Cognitive dysfunction among people with systemic lupus erythematosus is associated with reduced participation in daily life.

OBJECTIVES: This study aimed to investigate the distribution of cognitive function in people with systemic lupus erythematosus (SLE) by objective and self-report measures and associations between cognition and participation among people with SLE. METHODS: Fifty-five volunteers with SLE (age: 39.7 ± 12.7yrs, female: 92.7%) completed the Montreal Cognitive Assessment (MoCA) to measure cognitive ability objectively, the Cognitive Symptom Inventory (CSI) and PROMIS Cognitive Function 8a (CF) to assess self-reported everyday cognition, and PROMIS-43 Profile to assess self-reported ability to participate in social roles and activities (participation) and other disease-associated symptoms (e.g., depression, pain, fatigue). RESULTS: The average MoCA score was 25.3 ± 3.1, with 47.3% of participants scoring <26, which is indicative of cognitive impairment. Group average CSI (35.8 ± 7.9), CF (T-score = 45.0 ± 8.5), and participation (T-score = 46.9 ± 11.2) scores suggest mildly impaired functional cognition and participation compared to normative data. Participation correlated with self-reported everyday cognition measures (r ≥ 0.56, p < 0.01) but not with MoCA (r = 0.25, p = 0.06). In hierarchical linear regression analysis, CSI, fatigue, and pain were each significant independent predictors of participation (R2 = 0.78, p < 0.01). CONCLUSIONS: We found that cognitive dysfunction is common among people with SLE. Along with pain and fatigue, reduced everyday cognitive function contributes to reduced participation in social, leisure, work, and family-related activities.

Survival of veterans treated with enzalutamide and abiraterone for metastatic castrate resistant prostate cancer based on comorbid diseases.

BACKGROUND: Comorbid diseases influence patient outcomes, yet little is known about how comorbidities interact with treatments for metastatic castrate-resistant prostate cancer (mCRPC). No head-to-head trials have compared the efficacy of abiraterone and enzalutamide - oral androgen-receptor targeted agents (ARTAs) for mCRPC. In patients with comorbid disease, outcomes with ARTAs may differ due to disparate mechanisms of action, adverse events, and drug interactions. METHODS: Retrospective observational study of US veterans initiating treatment for mCRPC with abiraterone or enzalutamide between September 2014 and June 2017. Treatment duration and overall survival (OS) was compared based on age and comorbid diseases. The association between ARTA and OS was assessed using Cox proportional hazards and propensity-score matched modeling while adjusting for potential confounders. Sensitivity analyses were performed based on patient age, comorbidities, and subsequent treatments for mCRPC. RESULTS: Of 5822 veterans treated for mCRPC, 43.0% initially received enzalutamide and 57.0% abiraterone. Veterans initially treated with enzalutamide versus abiraterone were older (mean 75.8 vs. 75.0 years) with higher mean Charlson comorbidity index (4.4 vs. 4.1), and higher rates of cardiovascular disease or diabetes (74.2% vs. 70.6%). In the entire population, veterans initially treated with enzalutamide had longer median OS compared to those initially treated with abiraterone (24.2 vs. 22.1 months, p = 0.001). In veterans with cardiovascular disease or diabetes, median treatment duration with enzalutamide was longer (11.4 vs. 8.6 months, p < 0.001) with longer median OS compared to abiraterone (23.2 vs. 20.5 months, p < 0.001). In a propensity score matched cohort, enzalutamide was associated with decreased mortality compared to abiraterone (HR 0.90, 95% CI 0.84-0.96). CONCLUSIONS: Veterans with cardiovascular disease or diabetes had longer treatment duration and OS with enzalutamide compared to abiraterone. Further study of ARTA selection may benefit men with metastatic castrate resistant prostate cancer and likely hormone sensitive prostate cancer, especially among patients with comorbid diseases.

Longitudinal health study of US 1991 Gulf War veterans: changes in health status at 10-year follow-up.

The authors assessed changes in the health status of US 1991 Gulf War-era veterans from a 1995 baseline survey to a 2005 follow-up survey, using repeated measurement data from 5,469 deployed Gulf War veterans and 3,353 nondeployed Gulf War-era veterans who participated in both surveys. Prevalence differences in health status between the 2 surveys were estimated for adverse health indices and chronic diseases for each veteran group. Persistence risk ratios and incidence risk ratios were calculated after adjustment for demographic and military service characteristics through Mantel-Haenszel stratified analysis. At 10-year follow-up, deployed veterans were more likely to report persistent poor health, as measured by the health indices (functional impairment, limitation of activities, repeated clinic visits, recurrent hospitalizations, perception of health as fair or poor, chronic fatigue syndrome-like illness, and posttraumatic stress disorder), than nondeployed veterans. Additionally, deployed veterans were more likely to experience new onset of adverse health (as measured by the indices) and certain chronic diseases than were nondeployed veterans. During the 10-year period from 1995 to 2005, the health of deployed veterans worsened in comparison with nondeployed veterans because of a higher rate of new onset of various health outcomes and greater persistence of previously reported adverse health on the indices.

Risk of non-melanoma skin cancer in a national cohort of veterans with rheumatoid arthritis.

OBJECTIVE: To determine the incidence of and risk factors for non-melanoma skin cancer (NMSC) in a national cohort of veterans with RA. METHODS: We examined skin cancer risk in a cohort of 20 648 patients with RA derived from the Department of Veterans' Affairs (VA) national administrative databases. The cohort was divided into two medication groups: patients treated with non-biologic and TNF-α antagonist DMARDs. We defined skin cancer as the first occurrence of an International Classification of Disease, Version 9, Clinical Modification (ICD-9-CM) code for NMSC after initiation of a DMARD. Outcome risk was described using hazard ratios (HRs) with Cox proportional hazards regression for time-to-event analysis and logistic regression. We performed medical record review to validate the diagnosis of NMSC. RESULTS: Incidence of NMSC was 18.9 and 12.7 per 1000 patient-years in patients on TNF-α antagonists and non-biologic DMARDs, respectively. Patients on TNF-α antagonists had a higher risk of developing NMSC (HR 1.42; 95% CI 1.24, 1.63). Risk factors for NMSC included older age, male gender, NSAID and glucocorticoid use and a history of prior malignancies. There was substantial agreement between ICD-9-CM diagnosis of NMSC and medical record validation (κ = 0.61). CONCLUSION: TNF-α antagonist therapy in veterans with RA may be associated with an increased risk of NMSC, compared with therapy with non-biologic DMARDs. Rheumatologists should carefully screen patients receiving TNF-α antagonists for pre-cancerous skin lesions and skin cancer.

A twin study of spatial and non-spatial delayed response performance in middle age.

Delayed alternation and object alternation are classic spatial and non-spatial delayed response tasks. We tested 632 middle-aged male veteran twins on variants of these tasks in order to compare test difficulty, measure their inter-correlation, test order effects, and estimate heritabilities (proportion of observed variance due to genetic influences). Non-spatial alternation (NSA), which may involve greater reliance on processing of subgoals, was significantly more difficult than spatial alternation (SA). Despite their similarities, NSA and SA scores were uncorrelated. NSA performance was worse when administered second; there was no SA order effect. NSA scores were modestly heritable (h(2)=.25; 26); SA was not. There was shared genetic variance between NSA scores and general intellectual ability (r(g)=.55; .67), but this also suggests genetic influences specific to NSA. Compared with findings from small, selected control samples, high "failure" rates in this community-based sample raise concerns about interpretation of brain dysfunction in elderly or patient samples.

Evidence of overlapping genetic diathesis of panic attacks and gastrointestinal disorders in a sample of male twin pairs.

We explored the comorbidity between panic attacks (PA), whose symptoms can include gastrointestinal discomfort, and gastrointestinal disorders (GD). Structural equation modeling was used to analyze data from 1,874 MZ and 1,498 DZ male-male twin pairs from the Vietnam Era Twin Registry. PA and GD were associated (relative risk for GD = 2). The percentage of liability due to genetic factors was estimated to be 37% for PA and 31% for GD. There was significant correlation between the genetic risk factors for PA and GD (estimated r = .55, 95% CI of 34% to 82%) and no evidence of correlation between the environmental causes of PA and GD. Therefore, PA and GD comorbidity can be explained by overlapping genetic factors and not overlapping environmental factors. Although these data cannot identify a biological pathway for such a shared liability, it suggests the presence of GD may be informative for genetic studies of panic.

A cohort study of neuropsychological functioning in spouses of U.S. Gulf War veterans.

AIMS: Veterans of the 1991 Gulf War reported symptoms in their spouses that mirrored veterans' symptoms following their return from the war, including problems with attention and memory. Neuropsychological functioning in these spouses has not been examined with objective tests. This study sought to determine if these spouses exhibited deficits in neuropsychological functioning. MAIN METHODS: Spouses of a national cohort of 1991 Gulf War deployed (n = 470) and non-deployed veterans (n = 524) were examined with neuropsychological tests in 1999-2001. KEY FINDINGS: Neuropsychological tests were factor analyzed yielding five factors: verbal memory, visual memory, attention/working memory, visual organization, and motor speed. Spouses of deployed and nondeployed veterans did not differ on mean factor scores, percentage of impaired factors, or individual test scores. Spouse attention/working memory was related to their having diagnoses of PTSD or anxiety disorders, or self-reported symptoms of current anxiety. Spouse visual memory was related to a diagnosis of current depression. Spouse motor speed was related to their own status of having chronic multisymptom illness (CMI). SIGNIFICANCE: Spouses of Gulf War deployed and nondeployed veterans demonstrated similar neuropsychological functioning, although spouses with psychiatric diagnoses and symptoms, or CMI demonstrated neuropsychological impairments characteristic of those conditions, suggesting that monitoring spouses for these conditions and impairments may be warranted. This pattern of relative weaknesses mirrors some of the previously reported findings for Gulf War veterans, although the veterans displayed neuropsychological impairments beyond what was accounted for by these conditions.

Genetic and environmental influences on the size of specific brain regions in midlife: the VETSA MRI study.

The impact of genetic and environmental factors on human brain structure is of great importance for understanding normative cognitive and brain aging as well as neuropsychiatric disorders. However, most studies of genetic and environmental influences on human brain structure have either focused on global measures or have had samples that were too small for reliable estimates. Using the classical twin design, we assessed genetic, shared environmental, and individual-specific environmental influences on individual differences in the size of 96 brain regions of interest (ROIs). Participants were 474 middle-aged male twins (202 pairs; 70 unpaired) in the Vietnam Era Twin Study of Aging (VETSA). They were 51-59 years old, and were similar to U.S. men in their age range in terms of sociodemographic and health characteristics. We measured thickness of cortical ROIs and volume of other ROIs. On average, genetic influences accounted for approximately 70% of the variance in the volume of global, subcortical, and ventricular ROIs and approximately 45% of the variance in the thickness of cortical ROIs. There was greater variability in the heritability of cortical ROIs (0.00-0.75) as compared with subcortical and ventricular ROIs (0.48-0.85). The results did not indicate lateralized heritability differences or greater genetic influences on the size of regions underlying higher cognitive functions. The findings provide key information for imaging genetic studies and other studies of brain phenotypes and endophenotypes. Longitudinal analysis will be needed to determine whether the degree of genetic and environmental influences changes for different ROIs from midlife to later life.

Salivary cortisol and prefrontal cortical thickness in middle-aged men: A twin study.

Although glucocorticoid receptors are highly expressed in the prefrontal cortex, the hippocampus remains the predominant focus in the literature examining relationships between cortisol and brain. We examined phenotypic and genetic associations of cortisol levels with the thickness of prefrontal and anterior cingulate cortex regions, and with hippocampal volume in a sample of 388 middle-aged male twins who were 51-59 years old. Small but significant negative phenotypic associations were found between cortisol levels and the thickness of left dorsolateral (superior frontal gyrus, left rostral middle frontal gyrus) and ventrolateral (pars opercularis, pars triangularis, pars orbitalis) prefrontal regions, and right dorsolateral (superior frontal gyrus) and medial orbital frontal cortex. Most of the associations remained significant after adjusting for general cognitive ability, cardiovascular risk factors, and depression. Bivariate genetic analyses suggested that some of the associations were primarily accounted for by shared genetic influences; that is, some of the genes that tend to result in increased cortisol levels also tend to result in reduced prefrontal cortical thickness. Aging has been associated with reduced efficiency of hypothalamic-pituitary-adrenal function, frontal lobe shrinkage, and increases in health problems, but our present data do not allow us to determine the direction of effects. Moreover, the degree or the direction of the observed associations and the extent of their shared genetic underpinnings may well change as these individuals age. Longitudinal assessments are underway to elucidate the direction of the associations and the genetic underpinnings of longitudinal phenotypes for changes in cortisol and brain morphology.

Genetic vulnerability and phenotypic expression of depression and risk for ischemic heart disease in the Vietnam era twin study of aging.

OBJECTIVE: To determine if depression contributes to incident heart disease after accounting for genetic, behavioral, and medical factors associated with both conditions. METHODS: We used a prospective twin study with a 12-year follow-up. In 1992, lifetime diagnosis of depression was assessed in 1159 male-male twins and merged with longitudinal health data from the Vietnam Era Twin Registry Study of Aging. Incident heart disease was defined as having myocardial infarction, heart surgery, or angina at 12-year follow-up when twins were 55.4 years (standard deviation, 2.5 years) of age. Risks for heart disease were computed in a logistic regression model that included comparing twins at different levels of phenotypic expression of depression and varying levels of genetic vulnerability at the same time adjusting for pertinent covariates. RESULTS: After adjusting for sociodemographics, co-occurring psychopathology, smoking, obesity, diabetes, hypertension, and social isolation, twins at high genetic risk and exposed to depression remained at greater risk of developing ischemic heart disease (IHD) (odds ratio, 2.55; 95% confidence interval, 1.44-4.49) compared with those at low genetic risk and without phenotypic expression of depression. Odds ratios suggest that twins at genetic liability but without phenotypic expression were at risk of IHD, but the effect was not statistically significant. CONCLUSIONS: A history of depression is a risk factor for incident heart disease after adjusting for numerous covariates. Twins with both high genetic vulnerability and phenotypic expression of depression were at greatest risk of IHD. Trends suggest the genetic contribution to IHD that overlaps with depression may partly explain this association, but studies in larger samples are warranted.

Does parental education have a moderating effect on the genetic and environmental influences of general cognitive ability in early adulthood?

Hereditary influences account for a substantial proportion of the variance in many cognitive abilities. However, there is increasing recognition that the relative importance of genetic and environmental influences may vary across different socioeconomic levels. The overall goal of the present study was to examine whether parental education has a moderating effect on genetic and environmental influences of general cognitive ability in early adulthood (age 19.6 +/- 1.5). Participants were 5,955 male twins from the Vietnam Era Twin (VET) Registry. Significant effects of parental education on mean level of general cognitive ability scores were found, but a model without moderating effects of parental education on genetic or environmental influences on cognitive scores proved to be the best fitting model. Some, but not all, previous studies have found significant moderating effects; however, no consistent pattern emerged that could account for between-study differences regarding moderating effects on genetic and environmental influences.

Marriage and Divorce: A genetic perspective.

Marriage is considered one of the most important sources of social support that an individual receives as an adult. Although hypotheses have been formulated as to why individuals may dissolve a marriage, the determinants of marital success or failure are still relatively unknown. Behavioral geneticists have found that both marriage and divorce are, in part, genetically influenced. The goal of this research was to determine the degree of shared genetic and environmental variance between the two marital statuses. Participants were 6,225 twin pairs from the Vietnam Era Twin Registry. Data were obtained on marital history, and if the individual was no longer married, how the marriage ended. Univariate analyses were performed to determine the extent of genetic and environmental influences each of the marital statues (i.e., marriage and divorce), followed by a novel bivariate analysis to test the shared variance between marriage and divorce. Results from this analysis revealed that the two different marital statuses were influenced by entirely distinct genetic and environmental factors.

Herpes zoster risk factors in a national cohort of veterans with rheumatoid arthritis.

BACKGROUND: Herpes zoster occurs more commonly in patients taking immunosuppressive medications, although the risk associated with different medications is poorly understood. METHODS: We conducted a retrospective cohort study involving 20,357 patients who were followed in the Veterans Affairs healthcare system and treated for rheumatoid arthritis from October 1998 through June 2005. Cox proportional hazards regression was used to determine risk factors for herpes zoster and herpes zoster-free survival. Chart review was performed to validate the diagnosis of herpes zoster. RESULTS: The incidence of herpes zoster was 9.96 episodes per 1000 patient-years. In time-to-event analysis, patients receiving medications used to treat mild rheumatoid arthritis were less likely to have an episode of herpes zoster than patients receiving medications used to treat moderate and severe rheumatoid arthritis (P < .001). Independent risk factors for herpes zoster included older age, prednisone use, medications used to treat moderate and severe rheumatoid arthritis, malignancy, chronic lung disease, renal failure, and liver disease. Among patients receiving tumor necrosis factor-alpha antagonists, etanercept (hazard ratio, 0.62) and adalimumab (hazard ratio, 0.53) were associated with a lower risk of herpes zoster. There was excellent agreement between the International Classification of Diseases, Version 9, Clinical Modification diagnosis of herpes zoster and diagnosis by chart review (kappa = 0.92). CONCLUSIONS: Risk factors for herpes zoster included older age, prednisone use, medications used to treat moderate and severe rheumatoid arthritis, and several comorbid medical conditions. These results demonstrate that the Department of Veterans Affairs' national administrative databases can be used to study rare adverse drug events.

Genes determine stability and the environment determines change in cognitive ability during 35 years of adulthood.

Previous research has demonstrated stability of cognitive ability and marked heritability during adulthood, but questions remain about the extent to which genetic factors account for this stability. We conducted a 35-year longitudinal assessment of general cognitive ability using the Armed Forces Qualification Test administered to 7,232 male twins in early adulthood and readministered to a subset of 1,237 twins during late middle age. The proportion of variance in cognitive functioning explained by genetic factors was .49 in young adulthood and .57 in late middle age. The correlation between the two administrations was .74 with a genetic correlation of 1.0, indicating that the same genetic influences operated at both times. Genetic factors were primarily responsible for stability, and nonshared environmental factors were primarily responsible for change. The genetic factors influencing cognition may change across other eras, but the same genetic influences are operating from early adulthood to late middle age.

Factor structure of planning and problem-solving: a behavioral genetic analysis of the Tower of London task in middle-aged twins.

We examined the genetic architecture of a Tower of London test of planning and problem-solving in 690 middle-aged male twins. Phenotypic analyses revealed only one general factor, but the best-fitting genetic model indicated two correlated genetic factors: speed and efficiency. One variable-number of attempts required to mentally figure the puzzles-loaded on both factors. Shared environmental effects could be dropped with virtually no reduction in model fit. Despite significant nonshared environmental correlations across measures, there was no discernable nonshared environmental factor structure. The correlation between genetic factors (r = 0.46) and the variable loading on both factors could reflect modulation of planning, testing alternatives, and working memory that are required to perform the test. Such coordinated activity is consistent with the notion of a supervisory attentional system, a central executive, or metacognitive ability. The different phenotypic and genetic factor results suggest that relying solely on the former could obscure genetic associations.

Neuropsychological functioning of U.S. Gulf War veterans 10 years after the war.

Many U.S. Gulf War-era veterans complained of poor cognition following the war. This study assessed neuropsychological functioning in veterans 10 years after the war through objective tests. 2189 Gulf War-era veterans (1061 deployed, 1128 non-deployed) were examined at 1 of 16 U.S. Veterans Affairs medical centers. Outcomes included neuropsychological domains derived from factor analysis and individual test scores. Deployed veterans performed significantly worse than non-deployed veterans on 2 of 8 factors (motor speed & sustained attention, analysis not corrected for multiple comparisons) and on 4 of 27 individual test variables (Trails A & B, California Verbal Learning Test-List B, and Continuous Performance Test sensitivity, with only Trails B surviving Bonferroni correction). Within deployed veterans, Khamisiyah exposure was negatively correlated with motor speed after controlling for emotional distress. Depressive symptoms and self-reported exposure to toxicants were independently and significantly associated with worse sustained attention. Other factors were also associated with self-reported exposures. The findings were not a result of differential effort across groups. Gulf War deployment is associated with subtle declines of motor speed and sustained attention, despite overall intact neuropsychological functioning. Evidence suggests that toxicant exposures influence both these functions, and depressive symptoms also influence attention.

Mental health in spouses of U.S. Gulf War veterans.

Veterans' spouses are at risk for mental distress and substance use. We examined long term psychological functioning in spouses from a national cohort of 1991 Gulf War era veterans. From clinical interviews, spouses of deployed veterans (n = 488) did not have a greater prevalence of post-war mental disorders compared to spouses of non-deployed veterans (n = 536); however, in couples that were living together since the war, there was an increased risk of anxiety disorders or any one disorder. On questionnaires, the impact varied but was most consistently observed in more severe depression and greater functional impairment in spouses of deployed compared to non-deployed veterans. If a veteran developed post-war anxious/depressive disorders or any one mental disorder, the matched spouse was more likely to develop post-war anxious/depressive disorders or any one mental disorder, respectively. Veteran combat exposure did not similarly increase the risk of spouse post-war mental disorders. Greater spouse self-reported symptomatology was observed in spouses of veterans with anxious/depressive disorders even when controlling for deployment. In summary, the war conferred greater risk for spouse mental disorders and distress for spouses of veterans with mental health disorders, with some increased risk for spouses of deployed veterans, especially in couples together since the war.

Pretrauma cognitive ability and risk for posttraumatic stress disorder: a twin study.

CONTEXT: Cognitive deficits are associated with posttraumatic stress disorder (PTSD), but whether such deficits reflect sequelae or risk factors is not fully resolved. OBJECTIVE: To determine, in a representative sample, whether preexposure cognitive ability is associated with risk for PTSD, and whether that risk is genetically mediated. DESIGN, SETTING, AND PARTICIPANTS: The co-twin-control study involved 2386 male Vietnam-era twin veterans with a mean (SD) age of 41.9 (2.7) years, a population-based sample of men who were in military service during this era. Cognitive ability scores were obtained just before military induction at a mean (SD) age of 19.7 (1.5) years. Participants included only individuals who were exposed to potentially traumatic events and underwent preexposure cognitive testing. MAIN OUTCOME MEASURES: Armed Forces Qualification Test (of cognitive ability) percentile scores and PTSD diagnosed by means of structured interviews. RESULTS: We found a significant dose-response relationship between preexposure cognitive ability and risk for PTSD. After controlling for confounders, the highest cognitive ability quartile had a 48% lower risk than the lowest ability quartile (P<.001). Non-PTSD-concordant pairs had the highest scores; PTSD-concordant pairs had the lowest scores; and PTSD-discordant pairs had intermediate scores. Differences in Armed Forces Qualification Test scores within twin pairs were significant only in PTSD-discordant pairs (P=.04) and were accounted for specifically by the discordant dizygotic pairs (P=.002). Genetic influences on preexposure cognitive ability explained 5% of the variation in PTSD, but 100% of that relationship was explained by common genes. CONCLUSIONS: Preexposure cognitive ability is a risk or a protective factor for PTSD. The variance in PTSD explained by preexposure cognitive ability is accounted for entirely by common genetic factors. Lower cognitive ability may be a marker of less adaptive coping against adverse mental health consequences of exposure to potentially traumatic events. Further study of the potential mechanisms through which cognitive ability confers risk is needed.

Genetic and environmental contributions to nicotine, alcohol and cannabis dependence in male twins.

AIMS: To compute the common and specific genetic and environmental contributions to nicotine dependence (ND) alcohol dependence (AD) and cannabis dependence (CD). DESIGN: Twin model. PARTICIPANTS: Data from 1874 monozygotic and 1498 dizygotic twin pair members of the Vietnam Era Twin Registry were obtained via telephone administration of a structured psychiatric interview in 1992. MEASUREMENTS: Data to derive life-time diagnoses of DSM-III-R ND, AD and CD were obtained via telephone administration of the Diagnostic Interview Schedule. FINDINGS: The best-fitting model allowed for additive genetic contributions and unique environmental influences that were common to all three phenotypes. Risks for ND and AD were also due to genetic and unique environmental influences specific to each drug. A specific shared environmental factor contributed to CD. CONCLUSIONS: These results suggest that the life-time co-occurrence of ND, AD and CD is due to common and specific genetic factors as well as unique environmental influences, and vulnerability for CD is also due to shared environmental factors that do not contribute to ND and AD. The majority of genetic variance is shared across drugs and the majority of unique environmental influences are drug-specific in these middle-aged men. Because differences between models allowing for specific genetic versus shared environment were small, we are most confident in concluding that there are specific familial contributions-either additive genetic or shared environment-to CD.

Common genetic liability to major depression and posttraumatic stress disorder in men.

BACKGROUND: Major depression (MD) and posttraumatic stress disorder (PTSD) are highly comorbid. The degree to which a common genetic liability explains the etiology of the MD-PTSD association has not been quantified and has important implications for research and prevention. METHODS: This paper presents an analysis of data from 6744 members of the Vietnam Era Twin Registry. MD and PTSD were assessed using the Diagnostic Interview Schedule-III-R in 1991-92. Bivariate twin modeling was conducted to determine the genetic and environmental etiology of the MD-PTSD association. RESULTS: The best-fitting model for the MD-PTSD association included a substantial genetic correlation (r=.77; 95% CI, .50-1.00) and a modest individual-specific environmental correlation (r=.34; 95% CI, .19-.48). Common genetic liability explained 62.5% of MD-PTSD comorbidity. Genetic influences common to MD explained 15% of the total variance in risk for PTSD and 58% of the genetic variance in PTSD. Individual-specific environmental influences common to MD explained only 11% of the individual-specific environmental variance in PTSD. LIMITATIONS: Our participants were male Vietnam era veterans and our findings may not generalize to civilians, females or other cohorts. CONCLUSIONS: MD-PTSD comorbidity is largely explained by common genetic influences. Substantial genetic overlap between MD and PTSD implies that genes implicated in the etiology of MD are strong candidates for PTSD and vice versa. Environmental influences on MD and PTSD explain less of their covariation and appear to be largely disorder-specific. Research is needed to identify environmental factors that influence the development of MD versus PTSD in the context of common genetic liability.