| 1. |
- Thomas, HS, et al.
(författare)
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- 2019
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swepub:Mat__t
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| 2. |
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| 3. |
- Munn-Chernoff, M. A., et al.
(författare)
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Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies
- 2021
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Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 26:1
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Tidskriftsartikel (refereegranskat)abstract
- Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r(g)], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from similar to 2400 to similar to 537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r(g) = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r(g) = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r(g) = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r(gs) = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
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| 4. |
- Drake, TM, et al.
(författare)
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Surgical site infection after gastrointestinal surgery in children: an international, multicentre, prospective cohort study
- 2020
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Ingår i: BMJ global health. - : BMJ. - 2059-7908. ; 5:12
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Tidskriftsartikel (refereegranskat)abstract
- Surgical site infection (SSI) is one of the most common healthcare-associated infections (HAIs). However, there is a lack of data available about SSI in children worldwide, especially from low-income and middle-income countries. This study aimed to estimate the incidence of SSI in children and associations between SSI and morbidity across human development settings.MethodsA multicentre, international, prospective, validated cohort study of children aged under 16 years undergoing clean-contaminated, contaminated or dirty gastrointestinal surgery. Any hospital in the world providing paediatric surgery was eligible to contribute data between January and July 2016. The primary outcome was the incidence of SSI by 30 days. Relationships between explanatory variables and SSI were examined using multilevel logistic regression. Countries were stratified into high development, middle development and low development groups using the United Nations Human Development Index (HDI).ResultsOf 1159 children across 181 hospitals in 51 countries, 523 (45·1%) children were from high HDI, 397 (34·2%) from middle HDI and 239 (20·6%) from low HDI countries. The 30-day SSI rate was 6.3% (33/523) in high HDI, 12·8% (51/397) in middle HDI and 24·7% (59/239) in low HDI countries. SSI was associated with higher incidence of 30-day mortality, intervention, organ-space infection and other HAIs, with the highest rates seen in low HDI countries. Median length of stay in patients who had an SSI was longer (7.0 days), compared with 3.0 days in patients who did not have an SSI. Use of laparoscopy was associated with significantly lower SSI rates, even after accounting for HDI.ConclusionThe odds of SSI in children is nearly four times greater in low HDI compared with high HDI countries. Policies to reduce SSI should be prioritised as part of the wider global agenda.
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| 6. |
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| 7. |
- Frazier-Wood, Alexis C., et al.
(författare)
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Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses
- 2016
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Ingår i: Nature Genetics. - : Nature Research (part of Springer Nature). - 1061-4036 .- 1546-1718. ; 48, s. 624-
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Tidskriftsartikel (refereegranskat)abstract
- Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (vertical bar(p) over cap vertical bar approximate to 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.
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| 8. |
- Smith, Jennifer A, et al.
(författare)
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Genome-wide association study identifies 74 loci associated with educational attainment
- 2016
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Ingår i: Nature (London). - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 533:7604, s. 539-542
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Tidskriftsartikel (refereegranskat)abstract
- Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
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| 9. |
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| 10. |
- Ip, H. F., et al.
(författare)
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Genetic association study of childhood aggression across raters, instruments, and age
- 2021
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association metaanalysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE= 0.0038). We found no genome-wide significant SNPs for AGG(overall). The gene-based analysis returned three significant genes: ST3GAL3 (P= 1.6E-06), PCDH7 (P= 2.0E-06), and IPO13 (P= 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from r(g)= 0.46 between self- and teacher-assessment to r(g)d= 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range r(g): 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (r(g)=-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range |r(g)| : 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
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| 11. |
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| 13. |
- Becker, Joel, et al.
(författare)
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Resource profile and user guide of the Polygenic Index Repository
- 2021
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Ingår i: Nature Human Behaviour. - : Nature Research (part of Springer Nature). - 2397-3374. ; 51:6, s. 694-695
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Tidskriftsartikel (refereegranskat)abstract
- Polygenic indexes (PGIs) are DNA-based predictors. Their value for research in many scientific disciplines is growing rapidly. As a resource for researchers, we used a consistent methodology to construct PGIs for 47 phenotypes in 11 datasets. To maximize the PGIs’ prediction accuracies, we constructed them using genome-wide association studies—some not previously published—from multiple data sources, including 23andMe and UK Biobank. We present a theoretical framework to help interpret analyses involving PGIs. A key insight is that a PGI can be understood as an unbiased but noisy measure of a latent variable we call the ‘additive SNP factor’. Regressions in which the true regressor is this factor but the PGI is used as its proxy therefore suffer from errors-in-variables bias. We derive an estimator that corrects for the bias, illustrate the correction, and make a Python tool for implementing it publicly available. © 2021, The Author(s), under exclusive licence to Springer Nature Limited.
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| 14. |
- Brazel, David M., et al.
(författare)
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Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use
- 2019
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Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 85:11, s. 946-955
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk.METHODS: We analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci.RESULTS: Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals.CONCLUSIONS: Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.
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| 15. |
- Carninci, P, et al.
(författare)
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The transcriptional landscape of the mammalian genome
- 2005
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Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 309:5740, s. 1559-1563
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Tidskriftsartikel (refereegranskat)abstract
- This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5′ and 3′ boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.
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| 16. |
- Erzurumluoglu, A. Mesut, et al.
(författare)
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Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci
- 2020
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Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:10, s. 2392-2409
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Tidskriftsartikel (refereegranskat)abstract
- Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
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| 17. |
- Hicks, B. M., et al.
(författare)
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Gender differences and developmental change in externalizing disorders from late adolescence to early adulthood : A longitudinal twin study
- 2007
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Ingår i: Journal of Abnormal Psychology. - Washington : American Psychological Association (APA). - 0021-843X .- 1939-1846. ; 116:3, s. 433-447
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Tidskriftsartikel (refereegranskat)abstract
- Using data from over 1,000 male and female twins participating in the Minnesota Twin Family Study, the authors examined developmental change, gender differences, and genetic and environmental contributions to the symptom levels of four externalizing disorders (adult antisocial behavior, alcohol dependence, nicotine dependence, and drug dependence) from ages 17 to 24. Both men and women increased in symptoms for each externalizing disorder, with men increasing at a greater rate than women, such that a modest gender gap at age 17 widened to a large one at age 24. Additionally, a mean-level gender difference on a latent Externalizing factor could account for the mean-level gender differences for the individual disorders. Biometric analyses revealed increasing genetic variation and heritability for men but a trend toward decreasing genetic variation and increasing environmental effects for women. Results illustrate the importance of gender and developmental context for symptom expression and the utility of structural models to integrate general trends and disorder-specific characteristics.
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| 18. |
- Liu, X., et al.
(författare)
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Toward a minimal representation of aerosols in climate models : description and evaluation in the Community Atmosphere Model CAM5
- 2012
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Ingår i: Geoscientific Model Development. - : Copernicus GmbH. - 1991-959X .- 1991-9603. ; 5:3, s. 709-739
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Tidskriftsartikel (refereegranskat)abstract
- A modal aerosol module (MAM) has been developed for the Community Atmosphere Model version 5 (CAM5), the atmospheric component of the Community Earth System Model version 1 (CESM1). MAM is capable of simulating the aerosol size distribution and both internal and external mixing between aerosol components, treating numerous complicated aerosol processes and aerosol physical, chemical and optical properties in a physically-based manner. Two MAM versions were developed: a more complete version with seven lognormal modes (MAM7), and a version with three lognormal modes (MAM3) for the purpose of long-term (decades to centuries) simulations. In this paper a description and evaluation of the aerosol module and its two representations are provided. Sensitivity of the aerosol lifecycle to simplifications in the representation of aerosol is discussed. Simulated sulfate and secondary organic aerosol (SOA) mass concentrations are remarkably similar between MAM3 and MAM7. Differences in primary organic matter (POM) and black carbon (BC) concentrations between MAM3 and MAM7 are also small (mostly within 10 %). The mineral dust global burden differs by 10 % and sea salt burden by 30-40 % between MAM3 and MAM7, mainly due to the different size ranges for dust and sea salt modes and different standard deviations of the log-normal size distribution for sea salt modes between MAM3 and MAM7. The model is able to qualitatively capture the observed geographical and temporal variations of aerosol mass and number concentrations, size distributions, and aerosol optical properties. However, there are noticeable biases; e.g., simulated BC concentrations are significantly lower than measurements in the Arctic. There is a low bias in modeled aerosol optical depth on the global scale, especially in the developing countries. These biases in aerosol simulations clearly indicate the need for improvements of aerosol processes (e.g., emission fluxes of anthropogenic aerosols and precursor gases in developing countries, boundary layer nucleation) and properties (e.g., primary aerosol emission size, POM hygroscopicity). In addition, the critical role of cloud properties (e. g., liquid water content, cloud fraction) responsible for the wet scavenging of aerosol is highlighted.
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| 19. |
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| 20. |
- McCarthy, Shane, et al.
(författare)
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A reference panel of 64,976 haplotypes for genotype imputation
- 2016
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:10, s. 1279-1283
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Tidskriftsartikel (refereegranskat)abstract
- We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.
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| 21. |
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| 23. |
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| 24. |
- Sharma, Sapna, et al.
(författare)
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Long-term ice phenology records spanning up to 578 years for 78 lakes around the Northern Hemisphere
- 2022
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Ingår i: Scientific Data. - : Springer Nature. - 2052-4463. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- In recent decades, lakes have experienced unprecedented ice loss with widespread ramifications for winter ecological processes. The rapid loss of ice, resurgence of winter biology, and proliferation of remote sensing technologies, presents a unique opportunity to integrate disciplines to further understand the broad spatial and temporal patterns in ice loss and its consequences. Here, we summarize ice phenology records for 78 lakes in 12 countries across North America, Europe, and Asia to permit the inclusion and harmonization of in situ ice phenology observations in future interdisciplinary studies. These ice records represent some of the longest climate observations directly collected by people. We highlight the importance of applying the same definition of ice-on and ice-off within a lake across the time-series, regardless of how the ice is observed, to broaden our understanding of ice loss across vast spatial and temporal scales.
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| 25. |
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| 26. |
- Venables, N. C., et al.
(författare)
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Evidence of a prominent genetic basis for associations between psychoneurometric traits and common mental disorders
- 2017
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Ingår i: International Journal of Psychophysiology. - Amsterdam : Elsevier. - 0167-8760 .- 1872-7697. ; 115, s. 4-12
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Tidskriftsartikel (refereegranskat)abstract
- Threat sensitivity (THT) and weak inhibitory control (or disinhibition; DIS) are trait constructs that relate to multiple types of psychopathology and can be assessed psychoneurometrically (i.e., using self-report and physiological indicators combined). However, to establish that psychoneurometric assessments of THT and DIS index biologically-based liabilities, it is important to clarify the etiologic bases of these variables and their associations with clinical problems. The current work addressed this important issue using data from a sample of identical and fraternal adult twins (N = 454). THT was quantified using a scale measure and three physiological indicators of emotional reactivity to visual aversive stimuli. DIS was operationalized using scores on two scale measures combined with two brain indicators from cognitive processing tasks. THT and DIS operationalized in these ways both showed appreciable heritability (0.45, 0.68), and genetic variance in these traits accounted for most of their phenotypic associations with fear, distress, and substance use disorder symptoms. Our findings suggest that, as indices of basic dispositional liabilities for multiple forms of psychopathology with direct links to neurophysiology, psychoneurometric assessments of THT and DIS represent novel and important targets for biologically-oriented research on psychopathology.
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| 27. |
- Venables, N. C., et al.
(författare)
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Psychoneurometric assessment of dispositional liabilities for suicidal behavior : Phenotypic and etiological associations
- 2018
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Ingår i: Psychological Medicine. - Cambridge : Cambridge University Press. - 0033-2917 .- 1469-8978. ; 48:3, s. 463-472
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Tidskriftsartikel (refereegranskat)abstract
- Background: Can core genetic liabilities for suicidal behavior be indexed using psychological and neural indicators combined? The current work addressed this question by examining phenotypic and genetic associations of two biobehavioral traits, threat sensitivity (THT) and disinhibition (DIS) - operationalized as psychoneurometric variables (i.e., composites of psychological-scale and neurophysiological measures) - with suicidal behaviors in a sample of adult twins.Methods: Participants were 444 identical and fraternal twins recruited from an urban community. THT was assessed using a psychological-scale measure of fear/fearlessness combined with physiological indicators of reactivity to aversive pictures, and DIS was assessed using scale measures of disinhibitory tendencies combined with indicators of brain response from lab performance tasks. Suicidality was assessed using items from structured interview and questionnaire protocols.Results: THT and DIS each contributed uniquely to prediction of suicidality when assessed psychoneurometrically (i.e., as composites of scale and neurophysiological indicators). In addition, these traits predicted suicidality interactively, with participants high on both reporting the greatest degree of suicidal behaviors. Biometric (twin-modeling) analyses revealed that a high percentage of the predictive association for each psychoneurometric trait (83% for THT, 68% for DIS) was attributable to genetic variance in common with suicidality.Conclusions: Findings indicate that psychoneurometric assessments of biobehavioral traits index genetic liability for suicidal behavior, and as such, can serve as innovative targets for research on core biological processes contributing to severe psychopathology, including suicidal proclivities and actions.
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| 28. |
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| 29. |
- Weiss, A, et al.
(författare)
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Personality Polygenes, Positive Affect, and Life Satisfaction
- 2016
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Ingår i: Twin research and human genetics : the official journal of the International Society for Twin Studies. - : Cambridge University Press (CUP). - 1832-4274 .- 1839-2628. ; 19:5, s. 407-417
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Tidskriftsartikel (refereegranskat)abstract
- Approximately half of the variation in wellbeing measures overlaps with variation in personality traits. Studies of non-human primate pedigrees and human twins suggest that this is due to common genetic influences. We tested whether personality polygenic scores for the NEO Five-Factor Inventory (NEO-FFI) domains and for item response theory (IRT) derived extraversion and neuroticism scores predict variance in wellbeing measures. Polygenic scores were based on published genome-wide association (GWA) results in over 17,000 individuals for the NEO-FFI and in over 63,000 for the IRT extraversion and neuroticism traits. The NEO-FFI polygenic scores were used to predict life satisfaction in 7 cohorts, positive affect in 12 cohorts, and general wellbeing in 1 cohort (maximalN= 46,508). Meta-analysis of these results showed no significant association between NEO-FFI personality polygenic scores and the wellbeing measures. IRT extraversion and neuroticism polygenic scores were used to predict life satisfaction and positive affect in almost 37,000 individuals from UK Biobank. Significant positive associations (effect sizes <0.05%) were observed between the extraversion polygenic score and wellbeing measures, and a negative association was observed between the polygenic neuroticism score and life satisfaction. Furthermore, using GWA data, genetic correlations of -0.49 and -0.55 were estimated between neuroticism with life satisfaction and positive affect, respectively. The moderate genetic correlation between neuroticism and wellbeing is in line with twin research showing that genetic influences on wellbeing are also shared with other independent personality domains.
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