Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans.

The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.

Latent classes of childhood trauma exposure predict the development of behavioral health outcomes in adolescence and young adulthood.

BACKGROUND: To develop latent classes of exposure to traumatic experiences before the age of 13 years in an urban community sample and to use these latent classes to predict the development of negative behavioral outcomes in adolescence and young adulthood. METHOD: A total of 1815 participants in an epidemiologically based, randomized field trial as children completed comprehensive psychiatric assessments as young adults. Reported experiences of nine traumatic experiences before age 13 years were used in a latent class analysis to create latent profiles of traumatic experiences. Latent classes were used to predict psychiatric outcomes at age ⩾13 years, criminal convictions, physical health problems and traumatic experiences reported in young adulthood. RESULTS: Three latent classes of childhood traumatic experiences were supported by the data. One class (8% of sample), primarily female, was characterized by experiences of sexual assault and reported significantly higher rates of a range of psychiatric outcomes by young adulthood. Another class (8%), primarily male, was characterized by experiences of violence exposure and reported higher levels of antisocial personality disorder and post-traumatic stress. The final class (84%) reported low levels of childhood traumatic experiences. Parental psychopathology was related to membership in the sexual assault group. CONCLUSIONS: Classes of childhood traumatic experiences predict specific psychiatric and behavioral outcomes in adolescence and young adulthood. The long-term adverse effects of childhood traumas are primarily concentrated in victims of sexual and non-sexual violence. Gender emerged as a key covariate in the classes of trauma exposure and outcomes.

Smoking cessation is associated with lower rates of mood/anxiety and alcohol use disorders.

BACKGROUND: The psychological outcomes that accompany smoking cessation are not yet conclusive but positive outcomes could help to persuade quitting. METHOD: We used data from the longitudinal National Epidemiological Study of Alcohol and Related Conditions. Logistic regression was used to examine associations between cigarette smoking reduction and Wave 2 status of addiction/mental health disorder among daily smokers at Wave 1, stratified by status of the diagnosis of interest at Wave 1. We adjusted for differences in baseline covariates between smokers with different levels of smoking reduction between Wave 1 and Wave 2 using propensity score regression adjustment. RESULTS: After adjusting for propensity scores and other mental health/addiction co-morbidities at Wave 2, among daily smokers who had current or lifetime history diagnosis of the outcome of interest at Wave 1, quitting by Wave 2 predicted a decreased risk of mood/anxiety disorder [adjusted odds ratio (aOR) 0.6, 95% confidence interval (CI) 0.4-0.9] and alcohol disorder (aOR 0.7, 95% CI 0.5-0.99) at Wave 2. Among daily smokers with no lifetime history diagnosis of the outcome of interest at Wave 1, quitting smoking by Wave 2 predicted a decreased risk of drug use disorder at Wave 2 (aOR 0.3, 95% CI 0.1-0.9). CONCLUSIONS: There is no support in our data for the concern that smoking cessation would result in smokers' increased risk of some mental disorders. To the contrary, our data suggest that smoking cessation is associated with risk reduction for mood/anxiety or alcohol use disorder, even among smokers who have had a pre-existing disorder.

Childhood maltreatment, juvenile disorders and adult post-traumatic stress disorder: a prospective investigation.

BACKGROUND: We examine prospectively the influence of two separate but potentially inter-related factors in the etiology of post-traumatic stress disorder (PTSD): childhood maltreatment as conferring a susceptibility to the PTSD response to adult trauma and juvenile disorders as precursors of adult PTSD. METHOD: The Dunedin Multidisciplinary Health and Development Study (DMHDS) is a birth cohort (n = 1037) from the general population of New Zealand's South Island, with multiple assessments up to age 38 years. DSM-IV PTSD was assessed among participants exposed to trauma at ages 26-38. Complete data were available on 928 participants. RESULTS: Severe maltreatment in the first decade of life, experienced by 8.5% of the sample, was associated significantly with the risk of PTSD among those exposed to adult trauma [odds ratio (OR) 2.64, 95% confidence interval (CI) 1.16-6.01], compared to no maltreatment. Moderate maltreatment, experienced by 27.2%, was not associated significantly with that risk (OR 1.55, 95% CI 0.85-2.85). However, the two estimates did not differ significantly from one another. Juvenile disorders (ages 11-15), experienced by 35% of the sample, independent of childhood maltreatment, were associated significantly with the risk of PTSD response to adult trauma (OR 2.35, 95% CI 1.32-4.18). CONCLUSIONS: Severe maltreatment is associated with risk of PTSD response to adult trauma, compared to no maltreatment, and juvenile disorders, independent of earlier maltreatment, are associated with that risk. The role of moderate maltreatment remains unresolved. Larger longitudinal studies are needed to assess the impact of moderate maltreatment, experienced by the majority of adult trauma victims with a history of maltreatment.

Neuroticism and post-traumatic stress disorder: a prospective investigation.

BACKGROUND: Neuroticism has been consistently correlated with the post-traumatic stress disorder (PTSD) response to traumatic events. Interpretation of these findings is limited by the retrospective nature of these findings: neuroticism was measured after the trauma had occurred. The prospective association of neuroticism with PTSD has not been examined (the relationship of neuroticism with PTSD symptoms was examined in a few prospective studies). We evaluate prospectively the relationship of neuroticism, measured at baseline, with the cumulative occurrence of PTSD during the subsequent 10 years, using data from a longitudinal epidemiological study of young adults. METHOD: A sample of 1007 young adults randomly selected from the membership of a large health maintenance organization in southeast Michigan was assessed at baseline and followed up at 3, 5 and 10 years later. We conducted a series of multinomial logistic regressions to estimate the relative risk (RR) of exposure to trauma and PTSD by neuroticism at baseline, adjusting for history of major depression (n = 990). RESULTS: During the 10-year follow-up, 50.2% of the sample experienced traumatic events and 5.2% developed PTSD. Neuroticism score at baseline increased significantly the RR of PTSD response to trauma. Additional analysis revealed that, among persons with history of major depression at baseline, RR for PTSD associated with neuroticism was equal to the null value of 1, but was increased significantly among those with no history of major depression. CONCLUSIONS: The results confirm the role of neuroticism as diathesis in the PTSD response to traumatic experiences.

Influence of predispositions on post-traumatic stress disorder: does it vary by trauma severity?

BACKGROUND: Only a minority of trauma victims (<10%) develops post-traumatic stress disorder (PTSD), suggesting that victims vary in predispositions to the PTSD response to traumas. It is assumed that the influence of predispositions is inversely related to trauma severity: when trauma is extreme predispositions are assumed to play a secondary role. This assumption has not been tested. We estimate the influence of key predispositions on PTSD induced by an extreme trauma - associated with a high percentage of PTSD - (sexual assault), relative to events of lower magnitude (accidents, disaster, and unexpected death of someone close). METHOD: The National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) is representative of the adult population of the USA. A total of 34 653 respondents completed the second wave in which lifetime PTSD was assessed. We conducted three series of multinomial logistic regressions, comparing the influence of six predispositions on the PTSD effect of sexual assault with each comparison event. Three pre-existing disorders and three parental history variables were examined. RESULTS: Predispositions predicted elevated PTSD risk among victims of sexual assault as they did among victims of comparison events. We detected no evidence that the influence of predispositions on PTSD risk was significantly lower when the event was sexual assault, relative to accidents, disasters and unexpected death of someone close. CONCLUSIONS: Important predispositions increase the risk of PTSD following sexual assault as much as they do following accidents, disaster, and unexpected death of someone close. Research on other predispositions and alternative classifications of event severity would be illuminating.

ADH1B is associated with alcohol dependence and alcohol consumption in populations of European and African ancestry.

A coding variant in alcohol dehydrogenase 1B (ADH1B) (rs1229984) that leads to the replacement of Arg48 with His48 is common in Asian populations and reduces their risk for alcoholism, but because of very low allele frequencies the effects in European or African populations have been difficult to detect. We genotyped and analyzed this variant in three large European and African-American case-control studies in which alcohol dependence was defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, and demonstrated a strong protective effect of the His48 variant (odds ratio (OR) 0.34, 95% confidence interval (CI) 0.24, 0.48) on alcohol dependence, with genome-wide significance (6.6 × 10(-10)). The hypothesized mechanism of action involves an increased aversive reaction to alcohol; in keeping with this hypothesis, the same allele is strongly associated with a lower maximum number of drinks in a 24-hour period (lifetime), with P=3 × 10(-13). We also tested the effects of this allele on the development of alcoholism in adolescents and young adults, and demonstrated a significantly protective effect. This variant has the strongest effect on risk for alcohol dependence compared with any other tested variant in European populations.

Race/ethnic differences in exposure to traumatic events, development of post-traumatic stress disorder, and treatment-seeking for post-traumatic stress disorder in the United States.

BACKGROUND: To identify sources of race/ethnic differences related to post-traumatic stress disorder (PTSD), we compared trauma exposure, risk for PTSD among those exposed to trauma, and treatment-seeking among Whites, Blacks, Hispanics and Asians in the US general population. METHOD: Data from structured diagnostic interviews with 34 653 adult respondents to the 2004-2005 wave of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) were analysed. RESULTS: The lifetime prevalence of PTSD was highest among Blacks (8.7%), intermediate among Hispanics and Whites (7.0% and 7.4%) and lowest among Asians (4.0%). Differences in risk for trauma varied by type of event. Whites were more likely than the other groups to have any trauma, to learn of a trauma to someone close, and to learn of an unexpected death, but Blacks and Hispanics had higher risk of child maltreatment, chiefly witnessing domestic violence, and Asians, Black men, and Hispanic women had higher risk of war-related events than Whites. Among those exposed to trauma, PTSD risk was slightly higher among Blacks [adjusted odds ratio (aOR) 1.22] and lower among Asians (aOR 0.67) compared with Whites, after adjustment for characteristics of trauma exposure. All minority groups were less likely to seek treatment for PTSD than Whites (aOR range: 0.39-0.61), and fewer than half of minorities with PTSD sought treatment (range: 32.7-42.0%). CONCLUSIONS: When PTSD affects US race/ethnic minorities, it is usually untreated. Large disparities in treatment indicate a need for investment in accessible and culturally sensitive treatment options.

Change in teachers' ratings of attention problems and subsequent change in academic achievement: a prospective analysis.

BACKGROUND: Recent research has documented a link between attention problems at school entry and later academic achievement. Little is known about the association of change in attention problems during the early school years with subsequent change in academic achievement. METHOD: A community-based cohort was followed up and assessed for attention problems at ages 6 and 11 (Teacher Report Form; TRF) and for academic achievement in math and reading at ages 11 and 17 (Woodcock-Johnson Psycho-Educational Battery). Complete data were available on 590 children (72% of the initial sample). Ordinary least squares regressions were used to estimate change in academic achievement from age 11 to age 17 in relation to change in TRF-attention problems from age 6 to age 11. Children's IQ and family factors were statistically controlled. RESULTS: Change in teachers' ratings of attention problems from age 6 to age 11 was negatively associated with change in math and reading from age 11 to age 17, controlling for children's IQ and family factors. Externalizing problems had no significant association with change in math or reading, when added to the multivariable model. CONCLUSIONS: Increases in teacher-rated attention problems from age 6 to age 11 were followed by declines in academic achievement from age 11 to age 17; decreases were followed by gains. The results underscore the need for research on the course of attention problems, the testing of interventions to address children's early attention problems and the evaluation of their effects on subsequent academic achievement.

Does brain dysfunction increased children's vulnerability to environmental stress?

Previous research has shown that children with physical conditions involving the brain are at increased risk for psychopathology. It is unclear whether brain dysfunction leads to disturbance directly or whether it does so by increasing the children's vulnerability to environmental stress. I examined the vulnerability hypothesis in a sample of 157 children with cerebral palsy, myelodysplasia, or multiple handicaps and in 339 randomly selected controls. Data on psychopathology came from direct interviews with the children; data on the family environment came from mothers' reports. Physical disabilities were associated with significant increases in depressive symptoms and inattention. Family environment had a significant main effect on depressive symptoms; effect on disabled children was not significantly different from effect on controls. Family environment had no significant effects on symptoms of inattention in disabled children. The findings provided no support for the hypothesis that brain dysfunction renders children vulnerable to environmental stress.

Siblings of disabled children. Effects of chronic stress in the family.

We examined the effects of chronic stress in families of severely disabled children on psychopathology in siblings. We present findings from a five-year follow-up of 192 siblings of disabled children and a geographically based probability sample of 284 children (controls), who were 6 to 18 years old at initial assessment (time 1) and 11 to 23 years old at follow-up (time 2). Data on the Psychiatric Screening Inventory were obtained from mothers at times 1 and 2. Additionally, at time 2 the Diagnostic Interview Schedule for Children was administered to the children themselves. At follow-up, the siblings' picture according to mothers' assessment appears worse than it did initially: In addition to the excess in aggressive symptoms seen at time 1, they manifested an excess in depressive affect and social isolation. The time 2 interviews with the children themselves show that the siblings scored significantly higher than controls on depressive symptoms, although the rate of DSM-III major depression was not significantly different. An excess in depressive symptoms was observed also in mothers of disabled children, who, like the siblings, were not at increased risk for major depression.

Chronic stress and major depression.

Six-month and lifetime rates of DSM-III major depressive disorder (MDD) and characteristics of the disorder were compared in mothers of children with disabilities (chronic stress sample, n = 310) and in a geographically based probability sample (controls, n = 357). The presence of DSM-III MDD was ascertained by the National Institute of Mental Health Diagnostic Interview Schedule. Although mothers in the chronic stress sample had significantly more depressive symptoms, rates of MDD were not significantly different in the two samples. The women with MDD in the chronic stress sample reported a lower age of onset and more episodes in lifetime than diagnostically comparable controls, but the two samples did not differ in symptomatology of worst episode. The data do not support an etiologic role for chronic stress in MDD, nor do they support the hypothesis that chronic stress is associated with a unique symptom profile or more severe episodes. They suggest a role for chronic stress in precipitating episodes, although the evidence on this point must be interpreted with caution.

Posttraumatic stress disorder and drug disorders: testing causal pathways.

BACKGROUND: Although there is a high degree of comorbidity between posttraumatic stress disorder (PTSD) and drug use disorders, little is known about causal relationships between PTSD, exposure to traumatic events, and drug use disorders. METHODS: In a longitudinal study in southeast Michigan, 1007 adults aged 21 to 30 years were initially assessed in 1989 and were followed up 3 and 5 years later, in 1992 and 1994. Psychiatric disorders according to DSM-III-R criteria were measured by the National Institute of Mental Health Diagnostic Interview Schedule. To take into account temporal sequencing, the associations between PTSD, traumatic events, and drug use disorders were analyzed by using Cox proportional hazards models with time-dependent covariates. RESULTS: Posttraumatic stress disorder signaled an increased risk of drug abuse or dependence (hazards ratio, 4.5; 95% confidence interval, 2.6-7.6, adjusted for sex), whereas exposure to traumatic events in the absence of PTSD did not increase the risk of drug abuse or dependence. The risk for abuse or dependence was the highest for prescribed psychoactive drugs (hazards ratio, 13.0; 95% confidence interval, 5.3-32.0). There was no evidence that preexisting drug abuse or dependence increased the risk of subsequent exposure to traumatic events or the risk of PTSD after traumatic exposure. CONCLUSION: The results suggest that drug abuse or dependence in persons with PTSD might be the inadvertent result of efforts to medicate symptoms, although the possibility of shared vulnerability to PTSD and drug use disorders cannot be ruled out.

Smoking and panic attacks: an epidemiologic investigation.

BACKGROUND: Epidemiologic studies have reported a lifetime association between smoking and panic disorder. In this study, we examine potential explanations for this association. METHODS: Analysis was conducted on data from 2 epidemiologic studies, the Epidemiologic Study of Young Adults in southeast Michigan (N = 1007) and the National Comorbidity Survey Tobacco Supplement (n = 4411). Cox proportional hazards models with time-dependent covariates were used to estimate the risk for onset of panic attacks associated with prior smoking and vice versa, controlling for history of major depression. The role of lung disease in the smoking-panic attacks association was explored. RESULTS: Daily smoking signaled an increased risk for first occurrence of panic attack and disorder; the risk was higher in active than past smokers. No significant risk was detected for onset of daily smoking in persons with prior panic attacks or disorder. Exploratory analyses suggest that lung disease might be one of the mechanisms linking smoking to panic attacks. CONCLUSIONS: The evidence that the association between smoking and panic disorder might result primarily from an influence in one direction (i.e., from prior smoking to first panic attack) and the possibility of a higher risk in active than past smokers suggest a causal hypothesis for the smoking-panic attacks relationship.

Nicotine dependence, major depression, and anxiety in young adults.

To determine whether nicotine dependence, classified by level of severity, was associated with other substance dependence, major depression, and anxiety disorders, we studied a random sample of 1007 young adults in the Detroit (Mich) area using the National Institute of Mental Health Diagnostic Interview Schedule, revised according to DSM-III-R. The systematic coverage of DSM-III-R criteria of nicotine dependence provides an unprecedented opportunity to separate persons with nicotine dependence from the larger class of persons with a history of smoking and to examine the prevalence of psychiatric disorders among persons with nicotine dependence and among nondependent smokers. The lifetime prevalence of nicotine dependence was 20%. Nicotine dependence was associated with alcohol, cannabis, and cocaine dependence. Controlling for the effects of other substance dependencies, persons with nicotine dependence had higher rates of major depression and anxiety disorders. The strength of these associations varied by level of severity of nicotine dependence. Nondependent smokers had higher rates of other substance dependencies, but not of major depression or anxiety disorders.

Nicotine dependence and major depression. New evidence from a prospective investigation.

We examined prospectively the association between nicotine dependence and major depression (MDD). The following questions were addressed: (1) Are smokers with a history of MDD at increased risk for progression to nicotine dependence and more severe levels of dependence? (2) Are persons with a history of nicotine dependence at increased risk for MDD? A sample of 995 young adults were interviewed in 1989 and reinterviewed in 1990, 14 months later. The revised National Institute of Mental Health-Diagnostic Interview Schedule was used to ascertain DSM-III-R nicotine dependence and other substance use and psychiatric disorders. A history of MDD increased the risk for progression to nicotine dependence or more severe levels of dependence (odds ratio, 2.06; 95% confidence interval, 1.21 to 3.49). In addition, persons with a history of nicotine dependence had a higher rate of first-incidence MDD during the follow-up period than persons with no history of nicotine dependence (7.5% vs 3.2%; odds ratio, 2.45; 95% confidence interval, 1.17 to 5.15). The prospective data suggest that the association between nicotine dependence and MDD, observed previously in cross-sectional studies, might be either causal, with influences flowing in both directions, or, more probably, noncausal, reflecting the effects of common factors that predispose to both disorders.

Traumatic events and posttraumatic stress disorder in an urban population of young adults.

To ascertain the prevalence of posttraumatic stress disorder (PTSD) and risk factors associated with it, we studied a random sample of 1007 young adults from a large health maintenance organization in the Detroit, Mich, area. The lifetime prevalence of exposure to traumatic events was 39.1%. The rate of PTSD in those who were exposed was 23.6%, yielding a lifetime prevalence in the sample of 9.2%. Persons with PTSD were at increased risk for other psychiatric disorders; PTSD had stronger associations with anxiety and affective disorders than with substance abuse or dependence. Risk factors for exposure to traumatic events included low education, male sex, early conduct problems, extraversion, and family history of psychiatric disorder or substance problems. Risk factors for PTSD following exposure included early separation from parents, neuroticism, preexisting anxiety or depression, and family history of anxiety. Life-style differences associated with differential exposure to situations that have a high risk for traumatic events and personal predispositions to the PTSD effects of traumatic events might be responsible for a substantial part of PTSD in this population.

Psychiatric sequelae of posttraumatic stress disorder in women.

BACKGROUND: The risk for first-onset major depression, anxiety, and substance use disorders associated with prior posttraumatic stress disorder (PTSD) was estimated in a sample of women. METHODS: The National Institute of Mental Health Diagnostic Interview Schedule, revised according to DSM-III-R, was used to measure lifetime psychiatric disorders in a stratified random sample of 801 mothers of children, who participated in a study of cognitive and psychiatric outcomes by level of birth weight. Cox proportional hazards models with time-dependent covariates were used to calculate the hazards ratios of first onset of other disorders following PTSD. RESULTS: The lifetime prevalence of traumatic events was 40% and of PTSD, 13.8%. Posttraumatic stress disorder signaled increased risks for first-onset major depression (hazards ratio, 2.1) and alcohol use disorder (hazards ratio, 3.0). The risk for major depression following PTSD was of the same magnitude as the risk for major depression following other anxiety disorders. Women with preexisting anxiety and PTSD had significantly increased risk for first-onset major depression. Additional analysis showed that preexisting major depression increased women's vulnerability to the PTSD-inducing effects of traumatic events and risk for exposure to traumatic events. CONCLUSIONS: Posttraumatic stress disorder influences the risk for first-onset major depression and alcohol use disorder. The causal explanation of these temporally secondary disorders is unclear and might involve the effect of PTSD or underlying vulnerabilities exposed by the traumatic experience.

Nicotine dependence in the United States: prevalence, trends, and smoking persistence.

BACKGROUND: The prevalence of smoking in the United States has been closely monitored. However, little is known about the epidemiology of nicotine dependence. We studied DSM-III-R nicotine dependence in the United States, trends across cohorts, and the role of nicotine dependence in smoking persistence. METHODS: The Tobacco Supplement to the National Comorbidity Survey was administered to a representative subset of 4414 persons aged 15 to 54 years. The World Health Organization's Composite International Diagnostic Interview was used to assess nicotine dependence. RESULTS: Lifetime prevalence of nicotine dependence was 24%, nearly half of those who had ever smoked daily for a month or more. The highest risk for nicotine dependence occurred in the first 16 years after daily smoking began, at which point the rate declined and continued at a slower pace for several years. Nicotine dependence increased the risk of smoking persistence, with an odds ratio (OR) of 2.2 (95% confidence interval [CI], 1.6-3.0). Members of the most recent cohort, who were 15 to 24 years of age at the time of the survey, were the least likely to smoke daily, but those who smoked had the highest risk of dependence: OR for daily smoking in the most recent vs earliest cohort was 0.7 (95% CI, 0.5-0.9), and for dependence among smokers, 7.2 (95% CI, 5.0-10.4). CONCLUSIONS: Despite evidence that nicotine dependence is the leading preventable cause of death and morbidity, it remains a common psychiatric disorder. Smoking cessation and the decline in uptake in recent years varied across subgroups of the population.

Sex differences in posttraumatic stress disorder.

BACKGROUND: Epidemiologic surveys in the general population documented a higher rate of posttraumatic stress disorder (PTSD) in women than in men. To date, the finding has received little scientific attention. This study examines the extent to which sex differences in PTSD might be explained by previously identified risk factors and whether the sex difference in PTSD varied by age at exposure to traumatic events. METHODS: The NIMH-DIS (NIMH Diagnostic Interview Schedule, Version III Revised) was used to measure DSM-IIIR disorders in a random sample of 1007 young adults. Cox proportional hazards models were used to estimate changes in the hazards ratio for PTSD associated with sex when potential risk factors were included. RESULTS: Lifetime prevalence of exposure to traumatic events and number of traumatic events did not vary by sex. The prevalence of PTSD was higher for women than for men exposed to traumatic events (hazards ratio, 2.3; 95% confidence interval, 1.5-3.6). Preexisting anxiety disorders or major depressive disorders played a part in the observed sex difference in PTSD. Family history of anxiety disorder and early separation from parents, although significant risk factors for PTSD in subjects of both sexes, were unrelated to the sex difference in PTSD. The sex difference in PTSD was markedly greater if exposure occurred in childhood than later on. CONCLUSIONS: Posttraumatic stress disorder is more likely to develop in females than in males after exposure to a traumatic event. Susceptibility to PTSD in females might be greater in childhood than after age 15 years. Explanations of the sex difference might involve characteristics of individuals and of the traumatic experiences.