterring the control of or in generating new COVID-19 outbreaks. We conclude that what we really need is a new social contract, where the work of all workers is recognized and protected with adequate job contracts, employment security, and social protection in a new economy, both during and after the COVID-19 crisis.
  • Satizabal, Claudia L., et al. (författare)
  • Genetic architecture of subcortical brain structures in 38,851 individuals
  • 2019
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624-
  • Tidskriftsartikel (refereegranskat)abstract
    • Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
  • Andreou, Dimitrios, et al. (författare)
  • Associations between a locus downstream DRD1 gene and cerebrospinal fluid dopamine metabolite concentrations in psychosis
  • 2016
  • Ingår i: Neuroscience Letters. - 0304-3940 .- 1872-7972. ; 619, s. 126-130
  • Tidskriftsartikel (refereegranskat)abstract
    • Dopamine activity, mediated by the catecholaminergic neurotransmitter dopamine, is prominent in the human brain and has been implicated in schizophrenia. Dopamine targets five different receptors and is then degraded to its major metabolite homovanillic acid (HVA). We hypothesized that genes encoding dopamine receptors may be associated with cerebrospinal fluid (CSF) HVA concentrations in patients with psychotic disorder. We searched for association between 67 single nucleotide polymorphisms (SNPs) in the five dopamine receptor genes i.e., DRD1, DRD2, DRD3, DRD4 and DRD5, and the CSF HVA concentrations in 74 patients with psychotic disorder. Nominally associated SNPs were also tested in 111 healthy controls. We identified a locus, located downstream DRD1 gene, where four SNPs, rs11747728, rs11742274, rs265974 and rs11747886, showed association with CSF HVA concentrations in psychotic patients. The associations between rs11747728, which is a regulatory region variant, and rs11742274 with HVA remained significant after correction for multiple testing. These associations were restricted to psychotic patients and were absent in healthy controls. The results suggest that the DRD1 gene is implicated in the pathophysiology of psychosis and support the dopamine hypothesis of schizophrenia.
  • Andreou, Dimitrios, et al. (författare)
  • Cerebrospinal fluid monoamine metabolite concentrations as intermediate phenotypes between glutamate-related genes and psychosis
  • 2015
  • Ingår i: Psychiatry Research. - 0165-1781 .- 1872-7123. ; 229:1-2, s. 497-504
  • Tidskriftsartikel (refereegranskat)abstract
    • Glutamate-related genes have been associated with schizophrenia, but the results have been ambiguous and difficult to replicate. Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the major degradation products of the monoamines dopamine, serotonin and noradrenaline, respectively, and their concentrations in the cerebrospinal fluid (CSF), mainly HVA, have been associated with schizophrenia. In the present study, we hypothesized that CSF HVA, 5-HIAA and MHPG concentrations represent intermediate phenotypes in the association between glutamate-related genes and psychosis. To test this hypothesis, we searched for association between 238 single nucleotide polymorphisms (SNPs) in ten genes shown to be directly or indirectly implicated in glutamate transmission and CSF HVA, 5-HIAA and MHPG concentrations in 74 patients with psychotic disease. Thirty-eight nominally significant associations were found. Further analyses in 111 healthy controls showed that 87% of the nominal associations were restricted to the patients with psychosis. Some of the psychosis-only-associated SNPs found in the D-amino acid oxidase activator (DADA) and the kynurenine 3-monooxygenase (KMO) genes have previously been reported to be associated with schizophrenia. The present results suggest that CSF monoamine metabolite concentrations may represent intermediate phenotypes in the association between glutamate-related genes and psychosis.
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