A putative causal relationship between genetically determined female body shape and posttraumatic stress disorder

Polimanti, Renato; Amstadter, Ananda B.; Stein, Dan J.; Almli, Lynn M.; Baker, Dewleen G.; Bierut, Laura J.; Bradley, Bekh; Farrer, Lindsay A.; Johnson, Eric O.; King, Anthony P.; Kranzler, Henry R.; Maihofer, Adam X.; Rice, John P.; Roberts, Andrea L.; Saccone, Nancy L.; Zhao, Hongyu; Liberzon, Israel; Ressler, Kerry J.; Nievergelt, Caroline M.; Koenen, Karestan C.; Gelernter, Joel

doi:10.1186/s13073-017-0491-4

Cited by 32 publications

(37 citation statements)

References 53 publications

(52 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, negative r g with PTSD include subjective well-being, education, and a strong correlation with parents age at death (r g = -0.70). Significant positive correlations were also found for reproductive traits such as the number of children ever born, and, as previously reported for women, 26 PTSD was negatively correlated with age at first birth.…”

Section: Genetic Correlations Of Ptsd With Other Traits and Disorderssupporting

confidence: 85%

Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

Nievergelt

Klengel

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

Post-traumatic stress disorder (PTSD) is a common and debilitating disorder. The risk of PTSD following trauma is heritable, but robust common variants have yet to be identified by genome-wide association studies (GWAS). We have collected a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls. We first demonstrate significant genetic correlations across 60 PTSD cohorts to evaluate the comparability of these phenotypically heterogeneous studies. In this largest GWAS meta-analysis of PTSD to date we identify a total of 6 genome-wide significant loci, 4 in European and 2 in African-ancestry analyses. Follow-up analyses incorporated local ancestry and sex-specific effects, and functional studies. Along with other novel genes, a non-coding RNA (ncRNA) and a Parkinson's Disease gene, PARK2, were associated with PTSD. Consistent with previous reports, SNP-based heritability estimates for PTSD range between 10-20%. Despite a significant shared liability between PTSD and major depressive disorder, we show evidence that some of our loci may be specific to PTSD. These results demonstrate the role of genetic variation contributing to the biology of differential risk for PTSD and the necessity of expanding GWAS beyond European ancestry.Comparability of PGC2 studies PGC2 compiled the largest collection of global PTSD GWAS to date, with subjects recruited from both clinically deeply characterized, small patient groups and large cohorts with self-reported PTSD symptoms. We did not restrict the type of trauma subjects were exposed to, and trauma included both civilian and/or military events, often with pre-existing exposure to childhood trauma. To evaluate the comparability of these phenotypically heterogeneous studies we first estimated genetic correlations with LDSC, 15 a method that leverages GWAS summary results, the only data type available to PGC-PTSD for several of the larger military and non-US cohorts. We found significant genetic correlations (r g ) between studies using a cross-validation approach including all PGC2 EUA subjects (10 runs with studies randomly placed into 2 groups; mean r g = 0.56, mean SE = 0.23, mean p = 0.029, Supplementary Table 8).Next, additional analyses on the UK Biobank cohort (UKBB) were performed. This cohort comprises a very large proportion of the data, with almost as many EUA cases as the rest of the EUA PGC2 combined (referred to as PGC1.5). PTSD screening in UKBB was based on self-reported symptoms from a mental health survey. 16 We found a considerable genetic correlation between the UKBB and PGC1.5 EUA subjects (r g = 0.73, SE = 0.21, p = 0.0005; Supplementary Table 9). Further, sensitivity analyses in the UKBB using 3 alternative inclusion criteria for PTSD cases and controls showed stable correlations with PGC1.5 (P1 -P3; r g = 0.72 -0.79; Supplementary Table 10). Subsequent analyses were based on the UKBB phenotype including the largest number of subjects (P1; N = 126,188). Sex-stratified genetic correlations support the findings of a significant genetic signal...

show abstract

Section: Genetic Correlations Of Ptsd With Other Traits and Disorderssupporting

confidence: 85%

Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

Nievergelt

Klengel

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…34 For the variants included in the instrumental variable, we performed LD clumping by excluding alleles that have R 2 ≥ 0.001 within a 10,000-kb window with another variant with a smaller association P-value. Since different MR methods have different sensitivities to different potential issues, accommodate different scenarios, and vary in their statistical efficiency, 15 we considered a range of MR methods. The primary analysis was conducted considering a random-effect inverse-variance weighted (IVW) method.…”

Section: Causal Inferencementioning

confidence: 99%

“…Large scale genome-wide association studies (GWAS) have now identified genetic variants that can be used to define reliable genetic instruments that can be applied for causal inference in a MR analysis. [14][15][16][17][18] The basic principle in MR is that genetic variants that either alter the level of, or mirror the biological effects of, a modifiable environmental exposure that itself alters disease risk should be related to disease risk to the extent predicted by their influence on exposure to the environmental risk factor. 19 Previous large-scale GWAS conducted by the Social Science Genetic Association Consortium (SSGAC) investigated traits related to educational attainment (e.g., number of years of schooling and most advanced math course ever successfully completed), identifying a number of loci and biological pathways regulating brain mechanisms at the basis of the human cognitive ability.…”

Section: Introductionmentioning

confidence: 99%

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

Polimanti

Ratanatharathorn

Maihofer

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

Objectives: To investigate the genetic overlap and causal relationship between posttraumatic stress disorder (PTSD) and traits related to educational attainment.Design: Genetic correlation, polygenic risk scoring, and causal inference via multivariable Mendelian randomization (MR).Setting: Psychiatric Genomics Consortium for PTSD, UK Biobank, 23andMe, and Social Science Genetic Association Consortium.Participants: 23,185 PTSD cases and 151,309 controls; up to 1,131,881 individuals assessed for educational attainment and related traits.Main outcome measures: Genetic correlation obtained from linkage disequilibrium score regression, phenotypic variance explained by polygenic risk scores, and casual effects (beta values) estimated with MR Results: PTSD showed strong negative genetic correlations with educational attainment (EdAtt; rg=-0.26, p=4.6×10 -8 ). PRS based on genome-wide significant variants associated with EdAtt significantly predicted PTSD (p=6.16×10 -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 = 2.57×10 -5 and beta = 0.76, p = 6.75×10 -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). ConclusionsWe 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. What 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.A 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. What 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.Our findings indicate 1) the effect of traits related to educational attainment...

show abstract

“…Mendelian randomization (MR) is a method that relies on genetic data to infer causal relationships, for example, between an exposure (e.g., a metabolite) and an outcome (e.g., psychiatric disorder) using genetic variants as instrumental variables (27)(28)(29)(30)(31). There are few studies evaluating the role of metabolites on phenotypes resulting from exposure to trauma and no study to date has examined the putative causality between these factors using the MR approach.…”

Section: Introductionmentioning

confidence: 99%

Metabolome-Wide Mendelian Randomization Analysis of Emotional and Behavioral Responses to Traumatic Stress

Carvalho

Wendt

Stein

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Trauma exposure is an important risk factor for several psychiatric disorders; however, the mechanisms that underlie emotional and behavioral responses to traumatic stress are unclear. To understand these mechanisms, this study investigated the genetic overlap and causal relationship between blood metabolites and traits related to trauma response using genome-wide data. Five traits related to trauma response "in the past month" ascertained in the UK Biobank (52 816

show abstract

A putative causal relationship between genetically determined female body shape and posttraumatic stress disorder

Cited by 32 publications

References 53 publications

Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

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

Metabolome-Wide Mendelian Randomization Analysis of Emotional and Behavioral Responses to Traumatic Stress

Contact Info

Product

Resources

About