Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

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.Peer reviewe

Wie normativ ist Sprache? Der Richter zwischen Sprechautomat und Sprachgesetzgeber

Die juristische Arbeit besteht in der Entscheidung von Bedeutungskonflikten zur Festlegung auf Sprachnormen. Die deuten auf legitimatorische Standards und müssen angesichts der Vielfalt und Divergenz des Sprachgebrauchs immer wieder gesetzt und auch durchgesetzt werden. Das Normativitätsproblem verweist auf eine Praxis des Forderns und Lieferns von Gründen. Die juristische Entscheidung vollzieht sich im sozialen Raum eines diskursiven Verfahrens. In ihm geht es um einen Konflikt sich ausschließender Lesarten desselben Gesetzes. Es geht somit nicht um die Auffindung einer Sprachregel, sondern um eine Sprachnormierung. In der Frage der Legitimität einer Entscheidung über die widerstreitenden Lesarten liegt der Ansatzpunkt der verfahrensbezogenen Normen aus dem Umkreis des Rechtsstaatsprinzips. Das Rechtsstaatsprinzip kann als ein kodifizierter Sonderfall kommunikativer Ethik angesehen werden. Es kodifiziert eine bestimmte Kultur des Streitens, welche im juristischen Bereich durch Rechtsprechung und Lehre eine spezifische Ausprägung erfahren hat

The Drosophila foraging gene mediates adult plasticity and gene-environment interactions in behaviour, metabolites, and gene expression in response to food deprivation.

Nutrition is known to interact with genotype in human metabolic syndromes, obesity, and diabetes, and also in Drosophila metabolism. Plasticity in metabolic responses, such as changes in body fat or blood sugar in response to changes in dietary alterations, may also be affected by genotype. Here we show that variants of the foraging (for) gene in Drosophila melanogaster affect the response to food deprivation in a large suite of adult phenotypes by measuring gene by environment interactions (GEI) in a suite of food-related traits. for affects body fat, carbohydrates, food-leaving behavior, metabolite, and gene expression levels in response to food deprivation. This results in broad patterns of metabolic, genomic, and behavioral gene by environment interactions (GEI), in part by interaction with the insulin signaling pathway. Our results show that a single gene that varies in nature can have far reaching effects on behavior and metabolism by acting through multiple other genes and pathways

Associations of site-specific CD4+-T-cell hypomethylation within CD40-ligand promotor and enhancer regions with disease activity of women with systemic lupus erythematosus

Objective To comprehensively assess associations of site-specific CD4(+)-T-cell hypomethylation of the CD40-Ligand gene (CD40L) with disease activity of women with systemic lupus erythematosus (SLE). Methods CpG-sites within the DNA of the promotor and two enhancer regions (n = 22) of CD40L were identified and numbered consecutively. The rate of methylated DNA in isolated CD4(+)-T-cells of women with SLE were quantified for each methylation site by MALDI-TOF. Disease activity was assessed by SLE Disease Activity Index (SLEDAI). Associations of site-specific methylation rates with the SLEDAI scores were assessed by linear regression modelling. P values were adjusted according to Bonferroni-Holm as indicated. Results 60 female SLE patients participated in the study (age 45.7 +/- 11.1 years, disease duration 17.0 +/- 8.3 years). Significant associations to the SLEDAI were noted for CpG22 hypomethylation of the promotor (beta = -40.1, p = 0.017, adjusted p = 0.027), trends were noted for CpG17 hypomethylation of the promotor (beta = -30.5, p = 0.032, adjusted p = 0.6), and for CpG11 hypermethylation of the second enhancer (beta = 15.0, p = 0.046, adjusted p = 0.8). Conclusion Site-specific hypomethylation of the CD40L promotor in CD4(+)-T-cells show associations with disease activity in female SLE patients

Methyl donor micronutrients, CD40-ligand methylation and disease activity in systemic lupus erythematosus: A cross-sectional association study

Objective Hypomethylation of CD40-ligand (CD40L) in T-cells is associated with increased disease activity in systemic lupus erythematosus (SLE). We therefore investigated possible associations of dietary methyl donors and products with CD40L methylation status in SLE. Methods Food frequency questionnaires were employed to calculate methyl donor micronutrients in 61 female SLE patients (age 45.7 +/- 12.0 years, disease duration 16.2 +/- 8.4 years) and compared to methylation levels of previously identified key DNA methylation sites (CpG17 and CpG22) within CD40L promotor of T-cells using quantitative DNA methylation analysis on the EpiTYPER mass spectrometry platform. Disease activity was assessed by SLE Disease Activity Index (SLEDAI). Linear regression modelling was used. P values were adjusted according to Benjamini & Hochberg. Results Amongst the micronutrients assessed (g per day), methionine and cysteine were associated with methylation of CpG17 (beta = 5.0 (95%CI: 0.6-9.4), p = 0.04; and beta = 2.4 (0.6-4.1), p = 0.02, respectively). Methionine, choline, and cysteine were additionally associated with the mean methylation of the entire CD40L (beta = 9.5 (1.0-18.0), p = 0.04; beta = 1.6 (0.4-3.0), p = 0.04; and beta = 4.3 (0.9-7.7), p = 0.02, respectively). Associations of the SLEDAI with hypomethylation were confirmed for CpG17 (beta=-32.6 (-60.6 to -4.6), p = 0.04) and CpG22 (beta=-38.3 (-61.2 to -15.4), p = 0.004), but not the mean methylation of CD40L. Dietary products with the highest impact on methylation included meat, ice cream, white bread, and cooked potatoes. Conclusions Dietary methyl donors may influence DNA methylation levels and thereby disease activity in SLE