| 1. |
- Abbasi, Rasha, et al.
(författare)
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IceCube search for neutrinos from GRB 221009A
- 2023
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Ingår i: Proceedings of 38th International Cosmic Ray Conference (ICRC 2023). - : Sissa Medialab Srl.
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Konferensbidrag (refereegranskat)abstract
- GRB 221009A is the brightest Gamma Ray Burst (GRB) ever observed. The observed extremelyhigh flux of high and very-high-energy photons provide a unique opportunity to probe the predictedneutrino counterpart to the electromagnetic emission. We have used a variety of methods to searchfor neutrinos in coincidence with the GRB over several time windows during the precursor, promptand afterglow phases of the GRB. MeV scale neutrinos are studied using photo-multiplier ratescalers which are normally used to search for galactic core-collapse supernovae neutrinos. GeVneutrinos are searched starting with DeepCore triggers. These events don’t have directionallocalization, but instead can indicate an excess in the rate of events. 10 GeV - 1 TeV and >TeVneutrinos are searched using traditional neutrino point source methods which take into accountthe direction and time of events with DeepCore and the entire IceCube detector respectively. The>TeV results include both a fast-response analysis conducted by IceCube in real-time with timewindows of T0 − 1 to T0 + 2 hours and T0 ± 1 day around the time of GRB 221009A, as well asan offline analysis with 3 new time windows up to a time window of T0 − 1 to T0 + 14 days, thelongest time period we consider. The combination of observations by IceCube covers 9 ordersof magnitude in neutrino energy, from MeV to PeV, placing upper limits across the range forpredicted neutrino emission.
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| 2. |
- Dai, Qile, et al.
(författare)
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OTTERS: a powerful TWAS framework leveraging summary-level reference data
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Most existing TWAS tools require individual-level eQTL reference data and thus are not applicable to summary-level reference eQTL datasets. The development of TWAS methods that can harness summary-level reference data is valuable to enable TWAS in broader settings and enhance power due to increased reference sample size. Thus, we develop a TWAS framework called OTTERS (Omnibus Transcriptome Test using Expression Reference Summary data) that adapts multiple polygenic risk score (PRS) methods to estimate eQTL weights from summary-level eQTL reference data and conducts an omnibus TWAS. We show that OTTERS is a practical and powerful TWAS tool by both simulations and application studies.
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| 3. |
- Purcell, Shaun M., et al.
(författare)
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Common polygenic variation contributes to risk of schizophrenia and bipolar disorder
- 2009
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 460:7256, s. 748-752
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%(1,2). We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.
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| 4. |
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| 5. |
- Ruderfer, Douglas M., et al.
(författare)
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Mosaic copy number variation in schizophrenia
- 2013
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 21:9, s. 1007-1011
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Tidskriftsartikel (refereegranskat)abstract
- Recent reports suggest that somatic structural changes occur in the human genome, but how these genomic alterations might contribute to disease is unknown. Using samples collected as part of the International Schizophrenia Consortium (schizophrenia, n = 3518; control, n = 4238) recruited across multiple university research centers, we assessed single-nucleotide polymorphism genotyping arrays for evidence of chromosomal anomalies. Data from genotyping arrays on each individual were processed using Birdsuite and analyzed with PLINK. We validated potential chromosomal anomalies using custom nanostring probes and quantitative PCR. We estimate chromosomal alterations in the schizophrenia population to be 0.42%, which is not significantly different from controls (0.26%). We identified and validated a set of four extremely large (>10 Mb) chromosomal anomalies in subjects with schizophrenia, including a chromosome 8 trisomy and deletion of the q arm of chromosome 7. These data demonstrate that chromosomal anomalies are present at low frequency in blood cells of both control and schizophrenia subjects.
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| 6. |
- Almqvist, Catarina, et al.
(författare)
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LifeGene - A large prospective population-based study of global relevance
- 2011
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Ingår i: European Journal of Epidemiology. - Stockholm : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 26:1, s. 67-77
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Tidskriftsartikel (refereegranskat)abstract
- Studying gene-environment interactions requires that the amount and quality of the lifestyle data is comparable to what is available for the corresponding genomic data. Sweden has several crucial prerequisites for comprehensive longitudinal biomedical research, such as the personal identity number, the universally available national health care system, continuously updated population and health registries and a scientifically motivated population. LifeGene builds on these strengths to bridge the gap between basic research and clinical applications with particular attention to populations, through a unique design in a research-friendly setting. LifeGene is designed both as a prospective cohort study and an infrastructure with repeated contacts of study participants approximately every 5 years. Index persons aged 18-45 years old will be recruited and invited to include their household members (partner and any children). A comprehensive questionnaire addressing cutting-edge research questions will be administered through the web with short follow-ups annually. Biosamples and physical measurements will also be collected at baseline, and re-administered every 5 years thereafter. Event-based sampling will be a key feature of LifeGene. The household-based design will give the opportunity to involve young couples prior to and during pregnancy, allowing for the first study of children born into cohort with complete pre-and perinatal data from both the mother and father. Questions and sampling schemes will be tailored to the participants' age and life events. The target of LifeGene is to enrol 500,000 Swedes and follow them longitudinally for at least 20 years.
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| 7. |
- Andersson, Evelyn, et al.
(författare)
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Genetics of response to cognitive behavior therapy in adults with major depression : a preliminary report
- 2019
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Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 24:4, s. 484-490
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Tidskriftsartikel (refereegranskat)abstract
- Major depressive disorder is heritable and a leading cause of disability. Cognitive behavior therapy is an effective treatment for major depression. By quantifying genetic risk scores based on common genetic variants, the aim of this report was to explore the utility of psychiatric and cognitive trait genetic risk scores, for predicting the response of 894 adults with major depressive disorder to cognitive behavior therapy. The participants were recruited in a psychiatric setting, and the primary outcome score was measured using the Montgomery Asberg Depression Rating Scale-Self Rated. Single-nucleotide polymorphism genotyping arrays were used to calculate the genomic risk scores based on large genetic studies of six phenotypes: major depressive disorder, bipolar disorder, attention-deficit/hyperactivity disorder, autism spectrum disorder, intelligence, and educational attainment. Linear mixed-effect models were used to test the relationships between the six genetic risk scores and cognitive behavior therapy outcome. Our analyses yielded one significant interaction effect (B = 0.09, p < 0.001): the autism spectrum disorder genetic risk score correlated with Montgomery Asberg Depression Rating Scale-Self Rated changes during treatment, and the higher the autism spectrum disorder genetic load, the less the depressive symptoms decreased over time. The genetic risk scores for the other psychiatric and cognitive traits were not related to depressive symptom severity or change over time. Our preliminary results indicated, as expected, that the genomics of the response of patients with major depression to cognitive behavior therapy were complex and that future efforts should aim to maximize sample size and limit subject heterogeneity in order to gain a better understanding of the use of genetic risk factors to predict treatment outcome.
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| 8. |
- Benjamin, Bolduc, et al.
(författare)
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The IsoGenie database : an interdisciplinary data management solution for ecosystems biology and environmental research
- 2020
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Ingår i: PeerJ. - : PeerJ. - 2167-8359. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Modern microbial and ecosystem sciences require diverse interdisciplinary teams that are often challenged in “speaking” to one another due to different languages and data product types. Here we introduce the IsoGenie Database (IsoGenieDB; https://isogenie-db.asc.ohio-state.edu/), a de novo developed data management and exploration platform, as a solution to this challenge of accurately representing and integrating heterogenous environmental and microbial data across ecosystem scales. The IsoGenieDB is a public and private data infrastructure designed to store and query data generated by the IsoGenie Project, a ~10 year DOE-funded project focused on discovering ecosystem climate feedbacks in a thawing permafrost landscape. The IsoGenieDB provides (i) a platform for IsoGenie Project members to explore the project’s interdisciplinary datasets across scales through the inherent relationships among data entities, (ii) a framework to consolidate and harmonize the datasets needed by the team’s modelers, and (iii) a public venue that leverages the same spatially explicit, disciplinarily integrated data structure to share published datasets. The IsoGenieDB is also being expanded to cover the NASA-funded Archaea to Atmosphere (A2A) project, which scales the findings of IsoGenie to a broader suite of Arctic peatlands, via the umbrella A2A Database (A2A-DB). The IsoGenieDB’s expandability and flexible architecture allow it to serve as an example ecosystems database.
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| 9. |
- Boberg, Julia, et al.
(författare)
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Swedish multimodal cohort of patients with anxiety or depression treated with internet-delivered psychotherapy (MULTI-PSYCH)
- 2023
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Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 13:10
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Depression and anxiety afflict millions worldwide causing considerable disability. MULTI-PSYCH is a longitudinal cohort of genotyped and phenotyped individuals with depression or anxiety disorders who have undergone highly structured internet-based cognitive-behaviour therapy (ICBT). The overarching purpose of MULTI-PSYCH is to improve risk stratification, outcome prediction and secondary preventive interventions. MULTI-PSYCH is a precision medicine initiative that combines clinical, genetic and nationwide register data.Participants MULTI-PSYCH includes 2668 clinically well-characterised adults with major depressive disorder (MDD) (n=1300), social anxiety disorder (n=640) or panic disorder (n=728) assessed before, during and after 12 weeks of ICBT at the internet psychiatry clinic in Stockholm, Sweden. All patients have been blood sampled and genotyped. Clinical and genetic data have been linked to several Swedish registers containing a wide range of variables from patient birth up to 10 years after the end of ICBT. These variable types include perinatal complications, school grades, psychiatric and somatic comorbidity, dispensed medications, medical interventions and diagnoses, healthcare and social benefits, demographics, income and more. Long-term follow-up data will be collected through 2029.Findings to date Initial uses of MULTI-PSYCH include the discovery of an association between PRS for autism spectrum disorder and response to ICBT, the development of a machine learning model for baseline prediction of remission status after ICBT in MDD and data contributions to genome wide association studies for ICBT outcome. Other projects have been launched or are in the planning phase.Future plans The MULTI-PSYCH cohort provides a unique infrastructure to study not only predictors or short-term treatment outcomes, but also longer term medical and socioeconomic outcomes in patients treated with ICBT for depression or anxiety. MULTI-PSYCH is well positioned for research collaboration.
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| 10. |
- Byrnes, Andrea, et al.
(författare)
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Gene expression in peripheral blood leukocytes in monozygotic twins discordant for chronic fatigue : no evidence of a biomarker
- 2009
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:6, s. e5805-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Chronic fatiguing illness remains a poorly understood syndrome of unknown pathogenesis. We attempted to identify biomarkers for chronic fatiguing illness using microarrays to query the transcriptome in peripheral blood leukocytes. METHODS: Cases were 44 individuals who were clinically evaluated and found to meet standard international criteria for chronic fatigue syndrome or idiopathic chronic fatigue, and controls were their monozygotic co-twins who were clinically evaluated and never had even one month of impairing fatigue. Biological sampling conditions were standardized and RNA stabilizing media were used. These methodological features provide rigorous control for bias resulting from case-control mismatched ancestry and experimental error. Individual gene expression profiles were assessed using Affymetrix Human Genome U133 Plus 2.0 arrays. FINDINGS: There were no significant differences in gene expression for any transcript. CONCLUSIONS: Contrary to our expectations, we were unable to identify a biomarker for chronic fatiguing illness in the transcriptome of peripheral blood leukocytes suggesting that positive findings in prior studies may have resulted from experimental bias.
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| 11. |
- Chourpiliadis, Charilaos, et al.
(författare)
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Short-term improvement of mental health after a COVID-19 vaccination.
- 2023
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 18:2
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Tidskriftsartikel (refereegranskat)abstract
- The role of COVID-19 vaccination on the mental health of the general population remains poorly understood. This study aims to assess the short-term change in depressive and anxiety symptoms in relation to COVID-19 vaccination among Swedish adults.A prospective study of 7,925 individuals recruited from ongoing cohort studies at the Karolinska Institutet, Stockholm, Sweden, or through social media campaigns, with monthly data collections on self-reported depressive and anxiety symptoms from December 2020 to October 2021 and COVID-19 vaccination from July to October 2021. Prevalence of depressive and anxiety symptoms (defined as a self-reported total score of ≥10 in PHQ-9 and GAD-7, respectively) was calculated one month before, one month after the first dose, and, if applicable, one month after the second dose. For individuals not vaccinated or choosing not to report vaccination status (unvaccinated individuals), we selected three monthly measures of PHQ-9 and GAD-7 with 2-month intervals in-between based on data availability.5,079 (64.1%) individuals received two doses of COVID-19 vaccine, 1,977 (24.9%) received one dose, 305 (3.9%) were not vaccinated, and 564 (7.1%) chose not to report vaccination status. There was a lower prevalence of depressive and anxiety symptoms among vaccinated, compared to unvaccinated individuals, especially after the second dose. Among individuals receiving two doses of vaccine, the prevalence of depressive and anxiety symptoms was lower after both first (aRR = 0.82, 95%CI 0.76-0.88 for depression; aRR = 0.81, 95%CI 0.73-0.89 for anxiety) and second (aRR = 0.79, 95%CI 0.73-0.85 for depression; aRR = 0.73, 95%CI 0.66-0.81 for anxiety) dose, compared to before vaccination. Similar results were observed among individuals receiving only one dose (aRR = 0.76, 95%CI 0.68-0.84 for depression; aRR = 0.82, 95%CI 0.72-0.94 for anxiety), comparing after first dose to before vaccination.We observed a short-term improvement in depressive and anxiety symptoms among adults receiving COVID-19 vaccines in the current pandemic. Our findings provide new evidence to support outreach campaigns targeting hesitant groups.
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| 12. |
- Christmas, Matthew, et al.
(författare)
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Evolutionary constraint and innovation across hundreds of placental mammals
- 2023
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 380:6643
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Tidskriftsartikel (refereegranskat)abstract
- Zoonomia is the largest comparative genomics resource for mammals produced to date. By aligning genomes for 240 species, we identify bases that, when mutated, are likely to affect fitness and alter disease risk. At least 332 million bases (similar to 10.7%) in the human genome are unusually conserved across species (evolutionarily constrained) relative to neutrally evolving repeats, and 4552 ultraconserved elements are nearly perfectly conserved. Of 101 million significantly constrained single bases, 80% are outside protein-coding exons and half have no functional annotations in the Encyclopedia of DNA Elements (ENCODE) resource. Changes in genes and regulatory elements are associated with exceptional mammalian traits, such as hibernation, that could inform therapeutic development. Earth's vast and imperiled biodiversity offers distinctive power for identifying genetic variants that affect genome function and organismal phenotypes.
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| 13. |
- Cooper, Declan L.M., et al.
(författare)
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Consistent patterns of common species across tropical tree communities
- 2024
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Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 625:7996, s. 728-734
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Tidskriftsartikel (refereegranskat)abstract
- Trees structure the Earth’s most biodiverse ecosystem, tropical forests. The vast number of tree species presents a formidable challenge to understanding these forests, including their response to environmental change, as very little is known about most tropical tree species. A focus on the common species may circumvent this challenge. Here we investigate abundance patterns of common tree species using inventory data on 1,003,805 trees with trunk diameters of at least 10 cm across 1,568 locations 1–6 in closed-canopy, structurally intact old-growth tropical forests in Africa, Amazonia and Southeast Asia. We estimate that 2.2%, 2.2% and 2.3% of species comprise 50% of the tropical trees in these regions, respectively. Extrapolating across all closed-canopy tropical forests, we estimate that just 1,053 species comprise half of Earth’s 800 billion tropical trees with trunk diameters of at least 10 cm. Despite differing biogeographic, climatic and anthropogenic histories 7, we find notably consistent patterns of common species and species abundance distributions across the continents. This suggests that fundamental mechanisms of tree community assembly may apply to all tropical forests. Resampling analyses show that the most common species are likely to belong to a manageable list of known species, enabling targeted efforts to understand their ecology. Although they do not detract from the importance of rare species, our results open new opportunities to understand the world’s most diverse forests, including modelling their response to environmental change, by focusing on the common species that constitute the majority of their trees.
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| 14. |
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| 15. |
- Dittrich, Christian, et al.
(författare)
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ESMO / ASCO Recommendations for a Global Curriculum in Medical Oncology Edition 2016
- 2016
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Ingår i: ESMO Open. - : Elsevier BV. - 2059-7029. ; 1:5
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Tidskriftsartikel (refereegranskat)abstract
- The European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) are publishing a new edition of the ESMO/ ASCO Global Curriculum (GC) thanks to contribution of 64 ESMOappointed and 32 ASCO-appointed authors. First published in 2004 and updated in 2010, the GC edition 2016 answers to the need for updated recommendations for the training of physicians in medical oncology by defining the standard to be fulfilled to qualify as medical oncologists. At times of internationalisation of healthcare and increased mobility of patients and physicians, the GC aims to provide state-of-the-art cancer care to all patients wherever they live. Recent progress in the field of cancer research has indeed resulted in diagnostic and therapeutic innovations such as targeted therapies as a standard therapeutic approach or personalised cancer medicine specialised training for medical oncology trainees. Thus, several new chapters on technical contents such as molecular pathology, translational research or molecular imaging and on conceptual attitudes towards human principles like genetic counselling or survivorship have been integrated in the GC. The GC edition 2016 consists of 12 sections with 17 subsections, 44 chapters and 35 subchapters, respectively. Besides renewal in its contents, the GC underwent a principal formal change taking into consideration modern didactic principles. It is presented in a template-based format that subcategorises the detailed outcome requirements into learning objectives, awareness, knowledge and skills. Consecutive steps will be those of harmonising and implementing teaching and assessment strategies.
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| 16. |
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| 17. |
- Dufva, Ylva Eriksson, et al.
(författare)
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Swedish large-scale schizophrenia study : Why do patients and healthy controls participate?
- 2021
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Ingår i: Schizophrenia Research. - : Elsevier BV. - 0920-9964 .- 1573-2509. ; 228, s. 360-366
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Tidskriftsartikel (refereegranskat)abstract
- Insights into determination of study participation are useful for researchers, clinicians and for ethical considerations. Few large-scale genomic studies have involved motives for enrollment, in schizophrenia patients and unaffected controls. In a case-control study with participants recruited nation-wide in Sweden between 2005 and 2010, semi-structured interviews on motives and attitudes towards future studies were explored in 2767 schizophrenia cases and 4466 controls. In qualitative and quantitative analyses, we identified altruism as a major determinant in 84% of the cases and in 97% of the controls. Among pre-defined subcategories of altruism, cases with schizophrenia were more often referring to science for example, 'I want to help science move forward' or 'I want better medications for future generations' in relation to unaffected controls that were more often referring to common humanity such as 'It is my duty and responsibility to help'. In schizophrenia, motives related to personal benefit and social influence were reported by 9% and 5%. We conclude that individuals with schizophrenia frequently report altruistic motives for study participation, almost to the same extent as unaffected controls. In contrast to unfortunate stereotypes, people with schizophrenia wish others to benefit from their experiences with severe mental illness and should not be refrained from participating in genomic research.
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| 18. |
- Emerson, Joanne B., et al.
(författare)
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Host-linked soil viral ecology along a permafrost thaw gradient
- 2018
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Ingår i: Nature Microbiology. - : Springer Science and Business Media LLC. - 2058-5276. ; 3:8, s. 870-880
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Tidskriftsartikel (refereegranskat)abstract
- Climate change threatens to release abundant carbon that is sequestered at high latitudes, but the constraints on microbial metabolisms that mediate the release of methane and carbon dioxide are poorly understood(1-7). The role of viruses, which are known to affect microbial dynamics, metabolism and biogeochemistry in the oceans(8-10), remains largely unexplored in soil. Here, we aimed to investigate how viruses influence microbial ecology and carbon metabolism in peatland soils along a permafrost thaw gradient in Sweden. We recovered 1,907 viral populations (genomes and large genome fragments) from 197 bulk soil and size-fractionated metagenomes, 58% of which were detected in metatranscriptomes and presumed to be active. In silico predictions linked 35% of the viruses to microbial host populations, highlighting likely viral predators of key carbon-cycling microorganisms, including methanogens and methanotrophs. Lineage-specific virus/host ratios varied, suggesting that viral infection dynamics may differentially impact microbial responses to a changing climate. Virus-encoded glycoside hydrolases, including an endomannanase with confirmed functional activity, indicated that viruses influence complex carbon degradation and that viral abundances were significant predictors of methane dynamics. These findings suggest that viruses may impact ecosystem function in climate-critical, terrestrial habitats and identify multiple potential viral contributions to soil carbon cycling.
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| 19. |
- Evengård, Birgitta, 1952-, et al.
(författare)
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The epidemiology of chronic fatigue in the Swedish Twin Registry
- 2005
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Ingår i: Psychological Medicine. - 0033-2917 .- 1469-8978. ; 35:9, s. 1317-1326
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Tidskriftsartikel (refereegranskat)abstract
- CFS-like illness may be more common that previously acknowledged. There is a marked increase in risk by gender. Previous reports that CFS is more prevalent in individuals in certain occupational categories were not confirmed and may have been due to confounding by gender.
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| 20. |
- Figtree, Gemma A., et al.
(författare)
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Clinical Pathway for Coronary Atherosclerosis in Patients Without Conventional Modifiable Risk Factors JACC State-of-the-Art Review
- 2023
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Ingår i: Journal of the American College of Cardiology. - : ELSEVIER SCIENCE INC. - 0735-1097 .- 1558-3597. ; 82:13, s. 1343-1359
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Forskningsöversikt (refereegranskat)abstract
- Reducing the incidence and prevalence of standard modifiable cardiovascular risk factors (SMuRFs) is critical to tackling the global burden of coronary artery disease (CAD). However, a substantial number of individuals develop coronary atherosclerosis despite no SMuRFs. SMuRFless patients presenting with myocardial infarction have been observed to have an unexpected higher early mortality compared to their counterparts with at least 1 SMuRF. Evidence for optimal management of these patients is lacking. We assembled an international, multidisciplinary team to develop an evidence-based clinical pathway for SMuRFless CAD patients. A modified Delphi method was applied. The resulting pathway confirms underlying atherosclerosis and true SMuRFless status, ensures evidence-based secondary prevention, and considers additional tests and interventions for less typical contributors. This dedicated pathway for a previously overlooked CAD population, with an accompanying registry, aims to improve outcomes through enhanced adherence to evidence-based secondary prevention and additional diagnosis of modifiable risk factors observed. (c) 2023 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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| 21. |
- Forlenza, Michael J, et al.
(författare)
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Epidemiology of cancer-related fatigue in the Swedish twin registry
- 2005
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Ingår i: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 104:9, s. 2022-2031
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Tidskriftsartikel (refereegranskat)abstract
- A greater proportion of individuals who were listed in a national cancer registry reported experiencing fatigue compared with individuals in the general population.
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| 22. |
- Fresard, Laure, et al.
(författare)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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Ingår i: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Tidskriftsartikel (refereegranskat)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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| 23. |
- Furberg, Helena, et al.
(författare)
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Genome-wide meta-analyses identify multiple loci associated with smoking behavior
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:5, s. 134-441
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Tidskriftsartikel (refereegranskat)abstract
- Consistent but indirect evidence has implicated genetic factors in smoking behavior1,2. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], b = 1.03, standard error (s.e.) = 0.053, beta = 2.8 x 10(-73)). Two 10q25 SNPs (rs1329650[G], b = 0.367, s. e. = 0.059, beta = 5.7 x 10(-10); and rs1028936[A], b = 0.446, s. e. = 0.074, beta = 1.3 x 10(-9)) and one 9q13 SNP in EGLN2 (rs3733829[G], b = 0.333, s. e. = 0.058, P = 1.0 x 10(-8)) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 x 10(-8)). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 x 10(-8)) was significantly associated with smoking cessation.
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| 24. |
- Ganna, Andrea, et al.
(författare)
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Utilizing Twins as Controls for Non-Twin Case-Materials in Genome Wide Association Studies
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:12, s. e83101-
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Tidskriftsartikel (refereegranskat)abstract
- Twin registries around the globe have collected DNA samples from large numbers of monozygotic and dizygotic twins. The twin sample collections are frequently used as controls in disease-specific studies together with non-twins. This approach is unbiased under the hypothesis that twins and singletons are comparable in terms of allele frequencies; i.e. there are no genetic variants associated with being a twin per se. To test this hypothesis we performed a genome-wide association study comparing the allele frequency of 572,352 single nucleotide polymorphisms (SNPs) in 1,413 monozygotic (MZ) and 5,451 dizygotic (DZ) twins with 3,720 healthy singletons. Twins and singletons have been genotyped using the same platform. SNPs showing association with being a twin at P-value < 1 × 10-5 were selected for replication analysis in 1,492 twins (463 MZ and 1,029 DZ) and 1,880 singletons from Finland. No SNPs reached genome-wide significance (P-value < 5 × 10-8) in the main analysis combining MZ and DZ twins. In a secondary analysis including only DZ twins two SNPs (rs2033541 close to ADAMTSL1 and rs4149283 close to ABCA1) were genome-wide significant after meta-analysis with the Finnish population. The estimated proportion of variance on the liability scale explained by all SNPs was 0.08 (P-value=0.003) when MZ and DZ were considered together and smaller for MZ (0.06, P-value=0.10) compared to DZ (0.09, P-value=0.003) when analyzed separately. In conclusion, twins and singletons can be used in genetic studies together with general population samples without introducing large bias. Further research is needed to explore genetic variances associated with DZ twinning.
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| 25. |
- Genovese, Giulio, et al.
(författare)
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Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.
- 2014
-
Ingår i: The New England journal of medicine. - 1533-4406 .- 0028-4793. ; 371:26, s. 2477-87
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Tidskriftsartikel (refereegranskat)abstract
- Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent.
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| 26. |
- Guintivano, Jerry, et al.
(författare)
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Meta-Analyses of Genome-Wide Association Studies for Postpartum Depression
- 2023
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Ingår i: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 180:12, s. 884-895
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD.METHOD: Meta-analyses were conducted on 18 cohorts of European ancestry (17,339 PPD cases and 53,426 controls), one cohort of East Asian ancestry (975 cases and 3,780 controls), and one cohort of African ancestry (456 cases and 1,255 controls), totaling 18,770 PPD cases and 58,461 controls. Post-GWAS analyses included 1) single-nucleotide polymorphism (SNP)-based heritability ([Formula: see text]), 2) genetic correlations between PPD and other phenotypes, and 3) enrichment of the PPD GWAS findings in 27 human tissues and 265 cell types from the mouse central and peripheral nervous system.RESULTS: No SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. The [Formula: see text] of PPD was 0.14 (SE=0.02). Significant genetic correlations were estimated for PPD with MDD, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. Cell-type enrichment analyses implicate inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern that differs from MDD.CONCLUSIONS: While more samples are needed to reach genome-wide levels of significance, the results presented confirm PPD as a polygenic and heritable phenotype. There is also evidence that despite a high correlation with MDD, PPD may have unique genetic components. Cell enrichment results suggest GABAergic neurons, which converge on a common mechanism with the only medication approved by the U.S. Food and Drug Administration for PPD (brexanolone).
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| 27. |
- Halvorsen, Matthew, et al.
(författare)
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Increased burden of ultra-rare structural variants localizing to boundaries of topologically associated domains in schizophrenia
- 2020
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 11:1, s. 1842-
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Tidskriftsartikel (refereegranskat)abstract
- Despite considerable progress in schizophrenia genetics, most findings have been for large rare structural variants and common variants in well-imputed regions with few genes implicated from exome sequencing. Whole genome sequencing (WGS) can potentially provide a more complete enumeration of etiological genetic variation apart from the exome and regions of high linkage disequilibrium. We analyze high-coverage WGS data from 1162 Swedish schizophrenia cases and 936 ancestry-matched population controls. Our main objective is to evaluate the contribution to schizophrenia etiology from a variety of genetic variants accessible to WGS but not by previous technologies. Our results suggest that ultra-rare structural variants that affect the boundaries of topologically associated domains (TADs) increase risk for schizophrenia. Alterations in TAD boundaries may lead to dysregulation of gene expression. Future mechanistic studies will be needed to determine the precise functional effects of these variants on biology.
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| 28. |
- Hannon, Eilis, et al.
(författare)
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DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia
- 2021
-
Ingår i: eLIFE. - : eLife Sciences Publications. - 2050-084X. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.
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| 29. |
- Humphreys, Keith, et al.
(författare)
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The Genetic Structure of the Swedish Population
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:8, s. e22547-
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Tidskriftsartikel (refereegranskat)abstract
- Patterns of genetic diversity have previously been shown to mirror geography on a global scale and within continents and individual countries. Using genome-wide SNP data on 5174 Swedes with extensive geographical coverage, we analyzed the genetic structure of the Swedish population. We observed strong differences between the far northern counties and the remaining counties. The population of Dalarna county, in north middle Sweden, which borders southern Norway, also appears to differ markedly from other counties, possibly due to this county having more individuals with remote Finnish or Norwegian ancestry than other counties. An analysis of genetic differentiation (based on pairwise F(st)) indicated that the population of Sweden's southernmost counties are genetically closer to the HapMap CEU samples of Northern European ancestry than to the populations of Sweden's northernmost counties. In a comparison of extended homozygous segments, we detected a clear divide between southern and northern Sweden with small differences between the southern counties and considerably more segments in northern Sweden. Both the increased degree of homozygosity in the north and the large genetic differences between the south and the north may have arisen due to a small population in the north and the vast geographical distances between towns and villages in the north, in contrast to the more densely settled southern parts of Sweden. Our findings have implications for future genome-wide association studies (GWAS) with respect to the matching of cases and controls and the need for within-county matching. We have shown that genetic differences within a single country may be substantial, even when viewed on a European scale. Thus, population stratification needs to be accounted for, even within a country like Sweden, which is often perceived to be relatively homogenous and a favourable resource for genetic mapping, otherwise inferences based on genetic data may lead to false conclusions.
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| 30. |
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| 31. |
- Jonsson, Lina, 1982, et al.
(författare)
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Association of Occupational Dysfunction and Hospital Admissions With Different Polygenic Profiles in Bipolar Disorder.
- 2024
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Ingår i: The American journal of geriatric psychiatry. - 1064-7481. ; 181:7, s. 620-629
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Tidskriftsartikel (refereegranskat)abstract
- Many but not all persons with bipolar disorder require hospital care because of severe mood episodes. Likewise, some but not all patients experience long-term occupational dysfunction that extends beyond acute mood episodes. It is not known whether these dissimilar outcomes of bipolar disorder are driven by different polygenic profiles. Here, polygenic scores (PGSs) for major psychiatric disorders and educational attainment were assessed for associations with occupational functioning and psychiatric hospital admissions in bipolar disorder.A total of 4,782 patients with bipolar disorder and 2,963 control subjects were genotyped and linked to Swedish national registers. Longitudinal measures from at least 10 years of registry data were used to derive percentage of years without employment, percentage of years with long-term sick leave, and mean number of psychiatric hospital admissions per year. Ordinal regression was used to test associations between outcomes and PGSs for bipolar disorder, schizophrenia, major depressive disorder, attention deficit hyperactivity disorder (ADHD), and educational attainment. Replication analyses of hospital admissions were conducted with data from the Bipolar Disorder Research Network cohort (N=4,219).Long-term sick leave and unemployment in bipolar disorder were significantly associated with PGSs for schizophrenia, ADHD, major depressive disorder, and educational attainment, but not with the PGS for bipolar disorder. By contrast, the number of hospital admissions per year was associated with higher PGSs for bipolar disorder and schizophrenia, but not with the other PGSs.Bipolar disorder severity (indexed by hospital admissions) was associated with a different polygenic profile than long-term occupational dysfunction. These findings have clinical implications, suggesting that mitigating occupational dysfunction requires interventions other than those deployed to prevent mood episodes.
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| 32. |
- Kato, K, et al.
(författare)
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A population-based twin study of functional somatic syndromes
- 2009
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Ingår i: Psychological Medicine. - : Cambridge University Press. - 0033-2917 .- 1469-8978. ; 39:3, s. 497-505
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The mechanisms underlying the co-occurrence of the functional somatic syndromes are largely unknown. No empirical study has explicitly examined how genetic and environmental factors influence the co-morbidity of these syndromes. We aimed to examine how the co-morbidity of functional somatic syndromes is influenced by genetic and environmental factors that are in common to the syndromes. METHOD: A total of 31318 twins in the Swedish Twin Registry aged 41-64 years underwent screening interviews via a computer-assisted telephone system from 1998 to 2002. Four functional somatic syndromes (chronic widespread pain, chronic fatigue, irritable bowel syndrome, and recurrent headache) and two psychiatric disorders (major depression and generalized anxiety disorder) were assessed using structured questions based on standard criteria for each illness in a blinded manner. RESULTS: Multivariate twin analyses revealed that a common pathway model with two latent traits that were shared by the six illnesses fit best to the women's data. One of the two latent traits loaded heavily on the psychiatric disorders, whereas the other trait loaded on all four of the functional somatic syndromes, particularly chronic widespread pain, but not on the psychiatric disorders. All illnesses except the psychiatric disorders were also affected by genetic influences that were specific to each. CONCLUSIONS: The co-occurrence of functional somatic syndromes in women can be best explained by affective and sensory components in common to all these syndromes, as well as by unique influences specific to each of them. The findings clearly suggest a complex view of the multifactorial pathogenesis of these illnesses.
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| 33. |
- Kato, Kenji, et al.
(författare)
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Chronic widespread pain and its comorbidities : a population-based study
- 2006
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Ingår i: Archives of Internal Medicine. - : American Medical Association (AMA). - 0003-9926 .- 1538-3679. ; 166:15, s. 1649-1654
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Tidskriftsartikel (refereegranskat)abstract
- Associations between CWP and most comorbidities are mediated by unmeasured genetic and family environmental factors in the general population. The extent of mediation via familial factors is likely to be disorder specific.
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| 34. |
- Kato, Kenji, et al.
(författare)
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Importance of genetic influences on chronic widespread pain
- 2006
-
Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 54:5, s. 1682-1686
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Tidskriftsartikel (refereegranskat)abstract
- Individual differences in the likelihood of developing chronic widespread pain reflect modest genetic influences. There are no significant sex differences in the type or expression of the genes responsible for chronic widespread pain or in the magnitude of the relative importance of these influences on chronic widespread pain.
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| 35. |
- Kato, Kenji, et al.
(författare)
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Premorbid predictors of chronic fatigue
- 2006
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Ingår i: Archives of General Psychiatry. - : American Medical Association (AMA). - 0003-990X .- 1538-3636. ; 63:11, s. 1267-1272
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Tidskriftsartikel (refereegranskat)abstract
- Elevated premorbid stress is a significant risk factor for chronic fatigue-like illness, the effect of which may be buffered by genetic influences. Emotional instability assessed 25 years earlier is associated with chronic fatigue through genetic mechanisms contributing to both personality style and expression of the disorder. These findings suggest plausible mechanisms for chronic fatiguing illness.
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| 36. |
- Kehoe, Laura, et al.
(författare)
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Make EU trade with Brazil sustainable
- 2019
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6438, s. 341-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 37. |
- Kowalec, Kaarina, et al.
(författare)
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Increased schizophrenia family history burden and reduced premorbid IQ in treatment-resistant schizophrenia : a Swedish National Register and Genomic Study
- 2021
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Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 26, s. 4487-4495
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Tidskriftsartikel (refereegranskat)abstract
- A high proportion of those with schizophrenia experience treatment non-response, placing them at higher risk for mortality and suicide attempts, compared to treatment responders. The clinical, social, and economic burden of treatment-resistant schizophrenia (TRS) are substantial. Previous genomic and epidemiological studies of TRS were often limited by sample size or lack of comprehensive genomic data. We aimed to systematically understand the clinical, demographic, and genomic correlates of TRS using epidemiological and genetic epidemiological modelling in a Swedish national population sample (n = 24,706) and then in a subgroup with common variant genetic risk scores, rare copy-number variant burden, and rare exonic burden (n = 4936). Population-based analyses identified increasing schizophrenia family history to be significantly associated with TRS (highest quartile of familial burden vs. lowest: adjusted odds ratio (aOR): 1.31, P = 4.8 × 10-8). In males, a decrease of premorbid IQ of one standard deviation was significantly associated with greater risk of TRS (minimal aOR: 0.94, P = 0.002). In a subset of cases with extensive genomic data, we found no significant association between the genetic risk scores of four psychiatric disorders and two cognitive traits with TRS (schizophrenia genetic risk score: aOR = 1.07, P = 0.067). The association between copy number variant and rare variant burden measures and TRS did not reach the pre-defined statistical significance threshold (all P ≥ 0.005). In conclusion, direct measures of genomic risk were not associated with TRS; however, premorbid IQ in males and schizophrenia family history were significantly correlated with TRS and points to new insights into the architecture of TRS.
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| 38. |
- Kowalec, Kaarina, et al.
(författare)
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The association between family history and genomic burden with schizophrenia mortality : a Swedish population-based register and genetic sample study
- 2021
-
Ingår i: Translational Psychiatry. - : Springer Nature. - 2158-3188. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Individuals with schizophrenia (SCZ) have a 2-3-fold higher risk of mortality than the general population. Heritability of mortality in psychiatric disorders has been proposed; however, few have investigated SCZ family history and genetic variation, with all-cause and specific causes of death. We aimed to identify correlates of SCZ mortality using genetic epidemiological and genetic modelling in two samples: a Swedish national population sample and a genotyped subsample. In the Swedish national population sample followed from the first SCZ treatment contact until emigration, death or end of the follow-up, we investigated a standardised measure of SCZ family history. In a subgroup with comprehensive genetic data, we investigated the impact of common and rare genetic variation. Cox proportional hazards regression was used to estimate the association between various factors and mortality (all and specific causes). A total of 13727 SCZ cases fulfilled criteria for the population-based analyses (1268 deaths, 9.2%). The genomic subset contained 4991 cases (1353 deaths, 27.1%). Somatic mutations associated with clonal hematopoiesis with unknown drivers were associated with all-cause mortality (HR 1.77, 95% CI: 1.26-2.49). No other heritable measures were associated with all-cause mortality nor with any specific causes of death. Future studies in larger, comparable cohorts are warranted to further understand the association between hereditary measures and mortality in SCZ.
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| 39. |
- Kuhn, McKenzie A., et al.
(författare)
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Controls on Stable Methane Isotope Values in Northern Peatlands and Potential Shifts in Values Under Permafrost Thaw Scenarios
- 2024
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Ingår i: Journal of Geophysical Research - Biogeosciences. - : American Geophysical Union (AGU). - 2169-8953 .- 2169-8961. ; 129:7
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Tidskriftsartikel (refereegranskat)abstract
- Northern peatlands are a globally significant source of methane (CH4), and emissions are projected to increase due to warming and permafrost loss. Understanding the microbial mechanisms behind patterns in CH4 production in peatlands will be key to predicting annual emissions changes, with stable carbon isotopes (δ13C-CH4) being a powerful tool for characterizing these drivers. Given that δ13C-CH4 is used in top-down atmospheric inversion models to partition sources, our ability to model CH4 production pathways and associated δ13C-CH4 values is critical. We sought to characterize the role of environmental conditions, including hydrologic and vegetation patterns associated with permafrost thaw, on δ13C-CH4 values from high-latitude peatlands. We measured porewater and emitted CH4 stable isotopes, pH, and vegetation composition from five boreal-Arctic peatlands. Porewater δ13C-CH4 was strongly associated with peatland type, with δ13C enriched values obtained from more minerotrophic fens (−61.2 ± 9.1‰) compared to permafrost-free bogs (−74.1 ± 9.4‰) and raised permafrost bogs (−81.6 ± 11.5‰). Variation in porewater δ13C-CH4 was best explained by sedge cover, CH4 concentration, and the interactive effect of peatland type and pH (r2 = 0.50, p < 0.001). Emitted δ13C-CH4 varied greatly but was positively correlated with porewater δ13C-CH4. We calculated a mixed atmospheric δ13C-CH4 value for northern peatlands of −65.3 ± 7‰ and show that this value is more sensitive to landscape drying than wetting under permafrost thaw scenarios. Our results suggest northern peatland δ13C-CH4 values are likely to shift in the future which has important implications for source partitioning in atmospheric inversion models.
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| 40. |
- Lam, Matti, et al.
(författare)
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Single cell analysis of autism patient with bi-allelic NRXN1-alpha deletion reveals skewed fate choice in neural progenitors and impaired neuronal functionality
- 2019
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 383:1
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Tidskriftsartikel (refereegranskat)abstract
- We generated human iPS derived neural stem cells and differentiated cells from healthy control individuals and an individual with autism spectrum disorder carrying bi-allelic NRXN1-alpha deletion. We investigated the expression of NRXN1-alpha during neural induction and neural differentiation and observed a pivotal role for NRXN1-alpha during early neural induction and neuronal differentiation. Single cell RNA-seq pinpointed neural stem cells carrying NRXN1-alpha deletion shifting towards radial glia-like cell identity and revealed higher proportion of differentiated astroglia. Furthermore, neuronal cells carrying NRXN1-alpha deletion were identified as immature by single cell RNA-seq analysis, displayed significant depression in calcium signaling activity and presented impaired maturation action potential profile in neurons investigated with electrophysiology. Our observations propose NRXN1-alpha plays an important role for the efficient establishment of neural stem cells, in neuronal differentiation and in maturation of functional excitatory neuronal cells.
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| 41. |
- Lawler, Mark, et al.
(författare)
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A Catalyst for Change: The European Cancer Patient's Bill of Rights.
- 2014
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Ingår i: The Oncologist. - : Oxford University Press (OUP). - 1549-490X .- 1083-7159.
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Tidskriftsartikel (refereegranskat)abstract
- The European Cancer Concord is a unique patient-centered partnership that will act as a catalyst to achieve improved access to an optimal standard of cancer care and research for European citizens. In order to provide tangible benefits for European cancer patients, the partnership proposes the creation of a “European Cancer Patient's Bill of Rights,” a patient charter that will underpin equitable access to an optimal standard of care for Europe's citizens.
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| 42. |
- Lichtenstein, Paul, et al.
(författare)
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Common genetic determinants of schizophrenia and bipolar disorder in Swedish families : a population-based study
- 2009
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 373:9659, s. 234-239
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Tidskriftsartikel (refereegranskat)abstract
- Background Whether schizophrenia and bipolar disorder are the clinical outcomes of discrete or shared causative processes is much debated in psychiatry. We aimed to assess genetic and environmental contributions to liability for schizophrenia, bipolar disorder, and their comorbidity. Methods We linked the multi-generation register, which contains information about all children and their parents in Sweden, and the hospital discharge register, which includes all public psychiatric inpatient admissions in Sweden. We identified 9 009 202 unique individuals in more than 2 million nuclear families between 1973 and 2004. Risks for schizophrenia, bipolar disorder, and their comorbidity were assessed for biological and adoptive parents, offspring, full-siblings and half-siblings of probands with one of the diseases. We used a multivariate generalised linear mixed model for analysis of genetic and environmental contributions to liability for schizophrenia, bipolar disorder, and comorbidity. Findings First-degree relatives of probands with either schizophrenia (n=35 985) or bipolar disorder (n=40 487) were at increased risk of these disorders. Half-siblings had a significantly increased risk (schizophrenia: relative risk [RR] 3.6, 95% CI 2.3-5.5 for maternal half-siblings, and 2.7, 1. 9-3 . 8 for paternal half-siblings; bipolar disorder: 4.5, 2.7-7.4 for maternal half-siblings, and 2.4, 1.4-4-1 for paternal half-siblings), but substantially lower than that of the full-siblings (schizophrenia: 9.0, 8.5-11 .6; bipolar disorder: 7.9, 7.1-8.8). When relatives of probands with bipolar disorder were analysed, increased risks for schizophrenia existed for all relationships, including adopted children to biological parents with bipolar disorder. Heritability for schizophrenia and bipolar disorder was 64% and 59%, respectively. Shared environmental effects were small but substantial (schizophrenia: 4.5%, 4.4%-7.4%; bipolar disorder: 3.4%, 2.3%-6.2%) for both disorders. The comorbidity between disorders was mainly (63%) due to additive genetic effects common to both disorders. Interpretation Similar to molecular genetic studies, we showed evidence that schizophrenia and bipolar disorder partly share a common genetic cause. These results challenge the current nosological dichotomy between schizophrenia and bipolar disorder, and are consistent with a reappraisal of these disorders as distinct diagnostic entities. Funding Swedish Council for Working Life and Social Research, and the Swedish Research Council.
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| 43. |
- Lichtenstein, Paul, et al.
(författare)
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Familial risk and heritability of intellectual disability : a population-based cohort study in Sweden
- 2022
-
Ingår i: Journal of Child Psychology and Psychiatry. - Hoboken, New Jersey : Wiley-Blackwell Publishing Inc.. - 0021-9630 .- 1469-7610. ; 63:9, s. 1092-1102
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Tidskriftsartikel (refereegranskat)abstract
- Background: Intellectual disability (ID) aggregates in families, but factors affecting individual risk and heritability estimates remain unknown. Methods: A population-based family cohort study of 4,165,785 individuals born 1973–2013 in Sweden, including 37,787 ID individuals and their relatives. The relative risks (RR) of ID with 95% confidence intervals (95% CI) were obtained from stratified Cox proportional-hazards models. Relatives of ID individuals were compared to relatives of unaffected individuals. Structural equation modeling was used to estimate heritability. Results: Relatives of ID individuals were at increased risk of ID compared to individuals with unaffected relatives. The RR of ID among relatives increased proportionally to the degree of genetic relatedness with ID probands; 256.70(95% CI 161.30–408.53) for monozygotic twins, 16.47(13.32–20.38) for parents, 14.88(12.19–18.16) for children, 7.04(4.67–10.61) for dizygotic twins, 8.38(7.97–8.83) for full siblings, 4.56(4.02–5.16) for maternal, 2.90(2.49–3.37) for paternal half-siblings, 3.03(2.61–3.50) for nephews/nieces, 2.84(2.45–3.29) for uncles/aunts, and 2.04(1.91–2.20) for cousins. Lower RRs were observed for siblings of probands with chromosomal abnormalities (RR 5.53, 4.74–6.46) and more severe ID (mild RR 9.15, 8.55–9.78, moderate RR 8.13, 7.28–9.08, severe RR 6.80, 5.74–8.07, and profound RR 5.88, 4.52–7.65). Male sex of relative and maternal line of relationship with proband was related to higher risk (RR 1.33, 1.25–1.41 for brothers vs. sisters and RR 1.49, 1.34–1.68 for maternal vs. paternal half-siblings). ID was substantially heritable with 0.95(95% CI 0.93–0.98) of the variance in liability attributed to genetic influences. Conclusions: The risk estimates will benefit researchers, clinicians, families in understanding the risk of ID in the family and the whole population. The higher risk of ID related to male sex and maternal linage will be of value for planning and interpreting etiological studies in ID. © 2021 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health
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| 44. |
- Lichtenstein, Paul, et al.
(författare)
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Recurrence risks for schizophrenia in a Swedish national cohort
- 2006
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Ingår i: Psychological Medicine. - 0033-2917 .- 1469-8978. ; 36:10, s. 1417-1425
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Tidskriftsartikel (refereegranskat)abstract
- Background. Recurrence risk estimates for schizophrenia are fundamental to our understanding of this complex disease. Widely cited estimates are from small/older samples. If these estimates are biased upwards, then the rationale for molecular genetic studies of schizophrenia may not be as solid. Method. We created a population-based, Swedish national cohort by linking two Swedish national registers into a relational database (the Swedish Hospital Discharge Register and the MultiGeneration Register). Affection was defined as the lifetime presence of at least two in-patient hospitalizations with a core schizophrenia diagnosis. Results. Merging the Swedish national registers created a population-based cohort of 7 739 202 individuals of known parentage. The lifetime prevalence of the narrow definition of schizophrenia was 0(.)407% and we estimated that one in every 79 extended Swedish families had been impacted by schizophrenia. The proportion of affected families with multiple affected members was 3(.)81%. Recurrence risk estimates for all relative types were strikingly similar to those reported in smaller and older studies. For example, we estimated lambda(sibs) at 8(.)55 [95% confidence interval (CI) 7(.)86-9(.)57] compared with a literature estimate of 8(.)6. Conclusions. In the largest and most comprehensive sample yet studied, we confirm the accepted estimates of recurrence risks for schizophrenia, and provide more accurate estimates of recurrence risks of schizophrenia in relatives, an estimate of the familial impact of schizophrenia, and the multiplex proportion (essential for gauging the generalizability of findings from multiplex pedigrees). These data may be valuable for planning and interpreting genetic studies of schizophrenia.
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| 45. |
- Lu, Donghao, et al.
(författare)
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A shared genetic contribution to breast cancer and schizophrenia.
- 2020
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- An association between schizophrenia and subsequent breast cancer has been suggested; however the risk of schizophrenia following a breast cancer is unknown. Moreover, the driving forces of the link are largely unclear. Here, we report the phenotypic and genetic positive associations of schizophrenia with breast cancer and vice versa, based on a Swedish population-based cohort and GWAS data from international consortia. We observe a genetic correlation of 0.14 (95% CI 0.09-0.19) and identify a shared locus at 19p13 (GATAD2A) associated with risks of breast cancer and schizophrenia. The epidemiological bidirectional association between breast cancer and schizophrenia may partly be explained by the genetic overlap between the two phenotypes and, hence, shared biological mechanisms.
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| 46. |
- Magnusson, Patrik K. E., et al.
(författare)
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One CNV Discordance in NRXN1 Observed Upon Genome-wide Screening in 38 Pairs of Adult Healthy Monozygotic Twins
- 2016
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Ingår i: Twin Research and Human Genetics. - : Cambridge University Press (CUP). - 1832-4274 .- 1839-2628. ; 19:2, s. 97-103
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Tidskriftsartikel (refereegranskat)abstract
- Monozygotic (MZ) twins stem from the same single fertilized egg and therefore share all their inherited genetic variation. This is one of the unequivocal facts on which genetic epidemiology and twin studies are based. To what extent this also implies that MZ twins share genotypes in adult tissues is not precisely established, but a common pragmatic assumption is that MZ twins are 100% genetically identical also in adult tissues. During the past decade, this view has been challenged by several reports, with observations of differences in post-zygotic copy number variations (CNVs) between members of the same MZ pair. In this study, we performed a systematic search for differences of CNVs within 38 adult MZ pairs who had been misclassified as dizygotic (DZ) twins by questionnaire-based assessment. Initial scoring by PennCNV suggested a total of 967 CNV discor dances. The within-pair correlation in number of CNVs detected was strongly dependent on confidence score filtering and reached a plateau of r = 0.8 when restricting to CNVs detected with confidence score larger than 50. The top-ranked discordances were subsequently selected for validation by quantitative polymerase chain reaction (qPCR), from which one single similar to 120kb deletion in NRXN1 on chromosome 2 (bp 51017111-51136802) was validated. Despite involving an exon, no sign of cognitive/mental consequences was apparent in the affected twin pair, potentially reflecting limited or lack of expression of the transcripts containing this exon in nerve/brain.
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| 47. |
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| 48. |
- Moshontz, Hannah, et al.
(författare)
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The Psychological Science Accelerator: Advancing Psychology Through a Distributed Collaborative Network
- 2018
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Ingår i: Advances in Methods and Practices in Psychological Science. - : SAGE Publications. - 2515-2459 .- 2515-2467. ; 1:4, s. 501-515
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Tidskriftsartikel (refereegranskat)abstract
- Concerns about the veracity of psychological research have been growing. Many findings in psychological science are based on studies with insufficient statistical power and nonrepresentative samples, or may otherwise be limited to specific, ungeneralizable settings or populations. Crowdsourced research, a type of large-scale collaboration in which one or more research projects are conducted across multiple lab sites, offers a pragmatic solution to these and other current methodological challenges. The Psychological Science Accelerator (PSA) is a distributed network of laboratories designed to enable and support crowdsourced research projects. These projects can focus on novel research questions or replicate prior research in large, diverse samples. The PSA’s mission is to accelerate the accumulation of reliable and generalizable evidence in psychological science. Here, we describe the background, structure, principles, procedures, benefits, and challenges of the PSA. In contrast to other crowdsourced research networks, the PSA is ongoing (as opposed to time limited), efficient (in that structures and principles are reused for different projects), decentralized, diverse (in both subjects and researchers), and inclusive (of proposals, contributions, and other relevant input from anyone inside or outside the network). The PSA and other approaches to crowdsourced psychological science will advance understanding of mental processes and behaviors by enabling rigorous research and systematic examination of its generalizability.
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| 49. |
- Myers-Smith, Isla H., et al.
(författare)
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Complexity revealed in the greening of the Arctic
- 2020
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Ingår i: Nature Climate Change. - : Springer Science and Business Media LLC. - 1758-678X .- 1758-6798. ; 10:2, s. 106-117
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Tidskriftsartikel (refereegranskat)abstract
- As the Arctic warms, vegetation is responding, and satellite measures indicate widespread greening at high latitudes. This ‘greening of the Arctic’ is among the world’s most important large-scale ecological responses to global climate change. However, a consensus is emerging that the underlying causes and future dynamics of so-called Arctic greening and browning trends are more complex, variable and inherently scale-dependent than previously thought. Here we summarize the complexities of observing and interpreting high-latitude greening to identify priorities for future research. Incorporating satellite and proximal remote sensing with in-situ data, while accounting for uncertainties and scale issues, will advance the study of past, present and future Arctic vegetation change.
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| 50. |
- Natali, S. M., et al.
(författare)
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Large loss of CO2 in winter observed across the northern permafrost region
- 2019
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Ingår i: Nature Climate Change. - : Springer Science and Business Media LLC. - 1758-678X .- 1758-6798. ; 9:11, s. 852-857
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Tidskriftsartikel (refereegranskat)abstract
- Recent warming in the Arctic, which has been amplified during the winter(1-3), greatly enhances microbial decomposition of soil organic matter and subsequent release of carbon dioxide (CO2)(4). However, the amount of CO2 released in winter is not known and has not been well represented by ecosystem models or empirically based estimates(5,6). Here we synthesize regional in situ observations of CO2 flux from Arctic and boreal soils to assess current and future winter carbon losses from the northern permafrost domain. We estimate a contemporary loss of 1,662 TgC per year from the permafrost region during the winter season (October-April). This loss is greater than the average growing season carbon uptake for this region estimated from process models (-1,032 TgC per year). Extending model predictions to warmer conditions up to 2100 indicates that winter CO2 emissions will increase 17% under a moderate mitigation scenario-Representative Concentration Pathway 4.5-and 41% under business-as-usual emissions scenario-Representative Concentration Pathway 8.5. Our results provide a baseline for winter CO2 emissions from northern terrestrial regions and indicate that enhanced soil CO2 loss due to winter warming may offset growing season carbon uptake under future climatic conditions.
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