| 1. |
- Docherty, Anna R, et al.
(författare)
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GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
- 2023
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Ingår i: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738
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Tidskriftsartikel (refereegranskat)abstract
- Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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| 2. |
- Mullins, Niamh, et al.
(författare)
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Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
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| 3. |
- Fredin-Knutzén, Johan, et al.
(författare)
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Suicidprevention på järnväg : Två pilotstudier av skalbara åtgärder
- 2024
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Ingår i: Sammanställning av referat från Transportforum 2024. - Linköping : Statens väg- och transportforskningsinstitut. ; , s. 284-284
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- I Sverige inträffar årligen cirka 75 suicid på den svenska järnvägen. Olika åtgärder kan användas för att förebygga dessa händelser. Två nya och skalbara interventioner byggda av Trafikverket på två stationer i Stockholmsområdet har utvärderats. ”Spärrstaket” som separerar enkel tillgång till snabbtåg som passerar stationer, samt ”längsgående staket i plattformsände” som används för att minska motivationen till spårbeträdande från plattformsändar.Två naturliga experiment har utvärderats gällande de suicid- och personpåkörningspreventiva effekterna av åtgärderna som har byggts. Studieperioden har varit åren 2002-2021/2022 för variabeln personpåkörningar. I studien av ”längsgående staket i plattformsände” har även antal obehöriga spårbeträdanden samt förseningar utvärderats.Innan ”spärrstaketet” byggdes visade interventions- och kontrollstationerna liknande trender i antalet självmord. Efter installationen av spärrstaketet minskade antalet självmord med 62,5% vid interventionsstationen. Jämfört med kontrollgruppen syntes en signifikant minskning av antalet självmord (OR = 0,14, 95%CI 0,013-0,95). Efter installation av ”längsgående staket i plattformsände” har inga personpåkörningar inträffat (IRR = 0.32, 95%CI 0-1.82; ensidigt exakt p =0.1216). Det har varit en ~90 % minskning av antal obehöriga spårbeträdanden (IRR = 0.10, 95%CI 0.04-0.23; ensidigt exact p <0.0001) och en signifikant minskning av antalet förseningar på grund av obehöriga spårbeträdanden och personpåkörningar (Mann Whitney U=0, ensidigt exakt p=0.0455). "Spärrstaketen" visade en signifikant effekt i minskat antal suicid som sker vid plattformar på järnvägen. "Längsgående staket i plattformsände" visar en tendens till att minska antal personpåkörningar, men har en signifikant effekt i minskat antal obehöriga spårbeträdanden och förseningar. Detta är pilotstudier från två enskilda platser varför det finns ett stort mått av osäkerhet i hur stora effekterna är. Åtgärderna är skalbara och kan vara metoder för att nå uppställda målsättningar i att minska antal suicid och omkomna på järnvägen.
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| 4. |
- Hessle, Viktoria, et al.
(författare)
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The exosome Associates Cotranscriptionally with the Nascent Pre-mRNP through Interactions with Heterogeneous Nuclear Ribonucleoproteins
- 2009
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Ingår i: Molecular Biology of the Cell. - 1059-1524 .- 1939-4586. ; 20:15, s. 3459-3470
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Tidskriftsartikel (refereegranskat)abstract
- Eukaryotic cells have evolved quality control mechanisms to degrade aberrant mRNA molecules and prevent the synthesis of defective proteins that could be deleterious for the cell. The exosome, a protein complex with ribonuclease activity, is a key player in quality control. An early quality checkpoint takes place cotranscriptionally but little is known about the molecular mechanisms by which the exosome is recruited to the transcribed genes. Here we study the core exosome subunit Rrp4 in two insect model systems, Chironomus and Drosophila. We show that a significant fraction of Rrp4 is associated with the nascent pre-mRNPs and that a specific mRNA-binding protein, Hrp59/hnRNP M, interacts in vivo with multiple exosome subunits. Depletion of Hrp59 by RNA interference reduces the levels of Rrp4 at transcription sites, which suggests that Hrp59 is needed for the exosome to stably interact with nascent pre-mRNPs. Our results lead to a revised mechanistic model for cotranscriptional quality control in which the exosome is constantly recruited to newly synthesized RNAs through direct interactions with specific hnRNP proteins.
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| 5. |
- Sokolowski, Marcus
(författare)
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Control of human papillomavirus type 1 late mRNA stability and translation by an AU-rich RNA element
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Human Papillomaviruses (HPVs) infect the epithelial tissues in humans and infection with certain high-risk types is associated with cancer. The expressionof the HPV late capsid genes is dependent on cell differentiation. This may be one reason for the lack of HPV replication in vitro.Here we have studied an AU-rich sequence in the 3´ untranslated region (UTR) on the HPV type 1 (HPV-1) late mRNAs that acts in cis to posttranscriptionally inhibit HPV late gene expression in undifferentiated cells. Mapping revealed that the minimal AU-rich element (ARE) was 57 nts long, 93% AU-rich and that point mutations in two AUUUA- and three UUUUU-motifs inactivated the ARE. Analysis of the mRNA stability in HeLa cells showed that mRNAs containing the HPV-1 ARE (h1ARE) had reduced half life. The h1ARE also acted by suppressing translation independently of the effect on mRNA stability. Inhibition of translation appeared to occur by suppressing a function mediated by the 3´-poly(A) tails.Analysis of RNA-protein interactions in vitro revealed that both cytoplasmic and nuclear proteins interacted specifically with the h1ARE. Three cellular proteins were identified as the heterogeneous nuclear ribonucleoproteins (hnRNPs) C1 and C2 and the HuR protein. Recombinant HuR protein bound specifically to the AUUUA- and UUUUU-sites within the h1ARE and the apparent Kd value of HuR binding to the h1ARE or the inactive mutants thereof differed more than 50 fold. Binding of HuR and hnRNPC1/C2 to the AUUUA- and UUUUU-motifs suggested their importance for the function of the h1ARE. The h1ARE was the major negative element on HPV-1 late mRNAs whereas HPV-16 late mRNAs contained multiple negative elements. The number of negative elements correlated with the levels of virions produced by these HPV types in vivo.
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