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

Huckins, Laura; Breen, Michael S.; Chatzinakos, Chris; Hartmann, Jakob; Klengel, Torsten; Almeida, Ana Carolina da Veiga Rodarte de; Dobbyn, Amanda; Girdhar, Kiran; Hoffman, Gabriel E.; Klengel, Claudia; Logue, Mark W.; Lori, Adriana; Morrison, Filomene G.; Nguyen, Hoang; Park, Yong‐Jin; Ruderfer, Douglas M.; Sloofman, Laura; Rooij, Sanne Jh van; Baker, Dewleen G.; Chen, Chia‐Yen; Cox, Nancy J.; Duncan, Laramie; Geyer, Mark A.; Glatt, Stephen J.; Im, Hae Kyung; Maihofer, Adam X.; Risbrough, Victoria B.; Smoller, Jordan W.; Stein, Dan J.; Yehuda, Rachel; Liberzon, Israel; Koenen, Karestan C.; Jovanović, Tanja; Kellis, M; Bacanu, Silviu‐Alin; Nievergelt, Caroline M.; Buxbaum, Joseph D.; Sklar, Pamela; Ressler, Kerry J.; Stahl, Eli A.; Daskalakis, Nikolaos P.

doi:10.1101/581124

Cited by 3 publications

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“…In the field of WTC exposures, some work has already been done to elucidate gene expression and clinical outcomes. 2–10 Further, work by our group and others has demonstrated differential genetic heritability of PTSD according to trauma-type 11, 12 .…”

Section: Introductionmentioning

confidence: 68%

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Altered gene expression and PTSD symptom dimensions in World Trade Center responders

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Diab

et al. 2021

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Despite experiencing a significant trauma, only a subset of World Trade Center (WTC) rescue and recovery workers developed posttraumatic stress disorder (PTSD). Identification of biomarkers is critical to the development of targeted interventions for treating disaster responders and potentially preventing the development of PTSD in this population. Analysis of gene expression from these individuals can help in identifying biomarkers of PTSD. We established a well-phenotyped sample of 371 WTC responders, recruited from a longitudinal WTC responder cohort, by obtaining blood, self-reported and clinical interview data. Using bulk RNA-sequencing from whole blood, we examined the association between gene expression and WTC-related PTSD symptom severity on (i) highest lifetime Clinician-Administered PTSD Scale (CAPS) score, (ii) past-month CAPS score, and (iii) PTSD symptom dimensions using a 5-factor model of re-experiencing, avoidance, emotional numbing, dysphoric arousal and anxious arousal symptoms. We corrected for sex, age, genotype-derived principal components and surrogate variables. Finally, we performed a meta-analysis with existing PTSD studies (total N=1,016), using case/control status as the predictor and correcting for these variables. We identified 66 genes significantly associated with highest lifetime CAPS score (FDR-corrected p<0.05), and 31 genes associated with past-month CAPS. Our more granular analyses of PTSD symptom dimensions identified additional genes that did not reach statistical significance in our overall analysis. In particular, we identified 82 genes significantly associated with lifetime anxious arousal symptoms. Several genes significantly associated with multiple PTSD symptom dimensions and lifetime CAPS score (SERPINA1, RPS6KA1, and STAT3) have been previously associated with PTSD. Geneset enrichment of these findings has identified pathways significant in metabolism, immune signaling, other psychiatric disorders, neurological signaling, and cellular structure. Our meta-analysis revealed 10 genes that reached genome-wide significance, all of which were down-regulated in cases compared to controls (CIRBP, TMSB10, FCGRT, CLIC1, RPS6KB2, HNRNPUL1, ALDOA, NACA, ZNF429 and COPE). Additionally, cellular deconvolution highlighted an enrichment in CD4 T cells and eosinophils in responders with PTSD compared to controls. The distinction in significant genes between lifetime CAPS score and the anxious arousal symptom dimension of PTSD highlights a potential biological difference in the mechanism underlying the heterogeneity of the PTSD phenotype. Future studies should be clear about methods used to analyze PTSD status, as phenotypes based on PTSD symptom dimensions may yield different gene sets than combined CAPS score analysis. Potential biomarkers implicated from our meta-analysis may help improve therapeutic target development for PTSD.

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Section: Introductionmentioning

confidence: 68%

“…We tested for enrichment of 59 well-studied PTSD candidate genes 11 (Sup. Table 1) within our association statistics.…”

Section: Resultsmentioning

confidence: 99%

Altered gene expression and PTSD symptom dimensions in World Trade Center responders

Marchese

Cancelmo

Diab

et al. 2021

Preprint

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“…In the field of WTC exposures, some work has already been done to elucidate gene expression and clinical outcomes. [2][3][4][5][6][7][8][9][10] Further, work by our group and others has demonstrated differential genetic heritability of PTSD according to trauma-type 11,12 .…”

Section: Introductionmentioning

confidence: 69%

Altered gene expression and PTSD symptom dimensions in World Trade Center responders

et al. 2022

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“…The genetic etiology of PTSD varies according to gender [6][7][8] , and index trauma type [9][10][11] ; consequently, studies that examine relatively homogeneous cohorts -i.e. individuals exposed to only one specific type of trauma [12][13][14][15][16][17][18] -have identified genome-wide significant associations that…”

Section: Introductionmentioning

confidence: 99%

Disentangling the roles of trauma and genetics in psychiatric disorders using an Electronic Health Records-based approach

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Cuddleston

Seah

et al. 2022

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Posttraumatic stress disorder (PTSD) requires an exposure to trauma for diagnosis by the DSM-V. Despite this, there is no documented linear relationship between degree of trauma and severity/chronicity of PTSD.To determine whether traumatic and stressful life events (TSLEs) collected from Electronic Health Records (EHR) interact with PTSD genetics to better define individual risk of developing PTSD. We collected trauma information from patient records in the Mount Sinai BioMe™ biobank population-based cohort and tested for associations with PTSD. We generated a TSLE risk score (TRS), tested its association with PTSD, and for interactions with a polygenic risk score (PRS) of PTSD and a GWAS of PTSD using our biobank population.We used the Mount Sinai BioMe™ biobank patient population of 31,704 individuals with matched genotype and EHR data, which has been enrolling patients since 2006. Patient enrollment in BioMe™ is unrestricted, resulting in high diversity. Our study includes 1,990 individuals with PTSD and 28,478 individuals without PTSD from the Mount Sinai BioMe™ biobank.A total of 1,990 individuals with PTSD and 28,478 controls were analyzed (average age 42-78 years, 58.7% women). We identified a total of 22 EHR-derived TSLEs that were associated with PTSD (β> 0.029, p<1.61×10−3). TSLEs interacted with each other to increase the risk of developing PTSD, with the most significant interaction between being female (as a proxy for experiencing sexism) and being HIV+ (β=0.013, p=8.9×10−11). PRS of PTSD and lead SNPS from GWAS interacted with TSLEs and our TRS to increase PTSD risk. In addition to TRS interactions, we found significant interactions between PTSD PRS and domestic violence, and sexual assault in European Americans (β>207.74, p<1.80×10−3). rs113282988 and rs189796944 variants reached genome-wide significance in interactions with TRS (β>0.056, p<9.04×10−9), and rs189796944 in an interaction with Physical Survival TSLEs (β>0.127, p<4×10−8).In conclusion, quantification of trauma type, severity, and magnitude—alone and in concert with genetics—provides better prediction of PTSD risk than PRS alone. Understanding who is at risk of developing PTSD allows for timely clinical intervention and possible prevention.

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

Cited by 3 publications

References 66 publications

Altered gene expression and PTSD symptom dimensions in World Trade Center responders

Altered gene expression and PTSD symptom dimensions in World Trade Center responders

Altered gene expression and PTSD symptom dimensions in World Trade Center responders

Disentangling the roles of trauma and genetics in psychiatric disorders using an Electronic Health Records-based approach

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