Real-time resolution of point mutations that cause phenovariance in mice.

With the wide availability of massively parallel sequencing technologies, genetic mapping has become the rate limiting step in mammalian forward genetics. Here we introduce a method for real-time identification of N-ethyl-N-nitrosourea-induced mutations that cause phenotypes in mice. All mutations are identified by whole exome G1 progenitor sequencing and their zygosity is established in G2/G3 mice before phenotypic assessment. Quantitative and qualitative traits, including lethal effects, in single or multiple combined pedigrees are then analyzed with Linkage Analyzer, a software program that detects significant linkage between individual mutations and aberrant phenotypic scores and presents processed data as Manhattan plots. As multiple alleles of genes are acquired through mutagenesis, pooled "superpedigrees" are created to analyze the effects. Our method is distinguished from conventional forward genetic methods because it permits (1) unbiased declaration of mappable phenotypes, including those that are incompletely penetrant (2), automated identification of causative mutations concurrent with phenotypic screening, without the need to outcross mutant mice to another strain and backcross them, and (3) exclusion of genes not involved in phenotypes of interest. We validated our approach and Linkage Analyzer for the identification of 47 mutations in 45 previously known genes causative for adaptive immune phenotypes; our analysis also implicated 474 genes not previously associated with immune function. The method described here permits forward genetic analysis in mice, limited only by the rates of mutant production and screening.

Intermittent explosive disorder: associations with PTSD and other Axis I disorders in a US military veteran sample.

This study examined the prevalence of intermittent explosive disorder (IED) and its associations with trauma exposure, posttraumatic stress disorder (PTSD), and other psychiatric diagnoses in a sample of trauma-exposed veterans (n=232) with a high prevalence of PTSD. Structural associations between IED and latent dimensions of internalizing and externalizing psychopathology were also modeled to examine the location of IED within this influential structure. Twenty-four percent of the sample met criteria for a lifetime IED diagnosis and those with the diagnosis were more likely to meet criteria for lifetime PTSD than those without (30.3% vs. 14.3% respectively). Furthermore, regression analyses revealed lifetime PTSD severity to be a significant predictor of IED severity after controlling for combat, trauma exposure, and age. Finally, confirmatory factor analysis revealed significant cross-loadings of IED on both the externalizing and distress dimensions of psychopathology, suggesting that the association between IED and other psychiatric disorders may reflect underlying tendencies toward impulsivity and aggression and generalized distress and negative emotionality, respectively.

Psychological effects of the marathon bombing on Boston-area veterans with posttraumatic stress disorder.

This study examined the psychological impact of the Boston Marathon bombing using data from an ongoing longitudinal study of Boston-area veterans with posttraumatic stress disorder (PTSD; N = 71). Participants were assessed by telephone within 1 week of the end of the event; 42.3% of participants reported being personally affected by the bombings and/or the manhunt that followed. The majority of them reported that the bombing reminded them of their own traumas and/or caused other emotional distress. Examination of change in posttraumatic stress disorder (PTSD) symptoms from a prebombing assessment an average of 2 months earlier to 1 week after the event revealed no significant change in symptoms across the sample as a whole. However, examination of patterns of change at the individual level revealed significant correlations (r = .33; p = .005) between distress at the time of the event and change in total PTSD symptom severity, with this effect accounted for primarily by increases in intrusion and avoidance symptoms (rs = .35 and .31, ps = .002 and .008, respectively). Findings of this study should raise awareness of the potential impact of terror attacks, mass shootings, and other events of this type on the well-being of individuals with histories of trauma and/or pre-existing PTSD.

Alcohol and drug abuse among U.S. veterans: comparing associations with intimate partner substance abuse and veteran psychopathology.

This study examined the relative influences of posttraumatic stress disorder (PTSD), other psychopathology, and intimate partner alcohol and drug use on substance-related problems in U.S. veterans (242 couples, N = 484). Hierarchical regression analyses revealed that partner alcohol and drug use severity explained more variance in veteran alcohol use and drug use (20% and 13%, respectively) than did veteran PTSD, adult antisocial behavior, or depression symptoms combined (6% for veteran alcohol use; 7% for veteran drug use). Findings shed new light on the influence of relationship factors on veteran alcohol and drug use and underscore the importance of couples-oriented approaches to treating veterans with comorbid PTSD and substance abuse.