| 1. |
- Docherty, Anna R, et al.
(författare)
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GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
- 2023
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Ingår i: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738
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Tidskriftsartikel (refereegranskat)abstract
- Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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| 2. |
- Gkourogianni, Alexandra, et al.
(författare)
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Pre- and postnatal growth failure with microcephaly due to two novel heterozygous IGF1R mutations and response to growth hormone treatment
- 2020
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Ingår i: Acta Paediatrica. - : Wiley-Blackwell Publishing Inc.. - 0803-5253 .- 1651-2227. ; 109:10, s. 2067-2074
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To explore the phenotype and response to growth hormone in patients with heterozygous-mutations in the insulin-like growth factor I receptor gene (IGF1R).METHODS: Children with short-stature, microcephaly, born SGA combined with biochemical sign of IGF-I insensitivity were analyzed for IGF1R mutations or deletions using Sanger sequencing and Multiple ligation dependent probe amplification analysis.RESULTS: In two families, a novel heterozygous non-synonymous missense IGF1R variant was identified. In family 1, c.3364G>T, p.(Gly1122Cys) was found in the proband and co-segregated perfectly with the phenotype in three generations. In family 2, a de novo variant c.3530G>A, p.(Arg1177His) was detected. Both variants were rare, not present in the GnomAD database. Three individuals carrying IGF1R mutations have received rhGH treatment. The average gain in height SDS during treatment was 0.42 (range: 0.26 - 0.60) and 0.64 (range: 0.32 - 0.86) after 1 and 2 years of treatment, respectively.CONCLUSION: Our study presents two heterozygous IGF1R mutations causing pre- and postnatal growth failure and microcephaly and also indicates that individuals with heterozygous IGF1R mutations can respond to rhGH treatment. The findings highlight that sequencing of the IGF1R should be considered in children with microcephaly and short stature due to pre- and postnatal growth failure.
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| 3. |
- Jónsson, Gísli Gunnar, et al.
(författare)
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Dynamics of Selected Biomarkers in Cerebrospinal Fluid During Complex Endovascular Aortic Repair : A Pilot Study
- 2022
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Ingår i: Annals of Vascular Surgery. - : Elsevier. - 0890-5096 .- 1615-5947. ; 78, s. 141-151
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Ischemic spinal cord injury (SCI) is a serious complication of complex aortic repair. Prophylactic cerebrospinal fluid (CSF) drainage, used to decrease lumbar cerebrospinal fluid (CSF) pressure, enables monitoring of CSF biomarkers that may aid in detecting impending SCI. We hypothesized that biomarkers, previously evaluated in traumatic SCI and brain injury, would be altered in CSF over time following complex endovascular aortic repair (cEVAR). Objectives: To examine if a chosen cohort of CSF biomarker correlates to SCI and warrants further research. Methods: A prospective observational study on patients undergoing cEVAR with extensive aortic coverage. Vital parameters and CSF samples were collected on ten occasions during 72 hours post-surgery. A panel of ten biomarkers were analyzed (Neurofilament Light Polypeptide (NFL), Tau, Glial Fibrillary Acidic Protein (GFAP), Soluble Amyloid Precursos Protein (APP) α and β, Amyloid β 38, 40 and 42 (Aβ38, 40 and 42), Chitinase-3-like protein 1 (CHI3LI or YKL-40), Heart-type fatty acid binding protein (H-FABP).). Results: Nine patients (mean age 69, 7 males) were included. Median total aortic coverage was 68% [33, 98]. One patient died during the 30-day post-operative period. After an initial stable phase for the first few postoperative hours, most biomarkers showed an upward trend compared with baseline in all patients with >50% increase in value for NFL in 5/9 patients, in 7/9 patients for Tau and in 5/9 patients for GFAP. One patient developed spinal cord and supratentorial brain ischemia, confirmed with MRI. In this case, NF-L, GFAP and tau were markedly elevated compared with non-SCI patients (maximum increase compared with baseline in the SCI patient versus mean value of the maximal increase for all other patients: NF-L 367% vs 79%%, GFAP 95608% versus 3433%, tau 1020% vs 192%). Conclusion: This study suggests an increase in all ten studied CSF biomarkers after coverage of spinal arteries during endovascular aortic repair. However, the pilot study was not able to establish a specific correlation between spinal fluid biomarker elevation and clinical symptoms of SCI due to small sample size and event rate.
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| 4. |
- Jonsson, Mattias, et al.
(författare)
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Cost-effectiveness of silvicultural measures to increase substrate availability for red-listed wood-living organisms in Norway spruce forests
- 2006
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Ingår i: Biological Conservation. - : Elsevier. - 0006-3207 .- 1873-2917. ; 127:4, s. 443-467
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Tidskriftsartikel (refereegranskat)abstract
- It is important that measures to maintain biodiversity are taken in a way that is cost-effective for the landowner. We analyzed the cost-effectiveness of silvicultural measures that aim at increasing the substrate availability for red-listed (species that are threatened, near threatened or where species probably are threatened but data is deficient) saproxylic (wood-inhabiting) organisms. We modelled stands of Norway spruce (Picea abies) in three regions of Sweden by using computer simulations and a database with substrate requirements of saproxylic beetles and cryptogams on the Swedish Red-List. Conclusions concerning cost-effectiveness of silvicultural measures depend on the extinction thresholds of the species they are intended to conserve; measures that generate only small amounts of coarse woody debris (CWD) may provide too little substrate to be useful for species with high extinction thresholds. In northern Sweden, forestland is relatively inexpensive, so a cost-effective strategy to increase the amount of spruce CWD was to set aside more forests as reserves. In central and southern Sweden, more emphasis should instead be given to increasing the amount of CWD in the managed forest. The regulations by the Forest Stewardship Council (FSC) could be made more cost-effective by prescribing creation of more high stumps and retention of larger amounts of naturally dying trees. Large-sized CWD, CWD from slow-growing trees, and CWD in late decay stages are substrate types that were particularly rare in managed forest in relation to unmanaged forests. Manual soil scarification and retention of living trees are measures that can increase the proportion of these underrepresented CWD types.
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| 5. |
- Langenskiöld, Marcus, 1972, et al.
(författare)
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Deep Femoral Vein Reconstruction for Abdominal Aortic Graft Infections is Associated with Low Aneurysm Related Mortality and a High Rate of Permanent Discontinuation of Antimicrobial Treatment
- 2021
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Ingår i: European Journal of Vascular and Endovascular Surgery. - : Elsevier. - 1078-5884 .- 1532-2165. ; 62:6, s. 927-934
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Aortic prosthesis infection is a devastating complication of aortic surgery. In situ reconstruction with the neo-aorto-iliac system (NAIS) bypass technique has become increasingly used and is recommended in recent treatment guidelines. The main aim was to evaluate NAIS procedural outcomes when undertaken after previous open or endovascular aortic repair in Sweden.Methods: In this retrospective study, The National Quality Registry for Vascular Surgery (Swedvasc) was used to identify Swedish centres that offered the NAIS bypass procedure for aortic prosthesis infection between 2008 and 2018. Variables of special interest were procedural details, short and long term survival, renal and other complications, and the durtion of antimicrobial treatment.Results: Forty patients (36 males, four females [mean age 69 years], 32 open repairs, seven endovascular aortic repairs [EVAR] and one fenestrated EVAR; 21 presented with aorto-enteric fistula) operated on with NAIS bypass were reviewed. The median time from the primary aortic intervention to the NAIS bypass procedure was 32 months (range 0 – 252 months). Mean ± standard deviation operating time was 645 ± 160 minutes, mean blood loss was 6 277 ± 6 525 mL, mean length of intensive care unit stay was 5.3 ± 3.7 days, and mean length of overall hospital stay was 21.2 ± 11.4 days. Thirty-five patients (88%) had a positive microbial culture; the most commonly isolated pathogen was Candida spp. The majority of patients survived for 30 days (n = 35 [88%]), and 33 (83%) and 32 (80%) patients survived for 90 days and one year, respectively. The number of surviving patients free from antimicrobial treatment at 90 days, six months, and one year was 19 (58%), 29 (88%), and 30 (94%). After a mean long term follow up of 69.9 ± 44.7 months, 20 patients were still alive.Conclusion: The NAIS bypass procedure offered reasonable survival and functional outcomes, and was associated with a high cure rate, defined as freedom from any antimicrobial treatment.
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| 6. |
- Lindkvist, Björn, et al.
(författare)
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Metabolic risk factors for esophageal squamous cell carcinoma and adenocarcinoma: a prospective study of 580 000 subjects within the Me-Can project
- 2014
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Ingår i: BMC Cancer. - London : Springer Science and Business Media LLC. - 1471-2407. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background: Obesity is associated with an increased risk of esophageal adenocarcinoma (EAC) and a decreased risk of esophageal squamous cell carcinoma (ESCC). However, little is known about the risk of EAC and ESCC related to other metabolic risk factors. We aimed to examine the risk of EAC and ESCC in relation to metabolic risk factors, separately and combined in a prospective cohort study. Methods: The Metabolic Syndrome and Cancer cohort includes prospective cohorts in Austria, Norway and Sweden, with blood pressure, lipids, glucose and BMI available from 578 700 individuals. Relative risk (RR) for EAC and ESCC was calculated using Cox's proportional hazards analysis for metabolic risk factors categorized into quintiles and transformed into z-scores. The standardized sum of all z-scores was used as a composite score for the metabolic syndrome (MetS). Results: In total, 324 histologically verified cases of esophageal cancer were identified (114 EAC, 184 ESCC and 26 with other histology). BMI was associated with an increased risk of EAC (RR 7.34 (95% confidence interval, 2.88-18.7) top versus bottom quintile) and negatively associated with the risk of ESCC (RR 0.38 (0.23-0.62)). The mean value of systolic and diastolic blood pressure (mid blood pressure) was associated with the risk of ESCC (RR 1.77 (1.37-2.29)). The composite MetS score was associated with the risk of EAC (RR 1.56 (1.19-2.05) per one unit increase of z-score) but not ESCC. Conclusions: In accordance with previous studies, high BMI was associated with an increased risk of EAC and a decreased risk of ESCC. An association between high blood pressure and risk of ESCC was observed but alcohol consumption is a potential confounding factor that we were not able to adjust for in the analysis. The MetS was associated with EAC but not ESCC. However this association was largely driven by the strong association between BMI and EAC. We hypothesize that this association is more likely to be explained by factors directly related to obesity than the metabolic state of the MetS, considering that no other metabolic factor than BMI was associated with EAC.
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| 7. |
- Lindkvist, Björn, et al.
(författare)
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Prospective cohort study of metabolic risk factors and gastric adenocarcinoma risk in the Metabolic Syndrome and Cancer Project (Me-Can)
- 2013
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Ingår i: Cancer Causes and Control. - : Springer Science and Business Media LLC. - 1573-7225 .- 0957-5243. ; 24:1, s. 107-116
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Tidskriftsartikel (refereegranskat)abstract
- Little is known about the association between the metabolic syndrome (MetS) and the risk of gastric adenocarcinoma. The aim of this study was to investigate whether metabolic risk factors, together or combined, were associated with the risk of gastric adenocarcinoma. The Metabolic Syndrome and Cancer Project (Me-Can) is a pooling of prospective cohorts in Austria, Norway, and Sweden with information on blood pressure, lipids, glucose, and BMI available in 578,700 individuals. Cox proportional hazards analysis was used to calculate hazard ratio (HR) of gastric adenocarcinoma using metabolic risk factors categorized into quintiles and transformed into z-scores (with mean = 0 and SD = 1). The standardized sum of all z-scores created a composite MetS score. In total, 1,210 incident cases of gastric adenocarcinoma were identified. Glucose was significantly associated with the risk of gastric adenocarcinoma [calibrated HR 1.58 (1.14-2.20) per one unit increment in z-score] in women. There was a statistically significant association between triglycerides and risk of gastric adenocarcinoma per mmol increment in triglycerides [HR 1.20 (1.06-1.36) per mmol] but not for the adjusted z-score in women. There were no significant association between any metabolic factors and gastric cancer among men. The composite MetS score was associated with the risk of gastric adenocarcinoma in women [HR 1.18 (1.00-1.38) per one unit increment in z-score] but not in men. Glucose and high levels of the composite MetS score were associated with an increased risk of gastric adenocarcinoma in women but not in men.
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| 8. |
- Lundtoft, Christian, et al.
(författare)
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Complement C4 Copy Number Variation is Linked to SSA/Ro and SSB/La Autoantibodies in Systemic Inflammatory Autoimmune Diseases
- 2022
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 74:8, s. 1440-1450
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Tidskriftsartikel (refereegranskat)abstract
- Objective Copy number variation of the C4 complement components, C4A and C4B, has been associated with systemic inflammatory autoimmune diseases. This study was undertaken to investigate whether C4 copy number variation is connected to the autoimmune repertoire in systemic lupus erythematosus (SLE), primary Sjogrens syndrome (SS), or myositis. Methods Using targeted DNA sequencing, we determined the copy number and genetic variants of C4 in 2,290 well-characterized Scandinavian patients with SLE, primary SS, or myositis and 1,251 healthy controls. Results A prominent relationship was observed between C4A copy number and the presence of SSA/SSB autoantibodies, which was shared between the 3 diseases. The strongest association was detected in patients with autoantibodies against both SSA and SSB and 0 C4A copies when compared to healthy controls (odds ratio [OR] 18.0 [95% confidence interval (95% CI) 10.2-33.3]), whereas a weaker association was seen in patients without SSA/SSB autoantibodies (OR 3.1 [95% CI 1.7-5.5]). The copy number of C4 correlated positively with C4 plasma levels. Further, a common loss-of-function variant in C4A leading to reduced plasma C4 was more prevalent in SLE patients with a low copy number of C4A. Functionally, we showed that absence of C4A reduced the individuals capacity to deposit C4b on immune complexes. Conclusion We show that a low C4A copy number is more strongly associated with the autoantibody repertoire than with the clinically defined disease entities. These findings may have implications for understanding the etiopathogenetic mechanisms of systemic inflammatory autoimmune diseases and for patient stratification when taking the genetic profile into account.
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| 9. |
- Metcalfe, Daniel B., et al.
(författare)
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Patchy field sampling biases understanding of climate change impacts across the Arctic
- 2018
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Ingår i: Nature Ecology and Evolution. - : Springer Science and Business Media LLC. - 2397-334X. ; 2:9, s. 1443-1448
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Tidskriftsartikel (refereegranskat)abstract
- Effective societal responses to rapid climate change in the Arctic rely on an accurate representation of region-specific ecosystem properties and processes. However, this is limited by the scarcity and patchy distribution of field measurements. Here, we use a comprehensive, geo-referenced database of primary field measurements in 1,840 published studies across the Arctic to identify statistically significant spatial biases in field sampling and study citation across this globally important region. We find that 31% of all study citations are derived from sites located within 50 km of just two research sites: Toolik Lake in the USA and Abisko in Sweden. Furthermore, relatively colder, more rapidly warming and sparsely vegetated sites are under-sampled and under-recognized in terms of citations, particularly among microbiology-related studies. The poorly sampled and cited areas, mainly in the Canadian high-Arctic archipelago and the Arctic coastline of Russia, constitute a large fraction of the Arctic ice-free land area. Our results suggest that the current pattern of sampling and citation may bias the scientific consensuses that underpin attempts to accurately predict and effectively mitigate climate change in the region. Further work is required to increase both the quality and quantity of sampling, and incorporate existing literature from poorly cited areas to generate a more representative picture of Arctic climate change and its environmental impacts.
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| 10. |
- Mullins, Niamh, et al.
(författare)
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Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
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