| 1. |
- 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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| 2. |
- Jones, G., et al.
(författare)
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Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n=48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1p=4x10(-17)), arthritis (GDF5p=4x10(-13)), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing. Muscle weakness has been associated with morbidity and mortality in older people. Here, the authors have investigated this trait further by performing a genome-wide meta-analysis of grip strength and Mendelian randomization to discover causal relationships between muscle weakness and other diseases.
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| 3. |
- Hong, S. J., et al.
(författare)
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TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels
- 2021
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 17:10, s. 1628-1640
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. Methods We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates. Results We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1. Discussion Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.
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| 4. |
- Neumann, A., et al.
(författare)
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Rare variants in IFFO1, DTNB, NLRC3 and SLC22A10 associate with Alzheimer's disease CSF profile of neuronal injury and inflammation
- 2022
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 27, s. 1990-1999
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) biomarkers represent several neurodegenerative processes, such as synaptic dysfunction, neuronal inflammation and injury, as well as amyloid pathology. We performed an exome-wide rare variant analysis of six AD biomarkers (beta-amyloid, total/phosphorylated tau, NfL, YKL-40, and Neurogranin) to discover genes associated with these markers. Genetic and biomarker information was available for 480 participants from two studies: EMIF-AD and ADNI. We applied a principal component (PC) analysis to derive biomarkers combinations, which represent statistically independent biological processes. We then tested whether rare variants in 9576 protein-coding genes associate with these PCs using a Meta-SKAT test. We also tested whether the PCs are intermediary to gene effects on AD symptoms with a SMUT test. One PC loaded on NfL and YKL-40, indicators of neuronal injury and inflammation. Four genes were associated with this PC: IFFO1, DTNB, NLRC3, and SLC22A10. Mediation tests suggest, that these genes also affect dementia symptoms via inflammation/injury. We also observed an association between a PC loading on Neurogranin, a marker for synaptic functioning, with GABBR2 and CASZ1, but no mediation effects. The results suggest that rare variants in IFFO1, DTNB, NLRC3, and SLC22A10 heighten susceptibility to neuronal injury and inflammation, potentially by altering cytoskeleton structure and immune activity disinhibition, resulting in an elevated dementia risk. GABBR2 and CASZ1 were associated with synaptic functioning, but mediation analyses suggest that the effect of these two genes on synaptic functioning is not consequential for AD development.
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| 5. |
- Delvenne, A., et al.
(författare)
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Cerebrospinal fluid proteomic profiling of individuals with mild cognitive impairment and suspected non-Alzheimer's disease pathophysiology
- 2023
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:3, s. 807-820
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Tidskriftsartikel (refereegranskat)abstract
- Background Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker concept that encompasses individuals with neuronal injury but without amyloidosis. We aim to investigate the pathophysiology of SNAP, defined as abnormal tau without amyloidosis, in individuals with mild cognitive impairment (MCI) by cerebrospinal fluid (CSF) proteomics. Methods Individuals were classified based on CSF amyloid beta (A beta)1-42 (A) and phosphorylated tau (T), as cognitively normal A-T- (CN), MCI A-T+ (MCI-SNAP), and MCI A+T+ (MCI-AD). Proteomics analyses, Gene Ontology (GO), brain cell expression, and gene expression analyses in brain regions of interest were performed. Results A total of 96 proteins were decreased in MCI-SNAP compared to CN and MCI-AD. These proteins were enriched for extracellular matrix (ECM), hemostasis, immune system, protein processing/degradation, lipids, and synapse. Fifty-one percent were enriched for expression in the choroid plexus. Conclusion The pathophysiology of MCI-SNAP (A-T+) is distinct from that of MCI-AD. Our findings highlight the need for a different treatment in MCI-SNAP compared to MCI-AD.
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| 6. |
- Fjell, A. M., et al.
(författare)
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Self-reported Sleep Problems Related to Amyloid Deposition in Cortical Regions with High HOMER1 Gene Expression
- 2020
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Ingår i: Cerebral Cortex. - : Oxford University Press (OUP). - 1047-3211 .- 1460-2199. ; 30:4, s. 2144-2156
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Tidskriftsartikel (refereegranskat)abstract
- Sleep problems are related to the elevated levels of the Alzheimer's disease (AD) biomarker beta-amyloid (AD) Hypotheses about the causes of this relationship can be generated from molecular markers of sleep problems identified in rodents. A major marker of sleep deprivation is Homerla, a neural protein coded by the HOMER1 gene, which has also been implicated in brain A beta accumulation. Here, we tested whether the relationship between cortical A beta accumulation and self-reported sleep quality, as well as changes in sleep quality over 3 years, was stronger in cortical regions with high HOMER1 mRNA expression levels. In a sample of 154 cognitively healthy older adults, A beta correlated with poorer sleep quality cross-sectionally and longitudinally (n = 62), but more strongly in the younger than in older individuals. Effects were mainly found in regions with high expression of HOMER1. The anatomical distribution of the sleep-A beta relationship followed closely the A beta accumulation pattern in 69 patients with mild cognitive impairment or AD. Thus, the results indicate that the relationship between sleep problems and A beta accumulation may involve Homer1 activity in the cortical regions, where harbor A beta deposits in AD. The findings may advance our understanding of the relationship between sleep problems and AD risk.
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| 7. |
- Ford, Alex T., et al.
(författare)
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The Role of Behavioral Ecotoxicology in Environmental Protection
- 2021
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 55:9, s. 5620-5628
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Tidskriftsartikel (refereegranskat)abstract
- For decades, we have known that chemicals affect human and wildlife behavior. Moreover, due to recent technological and computational advances, scientists are now increasingly aware that a wide variety of contaminants and other environmental stressors adversely affect organismal behavior and subsequent ecological outcomes in terrestrial and aquatic ecosystems. There is also a groundswell of concern that regulatory ecotoxicology does not adequately consider behavior, primarily due to a lack of standardized toxicity methods. This has, in turn, led to the exclusion of many behavioral ecotoxicology studies from chemical risk assessments. To improve understanding of the challenges and opportunities for behavioral ecotoxicology within regulatory toxicology/risk assessment, a unique workshop with international representatives from the fields of behavioral ecology, ecotoxicology, regulatory (eco)toxicology, neurotoxicology, test standardization, and risk assessment resulted in the formation of consensus perspectives and recommendations, which promise to serve as a roadmap to advance interfaces among the basic and translational sciences, and regulatory practices.
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| 8. |
- Shi, L., et al.
(författare)
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Multiomics profiling of human plasma and cerebrospinal fluid reveals ATN-derived networks and highlights causal links in Alzheimer's disease
- 2023
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:8, s. 3359-3364
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionThis study employed an integrative system and causal inference approach to explore molecular signatures in blood and CSF, the amyloid/tau/neurodegeneration [AT(N)] framework, mild cognitive impairment (MCI) conversion to Alzheimer's disease (AD), and genetic risk for AD. MethodsUsing the European Medical Information Framework (EMIF)-AD cohort, we measured 696 proteins in cerebrospinal fluid (n = 371), 4001 proteins in plasma (n = 972), 611 metabolites in plasma (n = 696), and genotyped whole-blood (7,778,465 autosomal single nucleotide epolymorphisms, n = 936). We investigated associations: molecular modules to AT(N), module hubs with AD Polygenic Risk scores and APOE4 genotypes, molecular hubs to MCI conversion and probed for causality with AD using Mendelian randomization (MR). ResultsAT(N) framework associated with protein and lipid hubs. In plasma, Proprotein Convertase Subtilisin/Kexin Type 7 showed evidence for causal associations with AD. AD was causally associated with Reticulocalbin 2 and sphingomyelins, an association driven by the APOE isoform. DiscussionThis study reveals multi-omics networks associated with AT(N) and causal AD molecular candidates.
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| 9. |
- Bertram, Michael G., et al.
(författare)
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Frontiers in quantifying wildlife behavioural responses to chemical pollution
- 2022
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Ingår i: Biological Reviews. - : John Wiley & Sons. - 1464-7931 .- 1469-185X. ; 97:4
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Tidskriftsartikel (refereegranskat)abstract
- Animal behaviour is remarkably sensitive to disruption by chemical pollution, with widespread implications for ecological and evolutionary processes in contaminated wildlife populations. However, conventional approaches applied to study the impacts of chemical pollutants on wildlife behaviour seldom address the complexity of natural environments in which contamination occurs. The aim of this review is to guide the rapidly developing field of behavioural ecotoxicology towards increased environmental realism, ecological complexity, and mechanistic understanding. We identify research areas in ecology that to date have been largely overlooked within behavioural ecotoxicology but which promise to yield valuable insights, including within- and among-individual variation, social networks and collective behaviour, and multi-stressor interactions. Further, we feature methodological and technological innovations that enable the collection of data on pollutant-induced behavioural changes at an unprecedented resolution and scale in the laboratory and the field. In an era of rapid environmental change, there is an urgent need to advance our understanding of the real-world impacts of chemical pollution on wildlife behaviour. This review therefore provides a roadmap of the major outstanding questions in behavioural ecotoxicology and highlights the need for increased cross-talk with other disciplines in order to find the answers.
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| 10. |
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| 11. |
- Polverino, Giovanni, et al.
(författare)
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Sex-specific effects of psychoactive pollution on behavioral individuality and plasticity in fish
- 2023
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Ingår i: Behavioral Ecology. - 1045-2249 .- 1465-7279. ; 34:6, s. 969-978
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Tidskriftsartikel (refereegranskat)abstract
- Lay Summary Prozac is present in freshwater systems across the globe as the pharmaceutical contaminant fluoxetine. The effect of fluoxetine on aquatic species' behavioral variability is not yet clear. We show that male guppies become more similar to each other after exposure to fluoxetine, and females become less flexible in their behavior. These sex-specific differences in response to fluoxetine can have a meaningful impact on their ability to survive in a changing world. The global rise of pharmaceutical contaminants in the aquatic environment poses a serious threat to ecological and evolutionary processes. Studies have traditionally focused on the collateral (average) effects of psychoactive pollutants on ecologically relevant behaviors of wildlife, often neglecting effects among and within individuals, and whether they differ between males and females. We tested whether psychoactive pollutants have sex-specific effects on behavioral individuality and plasticity in guppies (Poecilia reticulata), a freshwater species that inhabits contaminated waterways in the wild. Fish were exposed to fluoxetine (Prozac) for 2 years across multiple generations before their activity and stress-related behavior were repeatedly assayed. Using a Bayesian statistical approach that partitions the effects among and within individuals, we found that males-but not females-in fluoxetine-exposed populations differed less from each other in their behavior (lower behavioral individuality) than unexposed males. In sharp contrast, effects on behavioral plasticity were observed in females-but not in males-whereby exposure to even low levels of fluoxetine resulted in a substantial decrease (activity) and increase (freezing behavior) in the behavioral plasticity of females. Our evidence reveals that psychoactive pollution has sex-specific effects on the individual behavior of fish, suggesting that males and females might not be equally vulnerable to global pollutants.
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| 12. |
- Becher, Peter Moritz, et al.
(författare)
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Eligibility for sotagliflozin in a real-world heart failure population based on the SOLOIST-WHF trial enrolment criteria: data from the Swedish heart failure registry
- 2023
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Ingår i: European Heart Journal - Cardiovascular Pharmacotherapy. - : OXFORD UNIV PRESS. - 2055-6837 .- 2055-6845. ; 9:4, s. 343-352
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Tidskriftsartikel (refereegranskat)abstract
- Aims The SOLOIST-WHF trial demonstrated efficacy of sotagliflozin in patients with type 2 diabetes mellitus (T2DM) and recent worsening heart failure (HF) regardless of ejection fraction (EF). Selection criteria in trials may limit their generalizability. Therefore, we aimed to investigate eligibility for sotagliflozin based on the SOLOIST-WHF criteria in a real-world HF population. Methods and results SOLOIST-WHF criteria were applied to patients stabilized after HF hospitalization in the Swedish HF Registry according to (i) literal scenario (all inclusion/exclusion criteria) or (ii) pragmatic scenario (only criteria likely to influence treatment decisions). Of 5453 inpatients with T2DM and recent worsening HF, 51.4% had reduced EF (HFrEF), 19.1% mildly reduced (HFmrEF), and 29.5% preserved EF (HFpEF). Eligibility (literal) was: 27.2% (32.4% in HFrEF, 24.7% in HFmrEF, 19.7% in HFpEF) and eligibility (pragmatic) was 62.8% (69.1%, 60.3%, 53.4%, respectively). In the literal scenario, criteria limiting eligibility were HF duration <3 months, eGFR <30 ml/min/1.73 m(2), age >85 years, acute coronary syndrome <3 months, and insufficiently high N-terminal pro-B-type natriuretic peptide levels. Eligible vs. non-eligible patients had more severe HF, higher cardiovascular (CV) comorbidity burden, higher use of HF treatments, and higher event rates (all-cause death 30.8 vs. 27.2 per 100 patient-years, CV death 19.1 vs. 16.6, and HF hospitalization 36.7 vs. 24.0). Conclusion In this large, real-world HF cohort with T2DM, similar to 1/3 of patients were eligible for sotagliflozin in the literal and similar to 2/3 of patients in the pragmatic scenario. Eligible patients had more severe HF and higher event rates, in particular CV and HF events.
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| 13. |
- Cerveny, D., et al.
(författare)
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Water temperature affects the biotransformation and accumulation of a psychoactive pharmaceutical and its metabolite in aquatic organisms
- 2021
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Ingår i: Environment International. - : Elsevier. - 0160-4120 .- 1873-6750. ; 155
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Tidskriftsartikel (refereegranskat)abstract
- Pharmaceutically active compounds (PhACs) have been shown to accumulate in aquatic and riparian food-webs. Yet, our understanding of how temperature, a key environmental factor in nature, affects uptake, biotransformation, and the subsequent accumulation of PhACs in aquatic organisms is limited. In this study, we tested to what extent bioconcentration of an anxiolytic drugs (temazepam and oxazepam) is affected by two temperature regimes (10 and 20 °C) and how the temperature affects the temazepam biotransformation and subsequent accumulation of its metabolite (oxazepam) in aquatic organisms. We used European perch (Perca fluviatilis) and dragonfly larvae (Sympetrum sp.), which represent predator and prey species of high ecological relevance in food chains of boreal and temperate aquatic ecosystems. Experimental organisms were exposed to target pharmaceuticals at a range of concentrations (0.2–6 µg L−1) to study concentration dependent differences in bioconcentration and biotransformation. We found that the bioconcentration of temazepam in perch was significantly reduced at higher temperatures. Also, temperature had a strong effect on temazepam biotransformation in the fish, with the production and subsequent accumulation of its metabolite (oxazepam) being two-fold higher at 20 °C compared to 10 °C. In contrast, we found no temperature dependency for temazepam bioconcentration in dragonfly larvae and no detectable biotransformation of the parent compound that would result in measurable concentrations of oxazepam in this organism. Our results highlight that while organisms may share the same aquatic ecosystem, their exposure to PhACs may change differently across temperature gradients in the environment.
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| 14. |
- Pease, Jessica E., et al.
(författare)
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Comparison of triploid and diploid rainbow trout (Oncorhynchus mykiss) fine-scale movement, migration and catchability in lowland lakes of western Washington
- 2023
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Ingår i: Movement Ecology. - 2051-3933. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Fisheries managers stock triploid (i.e., infertile, artificially produced) rainbow trout Oncorhynchus mykiss in North American lakes to support sport fisheries while minimizing the risk of genetic introgression between hatchery and wild trout. In Washington State, the Washington Department of Fish and Wildlife (WDFW) allocates approximately US $3 million annually to stock hatchery-origin rainbow trout in > 600 lakes, yet only about 10% of them are triploids. Many lakes in Washington State drain into waters that support wild anadromous steelhead O. mykiss that are listed as threatened under the U.S. Endangered Species Act. As a result, there is a strong interest in understanding the costs and benefits associated with stocking sterile, triploid rainbow trout as an alternative to traditional diploids. The objectives of this study were to compare triploid and diploid rainbow trout in terms of: (1) contribution to the sport fishery catch, (2) fine-scale movements within the study lakes, (3) rate of emigration from the lake, and (4) natural mortality. Our results demonstrated that triploid and diploid trout had similar day-night distribution patterns, but triploid trout exhibited a lower emigration rate from the lake and lower catch rates in some lakes. Overall, triploid rainbow trout represent a viable alternative to stocking of diploids, especially in lakes draining to rivers, because they are sterile, have comparable home ranges, and less often migrate.
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| 15. |
- Raatikainen, Kaisa J., et al.
(författare)
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Pathways towards a sustainable future envisioned by early-career conservation researchers
- 2021
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Ingår i: CONSERVATION SCIENCE AND PRACTICE. - : John Wiley & Sons. - 2578-4854. ; 3:9
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Tidskriftsartikel (refereegranskat)abstract
- Scientists have warned decision-makers about the severe consequences of the global environmental crisis since the 1970s. Yet ecological degradation continues and little has been done to address climate change. We investigated early-career conservation researchers' (ECR) perspectives on, and prioritization of, actions furthering sustainability. We conducted a survey (n = 67) and an interactive workshop (n = 35) for ECR attendees of the 5th European Congress of Conservation Biology (2018). Building on these data and discussions, we identified ongoing and forthcoming advances in conservation science. These include increased transdisciplinarity, science communication, advocacy in conservation, and adoption of a transformation-oriented social-ecological systems approach to research. The respondents and participants had diverse perspectives on how to achieve sustainability. Reformist actions were emphasized as paving the way for more radical changes in the economic system and societal values linked to the environment and inequality. Our findings suggest that achieving sustainability requires a strategy that (1) incorporates the multiplicity of people's views, (2) places a greater value on nature, and (3) encourages systemic transformation across political, social, educational, and economic realms on multiple levels. We introduce a framework for ECRs to inspire their research and practice within conservation science to achieve real change in protecting biological diversity.
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| 16. |
- Wagner, Ryan G., et al.
(författare)
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Community health workers to improve adherence to anti-seizure medication in rural South Africa : Is it cost-effective?
- 2021
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Ingår i: Epilepsia. - : John Wiley & Sons. - 0013-9580 .- 1528-1167. ; 62:1, s. 98-106
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Epilepsy is a common, chronic neurological disorder that disproportionately affects individuals living in low- and middle-income countries (LMICs), where the treatment gap remains high and adherence to medication remains low. Community health workers (CHWs) have been shown to be effective at improving adherence to chronic medications, yet no study assessing the costs of CHWs in epilepsy management has been reported.METHODS: Using a Markov model with age- and sex-varying transition probabilities, we determined whether deploying CHWs to improve epilepsy treatment adherence in rural South Africa would be cost-effective. Data were derived using published studies from rural South Africa. Official statistics and international disability weights provided cost and health state values, respectively, and health gains were measured using quality adjusted life years (QALYs).RESULTS: The intervention was estimated at International Dollars ($) 123 250 per annum per sub-district community and cost $1494 and $1857 per QALY gained for males and females, respectively. Assuming a costlier intervention and lower effectiveness, cost per QALY was still less than South Africa's Gross Domestic Product per capita of $13 215, the cost-effectiveness threshold applied.SIGNIFICANCE: CHWs would be cost-effective and the intervention dominated even when costs and effects of the intervention were unfavorably varied. Health system re-engineering currently underway in South Africa identifies CHWs as vital links in primary health care, thereby ensuring sustainability of the intervention. Further research on understanding local health state utility values and cost-effectiveness thresholds could further inform the current model, and undertaking the proposed intervention would provide better estimates of its efficacy on reducing the epilepsy treatment gap in rural South Africa.
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