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Nievergelt, C.

Publications and source records attributed to Nievergelt, C..

2 recordsLinked to original sources
bioRxiv2019

Analysis of Genetically Regulated Gene Expression identifies a trauma type specific PTSD gene, SNRNP35

PTSD has significant genetic heritability; however, it is unclear how genetic risk influences tissue-specific gene expression. We used brain and non-brain transcriptomic imputation models to impute genetically regulated gene expression (GReX) in 9,087 PTSD-cases and 23,811 controls and identified thirteen significant GReX-PTSD associations. The results suggest substantial genetic heterogeneity between civilian and military PTSD cohorts. The top study-wide significant PTSD-association was with predicted downregulation of the Small Nuclear Ribonucleoprotein U11/U12 Subunit 35 (SNRNP35) in the BA9 region of the prefrontal cortex (PFC) in military cohorts. In peripheral leukocytes from 175 U.S. Marines, the observed PTSD differential gene expression correlated with the predicted blood GReX differences for these individuals, and deployment stress downregulated SNRNP35 expression, primarily in Marines with post-deployment PTSD. SNRNP35 is a subunit of the minor spliceosome complex and SNRNP35 knockdown in cells validated its functional importance in U12-intron splicing. Finally, mimicking acute activation of the endogenous stress axis in mice downregulated PFC Snrnp35 expression.

genetics↗
bioRxiv2018

Economic status mediates the relationship between educational attainment and posttraumatic stress disorder: a multivariable Mendelian randomization study

ObjectivesTo investigate the genetic overlap and causal relationship between posttraumatic stress disorder (PTSD) and traits related to educational attainment.\n\nDesignGenetic correlation, polygenic risk scoring, and causal inference via multivariable Mendelian randomization (MR).\n\nSettingPsychiatric Genomics Consortium for PTSD, UK Biobank, 23andMe, and Social Science Genetic Association Consortium.\n\nParticipants23,185 PTSD cases and 151,309 controls; up to 1,131,881 individuals assessed for educational attainment and related traits.\n\nMain outcome measuresGenetic correlation obtained from linkage disequilibrium score regression, phenotypic variance explained by polygenic risk scores, and casual effects (beta values) estimated with MR\n\nResultsPTSD showed strong negative genetic correlations with educational attainment (EdAtt; rg=-0.26, p=4.6x10-8). PRS based on genome-wide significant variants associated with EdAtt significantly predicted PTSD (p=6.16x10-4), but PRS based on variants associated with PTSD did not predict EdAtt (p>0.05). MR analysis indicated that EdAtt has negative causal effects on PTSD (beta=-0.23, p=0.004). Investigating potential mediators of the EdAtt-PTSD relationship, we observed that propensity for trauma exposure and risk-taking behaviors are risk factors for PTSD independently from EdAtt (beta = 0.36, p = 2.57x10-5 and beta = 0.76, p = 6.75x10-4, respectively), while income fully mediates the causal effect of EdAtt on PSTD (MR: Income - beta = -0.18, p =0.001; EdAtt - beta =-0.23, p=0.004; multivariable MR: Income - beta = -0.32, p = 0.017; EdAtt - beta = -0.04, p = 0.786).\n\nConclusionsWe report novel findings based on large-scale datasets regarding the relationship between educational attainment and PTSD, supporting the role of economic status as the key mediator in the causal relationship observed.\n\nWhat is already known on this topicThere is a well-established negative association of educational attainment and other traits related to cognitive ability with posttraumatic stress disorders (PTSD). However, the findings of these previous studies support various possible causal explanations: 1) individuals with high educational attainment are more resilient with respect to developing PTSD, 2) PTSD negatively impacts cognitive ability, or 3) PTSD and educational attainment share some underlying determinants, including relevant molecular mechanisms.\n\nA key obstacle to disentangling the complex association between educational attainment and PTSD is reverse causation, i.e. the situation in which the outcome precedes and causes the exposure instead of the other way around.\n\nWhat this study addsWe conducted a causal-inference investigation based on large-scale information from the investigation of more than one million individuals. Our main assumption is that genetic information can strongly minimize the bias of reverse causation, because genetic variants are determined at conception and do not change throughout life.\n\nOur findings indicate 1) the effect of traits related to educational attainment on PTSD, 2) no reverse effect of PTSD on educational attainment, and 3) economic status mediates the relationship between educational attainment and PTSD, independently from the brain mechanisms related to educational attainment.

genetics↗