👤 Joel Gelernter

Resilience following combat exposure is an important factor in understanding posttraumatic stress disorder (PTSD), associated risk, and potentially resilience more generally. Identifying underlying genetic factors requires large samples; most biobanks lack extensive resilience assessments, although data regarding trauma and psychiatric symptoms are frequently present that allow computation of a resilience measure. We leveraged the Million Veteran Program (MVP) cohort to calculate discrepancy-based psychiatric resilience (DBPR) scores by regressing PTSD symptoms (PCL-17) onto combat exposure (Deployment Risk and Resilience Inventory-Combat Experiences Scale). We conducted a genome-wide association study (GWAS) of DBPR among European-ancestry (EUR) (n=94,360) and African-ancestry (AFR) participants (n=10,339). We performed conditional analyses with disorders frequently comorbid with PTSD (major depressive disorder, generalized anxiety), examined genetic correlations (r SNP-based heritability was 0.079 (SE=0.007) and three independent genome-wide significant loci were associated with DBPR in EUR; no significant loci were identified in AFR. Trans-ancestry meta-analysis revealed three significant SNPs mapping to RN7SKPP19*rs4650199, MAD1L1*rs12669370, and KANSL1:KANSL1-AS1*rs62060955. In EUR, eight genes were identified in TWAS. One gene (C7orf50) reached a posterior probability >0.90 in TWAS fine mapping. Significant correlations were observed between DBPR and other variables including neuroticism (-0.61), participation in religious groups (0.29) and engaging in sports (0.39, SE = 0.05). The r These findings extend the literature regarding DBPR as a resilience measure and help inform our understanding of the underlying biological mechanisms. Show less

Post-traumatic stress disorder (PTSD) is a major problem among military veterans and civilians alike, yet its pathophysiology remains poorly understood. We performed a genome-wide association study and bioinformatic analyses, which included 146,660 European Americans and 19,983 African Americans in the US Million Veteran Program, to identify genetic risk factors relevant to intrusive reexperiencing of trauma, which is the most characteristic symptom cluster of PTSD. In European Americans, eight distinct significant regions were identified. Three regions had values of P < 5 × 10 Show less

We previously mapped loci for the genome-wide association studies (GWAS) and genome-wide gene-by-alcohol dependence interaction (GW-GxAD) analyses of risky sexual behaviors (RSB). This study extends those findings by analyzing the ancestry- and sex-specific AD-stratified effects on RSB. We examined the concordance of findings for the AD-stratified GWAS and the GW-GxAD analysis of RSB, with concordance defined as genome-wide significance in one analysis and at least nominal significance in the second analysis. A total of 2,173 African-American (AA) and 1,751 European-American (EA) subjects were investigated. Information regarding RSB (lifetime experiences of unprotected sex and multiple sexual partners) and DSM-IV diagnosis of lifetime AD were derived from the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA). In our ancestry- and sex-specific analyses, we identified four independent genome-wide significant (GWS) loci (p < 5*10 Show less

Outcomes related to disordered metabolism are common in alcohol dependence (AD). To investigate alterations in the regulation of body mass that occur in the context of AD, we performed a genome-wide association study (GWAS) of body mass index (BMI) in African Americans (AAs) and European Americans (EAs) with AD. Subjects were recruited for genetic studies of AD or drug dependence and evaluated using the Semi-structured Assessment for Drug Dependence and Alcoholism. We investigated a total of 2587 AAs and 2959 EAs with DSM-IV AD diagnosis. In the stage 1 sample (N = 4137), we observed three genome-wide significant (GWS) single-nucleotide polymorphism associations, rs200889048 (P = 8.98 * 10 Show less

Functional variants that contribute to genomewide association study (GWAS) signals are difficult to identify. MicroRNAs could contribute to some of these gene-trait relationships. We compiled a set of GWAS trait gene SNPs that were predicted to affect microRNA regulation of mRNA. Trait associations were tested in a sample of 6725 European-American (EA) and African-American (AA) subjects that were interviewed using the polydiagnostic SSADDA to diagnose major psychiatric disorders. A predicted miR-330-3p target site SNP (rs41305272) in mitogen-activated protein kinase kinase 5 (MAP2K5) mRNA was in LD (d' = 1.0, r(2) = 0.02) with a reported GWAS-identified variant for restless legs syndrome (RLS), a disorder frequently comorbid with anxiety and depression, possibly because of a shared pathophysiology. We examined the SNP's association with mood and anxiety-related disorders. Rs41305272 was associated with agoraphobia (Ag) in EAs (odds ratio [OR] = 1.95, P = 0.007; 195 cases) and AAs (OR = 3.2, P = 0.03; 148 cases) and major depressive disorder (MDD) in AAs (OR = 2.64, P = 0.01; 427 cases), but not EAs (465 cases). Rs41305272*T carrier frequency was correlated with the number of anxiety and depressive disorders diagnosed per subject. RLS was not evaluated in our subjects. Predicted miR-330-3p target genes were enriched in pathways relevant to psychiatric disorders. These findings suggest that microRNA target site information may be useful in the analysis of GWAS signals for complex traits. MiR-330-3p and MAP2K5 are potentially important contributors to mood and anxiety-related traits. With support from additional studies, these findings could add to the large number of risk genes identified through association to medical disorders that have primary psychiatric effects. Show less

RGS17 and RGS20 encode two members of the regulator of G-protein signaling RGS-Rz subfamily. Variation in these genes may alter their transcription and thereby influence the function of G protein-coupled receptors, including opioid receptors, and modify risk for substance dependence. The association of 13 RGS17 and eight RGS20 tag single nucleotide polymorphisms (SNPs) was examined with four substance dependence diagnoses (alcohol (AD), cocaine (CD), opioid (OD) or marijuana (MjD)] in 1,905 African Americans (AAs: 1,562 cases and 343 controls) and 1,332 European Americans (EAs: 981 cases and 351 controls). Analyses were performed using both χ2 tests and logistic regression analyses that covaried sex, age, and ancestry proportion. Correlation of genotypes and mRNA expression levels was assessed by linear regression analyses. Seven RGS17 SNPs showed a significant association with at least one of the four dependence traits after a permutation-based correction for multiple testing (0.003≤P(empirical)≤0.037). The G allele of SNP rs596359, in the RGS17 promoter region, was associated with AD, CD, OD, or MjD in both populations (0.005≤P(empirical)≤0.019). This allele was also associated with significantly lower mRNA expression levels of RGS17 in YRI subjects (P = 0.002) and non-significantly lower mRNA expression levels of RGS17 in CEU subjects (P = 0.185). No RGS20 SNPs were associated with any of the four dependence traits in either population. This study demonstrated that variation in RGS17 was associated with risk for substance dependence diagnoses in both AA and EA populations. Show less