Distinguishing vulnerability and resilience to posttraumatic stress disorder evaluating traumatic experiences, genetic risk and electronic health records.

What distinguishes vulnerability and resilience to posttraumatic stress disorder (PTSD) remains unclear. Levering traumatic experiences reporting, genetic data, and electronic health records (EHR), we investigated and predicted the clinical comorbidities (co-phenome) of PTSD vulnerability and resilience in the UK Biobank (UKB) and All of Us Research Program (AoU), respectively. In 60,354 trauma-exposed UKB participants, we defined PTSD vulnerability and resilience considering PTSD symptoms, trauma burden, and polygenic risk scores. EHR-based phenome-wide association studies (PheWAS) were conducted to dissect the co-phenomes of PTSD vulnerability and resilience. Significant diagnostic endpoints were applied as weights, yielding a phenotypic risk score (PheRS) to conduct PheWAS of PTSD vulnerability and resilience PheRS in up to 95,761 AoU participants. EHR-based PheWAS revealed three significant phenotypes positively associated with PTSD vulnerability (top association "Sleep disorders") and five outcomes inversely associated with PTSD resilience (top association "Irritable Bowel Syndrome"). In the AoU cohort, PheRS analysis showed a partial inverse relationship between vulnerability and resilience with distinct comorbid associations. While PheRSvulnerability associations were linked to multiple phenotypes, PheRSresilience showed inverse relationships with eye conditions. Our study unveils phenotypic differences in PTSD vulnerability and resilience, highlighting that these concepts are not simply the absence and presence of PTSD.

Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals.

Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N = 903,147; African, N = 122,571; Latin American, N = 38,962; East Asian, N = 13,551; and South Asian, N = 1,716 ancestries). We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by a computational drug repurposing analysis. Cross-ancestry polygenic risk scores showed better performance of association in independent samples than single-ancestry polygenic risk scores. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. This study advances our knowledge of the genetic etiology of PAU, and these findings may bring possible clinical applicability of genetics insights-together with neuroscience, biology and data science-closer.

Diversity and Scale: Genetic Architecture of 2,068 Traits in the VA Million Veteran Program.

Genome-wide association studies (GWAS) have underrepresented individuals from non-European populations, impeding progress in characterizing the genetic architecture and consequences of health and disease traits. To address this, we present a population-stratified phenome-wide GWAS followed by a multi-population meta-analysis for 2,068 traits derived from electronic health records of 635,969 participants in the Million Veteran Program (MVP), a longitudinal cohort study of diverse U.S. Veterans genetically similar to the respective African (121,177), Admixed American (59,048), East Asian (6,702), and European (449,042) superpopulations defined by the 1000 Genomes Project. We identified 38,270 independent variants associating with one or more traits at experiment-wide P<4.6×10-11 significance; fine-mapping 6,318 signals identified from 613 traits to single-variant resolution. Among these, a third (2,069) of the associations were found only among participants genetically similar to non-European reference populations, demonstrating the importance of expanding diversity in genetic studies. Our work provides a comprehensive atlas of phenome-wide genetic associations for future studies dissecting the architecture of complex traits in diverse populations.

Multi-ancestry study of the genetics of problematic alcohol use in >1 million individuals.

Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. To improve our understanding of the genetics of PAU, we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals. We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine-mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and/or chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by drug repurposing analysis. Cross-ancestry polygenic risk scores (PRS) showed better performance in independent sample than single-ancestry PRS. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. The analysis of diverse ancestries contributed significantly to the findings, and fills an important gap in the literature.

Epidemiologic and Genetic Associations of Endometriosis With Depression, Anxiety, and Eating Disorders.

Importance: Endometriosis is a common chronic gynecologic pathology with a large negative impact on women's health. Beyond severe physical symptoms, endometriosis is also associated with several psychiatric comorbidities, including depression and anxiety. Objective: To investigate whether pleiotropy contributes to the association of endometriosis with depression, anxiety, and eating disorders. Design, Setting, and Participants: This genetic association study was performed between September 13, 2021, and June 24, 2022, in 202 276 unrelated female participants. Genotypic and phenotypic information from the UK Biobank was combined with genome-wide association statistics available from the Psychiatric Genomics Consortium (11 countries), the Million Veteran Program (US), the FinnGen study (Finland), and the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium (5 countries). Main Outcomes and Measures: The main outcomes were the phenotypic and genetic associations of endometriosis with anxiety, depression, and eating disorders. Results: A total of 8276 women with endometriosis (mean [SD] age, 53.1 [7.9] years) and 194 000 female controls (mean [SD] age, 56.7 [7.9] years) were included in the study. In a multivariate regression analysis accounting for age, body mass index, socioeconomic status, chronic pain-related phenotypes, irritable bowel syndrome, and psychiatric comorbidities, endometriosis was associated with increased odds of depression (odds ratio [OR], 3.61; 95% CI, 3.32-3.92), eating disorders (OR, 2.94; 95% CI, 1.96-4.41), and anxiety (OR, 2.61; 95% CI, 2.30-2.97). These associations were supported by consistent genetic correlations (rg) (depression rg, 0.36, P = 1.5 × 10-9; anxiety rg, 0.33, P = 1.17 × 10-5; and eating disorders rg, 0.61, P = .02). With the application of a 1-sample mendelian randomization, the genetic liabilities to depression and anxiety were associated with increased odds of endometriosis (depression: OR, 1.09; 95% CI, 1.08-1.11; anxiety: OR, 1.39; 95% CI, 1.13-1.65). A genome-wide analysis of pleiotropic associations shared between endometriosis and psychiatric disorders identified 1 locus, DGKB rs12666606, with evidence of pleiotropy between endometriosis and depression after multiple testing correction (z = -9.46 for endometriosis, z = 8.10 for depression, P = 5.56 × 10-8; false discovery rate q = 4.95 × 10-4). Conclusions and Relevance: These findings highlight that endometriosis is associated with women's mental health through pleiotropic mechanisms. To our knowledge, this is the first large-scale study to provide genetic and phenotypic evidence of the processes underlying the psychiatric comorbidities of endometriosis.

Factor structure of the posttraumatic stress disorder checklist (PCL-17) in 279,897 million veteran program participants.

The Million Veteran Program (MVP) uses the posttraumatic stress disorder symptoms (PTSD) Checklist 17 (PCL-17) self-report to assess PTSD. Existing literature suggests that the five-factor dysphoric arousal model best represents the PTSD symptom clusters; this can be tested within MVP, one of the largest samples collected with suitable data. We compared factor models within MVP across genetically defined subsamples (ancestry [European, African, admixed American, and East Asian], sex) via multi-group confirmatory factor analyses in a sample of 279,897 participants. The five-factor dysphoric arousal model best fit the PCL-17 data, consistent with previous findings. The factor structure could also be imposed across all groups tested. Verifying the factor structure provides a framework for future phenotypic and genotypic analyses within MVP and other samples.

The Associations of Racial Discrimination and Neighborhood Disadvantage With World Assumptions Among Black, Latine, and Asian Young Adults.

The theory of shattered assumptions proposes that experiencing traumatic events can change how people view themselves and the world. Most adults experience a traumatic event during their lifetime, and some subsequently develop post-traumatic stress disorder (PTSD). However, the current conceptualization of trauma (i.e., Criterion A PTSD) may be too narrow to adequately capture the range of potentially traumatizing events that People of Color experience, including racial discrimination and neighborhood disadvantage. This study investigated the association of racial discrimination and neighborhood disadvantage with core beliefs about the world being safe and predictable (i.e., world assumptions) among a sample of Black, Latine, and Asian young adults. Multi-step analyses of covariance tested associations between racial discrimination and neighborhood disadvantage with world assumptions and whether these held in the context of other traumatic exposures. Results indicated that racial discrimination negatively impacted world assumptions among Asian young adults only and this effect remained in the context of trauma. In addition, low neighborhood support negatively impacted world assumptions across all racial groups and neighborhood violence negatively impacted world assumptions among Latine young adults only; however, this effect did not remain in the context of trauma. This study indicates it is worthwhile to consider other adverse events in the conceptualization of trauma, such as racial discrimination and neighborhood disadvantage, that may impact world assumptions and contribute to subsequent post-trauma psychopathology.

Paradoxical age-related improvement in mental health in U.S. military veterans: Results from the national health and resilience in veterans study.

OBJECTIVE: To determine whether a seemingly "paradoxical" trend whereby mental health improves as a function of age despite declining physical and cognitive health occurs in U.S. military veterans, who are older, and have higher rates of trauma exposure and psychiatric morbidities relative to non-veterans. METHODS: Using data from a nationally representative, cross-sectional sample of 4069 U.S. veterans, polynomial regression analyses were conducted to examine changes in self-reported physical, cognitive, and mental health of veterans representing the full age spectrum. RESULTS: Physical health scores were consistently average and stable until around age 80 when they declined. In contrast, cognitive and mental health scores were markedly lower in young veterans and then increased linearly and positively well into late-life. CONCLUSIONS: While greater age is associated with relative stability and late-life decline in physical health in U.S. veterans, mental and cognitive health steadily improve until much later in life. Results may help inform age-specific prevention and treatment efforts to promote healthy aging in this population.

Genetically regulated multi-omics study for symptom clusters of posttraumatic stress disorder highlights pleiotropy with hematologic and cardio-metabolic traits.

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that may arise in response to severe traumatic event and is diagnosed based on three main symptom clusters (reexperiencing, avoidance, and hyperarousal) per the Diagnostic Manual of Mental Disorders (version DSM-IV-TR). In this study, we characterized the biological heterogeneity of PTSD symptom clusters by performing a multi-omics investigation integrating genetically regulated gene, splicing, and protein expression in dorsolateral prefrontal cortex tissue within a sample of US veterans enrolled in the Million Veteran Program (N total = 186,689). We identified 30 genes in 19 regions across the three PTSD symptom clusters. We found nine genes to have cell-type specific expression, and over-representation of miRNA-families - miR-148, 30, and 8. Gene-drug target prioritization approach highlighted cyclooxygenase and acetylcholine compounds. Next, we tested molecular-profile based phenome-wide impact of identified genes with respect to 1678 phenotypes derived from the Electronic Health Records of the Vanderbilt University biorepository (N = 70,439). Lastly, we tested for local genetic correlation across PTSD symptom clusters which highlighted metabolic (e.g., obesity, diabetes, vascular health) and laboratory traits (e.g., neutrophil, eosinophil, tau protein, creatinine kinase). Overall, this study finds comprehensive genomic evidence including clinical and regulatory profiles between PTSD, hematologic and cardiometabolic traits, that support comorbidities observed in epidemiologic studies of PTSD.

Resilience to traumatic stress in U.S. military veterans: Application of a novel classification approach in a nationally representative sample.

Resilience has been of particular interest to researchers and clinicians focused on response to trauma. In the current study, we employed a novel, discrepancy-based psychiatric resilience (DBPR) analytic approach to operationalizing resilience and examined its relation to potentially protective psychosocial factors in a nationally representative sample of U.S. veterans (N = 2704). Cumulative lifetime trauma burden, severity of PTSD symptoms, and protective factors such as personality characteristics (e.g., conscientiousness), protective psychosocial characteristics (e.g., purpose in life), and social connectedness (e.g., secure attachment style) were assessed. PTSD Checklist (PCL) scores were regressed onto cumulative trauma burden for the entire sample and a predicted PCL score was generated for each veteran. Resilience was operationalized as a lower actual relative to predicted PCL score. Results of a relative importance analysis revealed that somatic symptoms (22.5% relative variance explained [RVE]), emotional stability (22.4% RVE), and a secure attachment style (14.1%) explained the majority of the variance in resilience scores. These results demonstrate the utility of a DBPR approach to operationalizing resilience in U.S. military veterans. They also identify potentially modifiable psychosocial factors that may be bolstered in prevention and treatment efforts designed to mitigate the negative effects of trauma and promote resilience in this population.

Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions.

Major depressive disorder is the most common neuropsychiatric disorder, affecting 11% of veterans. Here we report results of a large meta-analysis of depression using data from the Million Veteran Program, 23andMe, UK Biobank and FinnGen, including individuals of European ancestry (n = 1,154,267; 340,591 cases) and African ancestry (n = 59,600; 25,843 cases). Transcriptome-wide association study analyses revealed significant associations with expression of NEGR1 in the hypothalamus and DRD2 in the nucleus accumbens, among others. We fine-mapped 178 genomic risk loci, and we identified likely pathogenicity in these variants and overlapping gene expression for 17 genes from our transcriptome-wide association study, including TRAF3. Finally, we were able to show substantial replications of our findings in a large independent cohort (n = 1,342,778) provided by 23andMe. This study sheds light on the genetic architecture of depression and provides new insight into the interrelatedness of complex psychiatric traits.

Sex-stratified gene-by-environment genome-wide interaction study of trauma, posttraumatic-stress, and suicidality.

Epidemiologic studies recognize that trauma and posttraumatic stress are associated with heightened suicidal behavior severity, yet examination of these associations from a genetic perspective is limited. We performed a multivariate gene-by-environment genome-wide interaction study (GEWIS) of suicidality in 123,633 individuals using a covariance matrix based on 26 environments related to traumatic experiences, posttraumatic stress, social support, and socioeconomic status. We discovered five suicidality risk loci, including the male-associated rs2367967 (CWC22), which replicated in an independent cohort. All GEWIS-significant loci exhibited interaction effects where at least 5% of the sample had environmental profiles conferring opposite SNP effects from the majority. We identified PTSD as a primary driving environment for GxE at suicidality risk loci. The male suicidality GEWIS was enriched for three middle-temporal-gyrus inhibitory neuron transcriptomic profiles: SCUBE- and PVALB-expressing cells (ß = 0.028, p = 3.74 × 10-4), OPRM1-expressing cells (ß = 0.030, p = 0.001), and SPAG17-expressing cells (ß = 0.029, p = 9.80 × 10-4). Combined with gene-based analyses (CNTN5 p association  = 2.38 × 10-9, p interaction  = 1.51 × 10-3; PSMD14 p association  = 2.04 × 10-7, p interaction  = 7.76 × 10-6; HEPACAM p association  = 2.43 × 10-6, p interaction  = 3.82 × 10-7) including information about brain chromatin interaction profiles (UBE2E3 in male neuron p = 1.07 × 10-5), our GEWIS points to extracellular matrix biology and synaptic plasticity as biological interactors with the effects of potentially modifiable lifetime traumatic experiences on genetic risk for suicidality. Characterization of molecular basis for the effects of traumatic experience and posttraumatic stress on risk of suicidal behaviors may help to identify novel targets for which more effective treatments can be developed for use in high-risk populations.

Measurement invariance of the World Assumptions Questionnaire across race/ethnic group, sex, and sexual orientation.

OBJECTIVE: The World Assumptions Questionnaire (WAQ) was developed to assess optimism and assumptions about the world, which often shift after traumatic events. However, no known study has investigated whether the WAQ holds similar meaning across demographic groups. The objective of this study was to investigate measurement invariance of the WAQ across race/ethnic group, sex, and sexual orientation. METHOD: Participants consisted of 1,181 college students (75% female; 25% Black, 13% Latinx, 18% Asian, 45% White; 90% heterosexual) who completed an online survey on stress, personality, substance use, and mental health. We investigated a unidimensional and the 4-factor structure of the WAQ using confirmatory factor analysis, and configural, metric, and scalar invariance using multigroup confirmatory factor analysis. RESULTS: After dropping 3 items, a 4-factor structure fit the data well (comparative fit index = .92; root mean square error of approximation =.05; 95% confidence interval [.045, .054]; standardized root mean square residual = .06). Mean WAQ scores were higher for participants with probable posttraumatic stress disorder on 2 of the 4 factors. We also identified multiple items that were not invariant across race/ethnic group, sex, and sexual orientation. However, after invariant items were removed, evidence of configural, scalar, and metric invariance was found. CONCLUSIONS: This study replicated the 4-factor structure, mapping onto the 4 WAQ subscales, and indicated that a unidimensional measure of world assumptions should not be used. After making the adjustments recommended herein, the WAQ can be used to investigate differences across race/ethnic group, sex, and sexual orientation. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The impact of world assumptions on the association between discrimination and internalizing and substance use outcomes.

This study investigated whether core beliefs about the world being safe and predictable (i.e. world assumptions) mediated the association between discrimination and internalizing and substance use problems among individuals from marginalized groups. Path analyses tested mediating effects of four types of world assumptions on the association between discrimination (race-, gender-, and sexual orientation-based) and anxiety, depression, alcohol and cannabis problems in college students (N = 1,181, agemean = 19.50, SD = 1.67). Limited support for mediation by world assumptions was found: among Asian students, race-based discrimination indirectly impacted anxiety symptoms through low perceived controllability of events. Direct effects across groups and discrimination types were also found.

Interpersonal Trauma Exposure and Depression in Young Adults: Considering the Role of World Assumptions.

The transition to young adulthood confers heightened risk for depression, and exposure to interpersonal trauma (IPT) can magnify this risk. However, not all IPT-exposed young adults develop depressive symptoms, and not all young adults with depressive symptoms report past IPT, suggesting a need to identify moderators of the IPT-depression link. This study investigated whether four different world assumptions-core beliefs about the nature of the world-moderated the association between IPT exposure and depressive symptoms in college students (N = 1,084, M age = 19.5, 74.1% female). Participants self-reported IPT exposure, depressive symptoms, and world assumptions via an online survey. We predicted that the IPT-depressive symptom association would be weaker among young adults with more positive assumptions about the safety of the world, trustworthiness of people, predictability of people, and controllability of events, versus those with more negative world assumptions in these domains. Hierarchical regression results supported this prediction with respect to one world assumption type: more positive beliefs about the world's safety significantly attenuated the relation between past IPT exposure and present depressive symptoms, ΔF(1, 1061) = 9.54, ΔR2 = 0.01, p = .002. The IPT-depressive symptom link was over 3 times as strong for young adults with weak "world-is-safe" assumptions, versus those with strong "world-is-safe" assumptions. No other world assumption types emerged as moderators. Lay theories of the world's safety may represent a basic, survival-oriented belief with implications for depressive symptoms following safety threats, such as IPT. Addressing "world-is-safe" assumptions may enhance depression prevention efforts for IPT-exposed young adults.

Characterizing the effect of background selection on the polygenicity of brain-related traits.

BACKGROUND: Genome-wide association studies (GWAS) have demonstrated that psychopathology phenotypes are affected by many risk alleles with small effect (polygenicity). It is unclear how ubiquitously evolutionary pressures influence the genetic architecture of these traits. METHODS: We partitioned SNP heritability to assess the contribution of background (BGS) and positive selection, Neanderthal local ancestry, functional significance, and genotype networks in 75 brain-related traits (8411 ≤ N ≤ 1,131,181, mean N = 205,289). We applied binary annotations by dichotomizing each measure based on top 2%, 1%, and 0.5% of all scores genome-wide. Effect size distribution features were calculated using GENESIS. We tested the relationship between effect size distribution descriptive statistics and natural selection. In a subset of traits, we explore the inclusion of diagnostic heterogeneity (e.g., number of diagnostic combinations and total symptoms) in the tested relationship. RESULTS: SNP-heritability was enriched (false discovery rate q < 0.05) for loci with elevated BGS (7 phenotypes) and in genic (34 phenotypes) and loss-of-function (LoF)-intolerant regions (67 phenotypes). These effects were strongest in GWAS of schizophrenia (1.90-fold BGS, 1.16-fold genic, and 1.92-fold LoF), educational attainment (1.86-fold BGS, 1.12-fold genic, and 1.79-fold LoF), and cognitive performance (2.29-fold BGS, 1.12-fold genic, and 1.79-fold LoF). BGS (top 2%) significantly predicted effect size variance for trait-associated loci (σ2 parameter) in 75 brain-related traits (ß = 4.39 × 10-5, p = 1.43 × 10-5, model r2 = 0.548). Considering the number of DSM-5 diagnostic combinations per psychiatric disorder improved model fit (σ2 ~ BTop2% × Genic × diagnostic combinations; model r2 = 0.661). CONCLUSIONS: Brain-related phenotypes with larger variance in risk locus effect sizes are associated with loci under BGS. We show exploratory results suggesting that diagnostic complexity may also contribute to the increased polygenicity of psychiatric disorders.

Profiles of psychosocial adversity and their associations with health risk behaviors and mental health outcomes in young adults.

Adverse psychosocial experiences operate simultaneously to affect mental health and behavior. The current study used mixture modeling to identify subgroups of young adults based on experiences of four types of psychosocial adversity and characterize their associations with depression, anxiety, world assumptions, substance use, and sexual risk behavior. Sexual assault, physical assault, and discrimination (interpersonal adversity) showed similar patterns within each group but diverged from neighborhood disadvantage in two groups. Groups characterized by higher interpersonal adversity reported the most negative health outcomes. Findings highlight variations in the co-occurrence of adverse experiences and differential links to risky health behaviors and mental health.

Genetic and Environmental Predictors of Adolescent PTSD Symptom Trajectories Following a Natural Disaster.

: Genes, environmental factors, and their interplay affect posttrauma symptoms. Although environmental predictors of the longitudinal course of posttraumatic stress disorder (PTSD) symptoms are documented, there remains a need to incorporate genetic risk into these models, especially in youth who are underrepresented in genetic studies. In an epidemiologic sample tornado-exposed adolescents (n = 707, 51% female, Mage = 14.54 years), trajectories of PTSD symptoms were examined at baseline and at 4-months and 12-months following baseline. This study aimed to determine if rare genetic variation in genes previously found in the sample to be related to PTSD diagnosis at baseline (MPHOSPH9, LGALS13, SLC2A2), environmental factors (disaster severity, social support), or their interplay were associated with symptom trajectories. A series of mixed effects models were conducted. Symptoms decreased over the three time points. Elevated tornado severity was associated with elevated baseline symptoms. Elevated recreational support was associated with lower baseline symptoms and attenuated improvement over time. Greater LGLAS13 variants attenuated symptom improvement over time. An interaction between MPHOSPH9 variants and tornado severity was associated with elevated baseline symptoms, but not change over time. Findings suggest the importance of rare genetic variation and environmental factors on the longitudinal course of PTSD symptoms following natural disaster trauma exposure.

Prevalence and predictors of PTSD among a college sample.

OBJECTIVE: This study examined the prevalence and correlates of probable posttraumatic stress disorder (PTSD) in freshman entering college and prospective associations of probable PTSD with additional outcomes. PARTICIPANTS: 2,310 students with data collected from Fall 2014 through Spring 2015. METHODS: Incoming freshman completed a survey assessing for relevant variables at the beginning of fall semester and during the spring semester. RESULTS: Seventy percent of the sample endorsed experiencing at least one potentially traumatic event (PTE). 34.4% of PTE exposed individuals met criteria for probable PTSD. Female sex, higher depressive and anxiety symptoms, and interpersonal PTE count were positively associated with PTSD symptoms. Higher PTSD symptoms were associated with higher anxiety and depressive symptoms, and new-onset interpersonal PTE. CONCLUSIONS: Identification of factors contributing to risk for PTSD is essential to inform prevention and intervention efforts. Intervention efforts should be targeted to students experiencing PTSD symptoms as they enter college.

The role of drinking motives and perceived controllability of events in the association between college women's sexual assault victimization and binge drinking.

Women with a history of sexual assault are at elevated risk for engaging in binge drinking. The aims of the current study are to investigate two types of drinking motives (coping and social) that potentially underlie the sexual assault-binge drinking link in a sample of female college drinkers (N = 691; 37.6% sexual assault prevalence), and to determine the extent to which the relationships between sexual assault history and each type of drinking motive depend on women's assumptions about the controllability of events. Conditional process analysis results indicated that women who experienced sexual assault (vs. those who did not) were more likely to report both coping and social drinking motives, which in turn, were both positively associated with increased binge drinking. Consistent with our hypothesis, results showed the relationship between sexual assault history and coping drinking motives was moderated by perceived controllability of events. Specifically, sexual assault victims reported high coping motives regardless of controllability of events. Nonvictims only reported high coping motives when their perceived controllability of events was low - comparable to coping motives of victims. This integrative approach affords a more comprehensive understanding of the context in which college women's binge drinking occurs, and offers insight into processes that could be targeted in interventions.