Negative emotionality (NE) was evaluated as a candidate mechanism linking prenatal maternal affective symptoms and offspring internalizing problems during the preschool/early school age period. The participants were 335 mother–infant dyads from the Maternal Adversity, Vulnerability and Neurodevelopment project. A Confirmatory Bifactor Analysis (CFA) based on self-report measures of prenatal depression and pregnancy-specific anxiety generated a general factor representing overlapping symptoms of prenatal maternal psychopathology and four distinct symptom factors representing pregnancy-specific anxiety, negative affect, anhedonia and somatization. NE was rated by the mother at 18 and 36 months. CFA based on measures of father, mother, child-rated measures and a semistructured interview generated a general internalizing factor representing overlapping symptoms of child internalizing psychopathology accounting for the unique contribution of each informant. Path analyses revealed significant relationships among the general maternal affective psychopathology, the pregnancy- specific anxiety, and the child internalizing factors. Child NE mediated only the relationship between pregnancy-specific anxiety and the child internalizing factors. We highlighted the conditions in which prenatal maternal affective symptoms predicts child internalizing problems emerging early in development, including consideration of different mechanistic pathways for different maternal prenatal symptom presentations and child temperament.

Family, adoption and twin studies show that genetics influences suicidal behavior, but does not indicate specific susceptibility variants. Stress response is thought to be mediated by the corticotrophin-releasing hormone (CRH), which is known to be a regulator of the hypothalamic–pituitary–adrenal pathway (HPA). Alterations in HPA system have been related to impulsivity, aggression and suicidal behaviour, that are common features in Bipolar Disorder (BD). CRH is a hypothalamic factor that stimulates the pituitary gland. Two CRH receptors are known, CRHR1 and CRHR2. To search for markers conferring genetic susceptibility to suicide, we typed three polymorphisms of the CRHR2 gene, CRHR2(CA), CRHR2(GT), and CRHR2(GAT), in 312 families where at least one subject had DSM-IV bipolar disorder. Family based association analyses in the suicide attempters using FBAT yielded no difference in the distribution of the alleles for all three markers. HBAT analysis for quantitative measures on suicide-related traits showed association between haplotype 5-2-3 and higher severity. The current results show that haplotype variation at the CRHR2 locus is associated with suicidal behaviour. This is to our knowledge the first investigation on suicidal behavior and genetic variation at the CRHR2 locus, an important regulator of the HPA axis.

A national need is to prepare for and respond to accidental or intentional disasters categorized as chemical, biological, radiological, nuclear, or explosive (CBRNE). These incidents require specific subject-matter expertise, yet have commonalities. We identify 7 core elements comprising CBRNE science that require integration for effective preparedness planning and public health and medical response and recovery. These core elements are (1) basic and clinical sciences, (2) modeling and systems management, (3) planning, (4) response and incident management, (5) recovery and resilience, (6) lessons learned, and (7) continuous improvement. A key feature is the ability of relevant subject matter experts to integrate information into response operations. We propose the CBRNE medical operations science support expert as a professional who (1) understands that CBRNE incidents require an integrated systems approach, (2) understands the key functions and contributions of CBRNE science practitioners, (3) helps direct strategic and tactical CBRNE planning and responses through first-hand experience, and (4) provides advice to senior decision-makers managing response activities. Recognition of both CBRNE science as a distinct competency and the establishment of the CBRNE medical operations science support expert informs the public of the enormous progress made, broadcasts opportunities for new talent, and enhances the sophistication and analytic expertise of senior managers planning for and responding to CBRNE incidents.

Prenatal adversity shapes child neurodevelopment and risk for later mental health problems. The quality of the early care environment can buffer some of the negative effects of prenatal adversity on child development. Retrospective studies, in adult samples, highlight epigenetic modifications as sentinel markers of the quality of the early care environment; however, comparable data from pediatric cohorts are lacking. Participants were drawn from the Maternal Adversity Vulnerability and Neurodevelopment (MAVAN) study, a longitudinal cohort with measures of infant attachment, infant development, and child mental health. Children provided buccal epithelial samples (mean age = 6.99, SD = 1.33 years, n = 226), which were used for analyses of genome-wide DNA methylation and genetic variation. We used a series of linear models to describe the association between infant attachment and (a) measures of child outcome and (b) DNA methylation across the genome. Paired genetic data was used to determine the genetic contribution to DNA methylation at attachment-associated sites. Infant attachment style was associated with infant cognitive development (Mental Development Index) and behavior (Behavior Rating Scale) assessed with the Bayley Scales of Infant Development at 36 months. Infant attachment style moderated the effects of prenatal adversity on Behavior Rating Scale scores at 36 months. Infant attachment was also significantly associated with a principal component that accounted for 11.9% of the variation in genome-wide DNA methylation. These effects were most apparent when comparing children with a secure versus a disorganized attachment style and most pronounced in females. The availability of paired genetic data revealed that DNA methylation at approximately half of all infant attachment-associated sites was best explained by considering both infant attachment and child genetic variation. This study provides further evidence that infant attachment can buffer some of the negative effects of early adversity on measures of infant behavior. We also highlight the interplay between infant attachment and child genotype in shaping variation in DNA methylation. Such findings provide preliminary evidence for a molecular signature of infant attachment and may help inform attachment-focused early intervention programs.

Prenatal maternal depression and a multilocus genetic profile of two susceptibility genes implicated in the stress response were examined in an interaction model predicting negative emotionality in the first 3 years. In 179 mother–infant dyads from the Maternal Adversity, Vulnerability, and Neurodevelopment cohort, prenatal depression (Center for Epidemiologic Studies Depressions Scale) was assessed at 24 to 36 weeks. The multilocus genetic profile score consisted of the number of susceptibility alleles from the serotonin transporter linked polymorphic region gene (5-HTTLPR): no long-rs25531(A) (LA: short/short, short/long-rs25531(G) [LG], or LG/LG] vs. any LA) and the dopamine receptor D4 gene (six to eight repeats vs. two to five repeats). Negative emotionality was extracted from the Infant Behaviour Questionnaire—Revised at 3 and 6 months and the Early Child Behavior Questionnaire at 18 and 36 months. Mixed and confirmatory regression analyses indicated that prenatal depression and the multilocus genetic profile interacted to predict negative emotionality from 3 to 36 months. The results were characterized by a differential susceptibility model at 3 and 6 months and by a diathesis–stress model at 36 months.

Disorganized attachment is an important early risk factor for socioemotional problems throughout childhood and into adulthood. Prevailing models of the etiology of disorganized attachment emphasize the role of highly dysfunctional parenting, to the exclusion of complex models examining the interplay of child and parental factors. Decades of research have established that extreme child birth weight may have long-term effects on developmental processes. These effects are typically negative, but this is not always the case. Recent studies have also identified the dopamine D4 receptor (DRD4) as a moderator of childrearing effects on the development of disorganized attachment. However, there are inconsistent findings concerning which variant of the polymorphism (seven-repeat long-form allele or non–seven-repeat short-form allele) is most likely to interact with caregiving in predicting disorganized versus organized attachment. In this study, we examined possible two- and three-way interactions and child DRD4 polymorphisms and birth weight and maternal caregiving at age 6 months in longitudinally predicting attachment disorganization at 36 months. Our sample is from the Maternal Adversity, Vulnerability and Neurodevelopment project, a sample of 650 mother–child dyads. Birth weight was cross-referenced with normative data to calculate birth weight percentile. Infant DRD4 was obtained with buccal swabs and categorized according to the presence of the putative allele seven repeat. Macroanalytic and microanalytic measures of maternal behavior were extracted from a videotaped session of 20 min of nonfeeding interaction followed by a 10-min divided attention maternal task at 6 months. Attachment was assessed at 36 months using the Strange Situation procedure, and categorized into disorganized attachment and others. The results indicated that a main effect for DRD4 and a two-way interaction of birth weight and 6-month maternal attention (frequency of maternal looking away behavior) and sensitivity predicted disorganized attachment in robust logistic regression models adjusted for social demographic covariates. Specifically, children in the midrange of birth weight were more likely to develop a disorganized attachment when exposed to less attentive maternal care. However, the association reversed with extreme birth weight (low and high). The DRD4 seven-repeat allele was associated with less disorganized attachment (protective), while non–seven-repeat children were more likely to be classified as disorganized attachment. The implications for understanding inconsistencies in the literature about which DRD4 genotype is the risk direction are also considered. Suggestions for intervention with families with infants at different levels of biological risk and caregiving risk are also discussed.

Nilpenia rossi new genus new species, described here from the Ediacara Member (Rawnsley Quartzite, South Australia), provides evidence of a Precambrian macroscopic sessile sediment-dweller. Nilpenia, ranging up to 30 cm in diameter, consists of two zones, a complex central area surrounded by radiating, dichotomously branching structures that decrease in diameter from the center to the outer edges. Other elements of the Ediacara Biota are interpreted to have been mat-encrusters but Nilpenia uniquely grew within the upper millimeters of the actual sediment displacing sediment with growth. This sediment surface was rippled and cohesive and may well have included an endobenthic mat. The branching network on the upper surface of the organisms would have been in contact with the water. The phylogenetic relationships of the Ediacara biota are not well constrained and Nilpenia is no exception. However, the morphology and ecology of Nilpenia represent a novel growth strategy present in the Ediacaran and not common today.

The growing number of reports on candidate genes an genomic regions of interest in bipolar disorder reveals a tremendously active field of study. As with other complex psychiatric syndromes, these early findings will require a great deal of effort to replicate and clarify. This review serves both as an update and an introduction to some of the issues confronting investigators. Potential strategies in study design, population selection, and molecular methods are explored as well.

Twin, family, and adoption studies indicate that genetic factors play a major role in predisposition to schizophrenia. To date, molecular genetic studies have implicated many different chromosomal locations for the disorder. However, no one site replicates across the majority of investigations. This creates an impasse in the study of schizophrenia genetics, because of the large number of chromosomal sites that require further detailed research. It is difficult to plan to move ahead with expensive and labor-intensive research in an attempt to determine the etiologie genetic factor, when any given site proves to be only weakly positive. Therefore, the use of a hypothesis-driven approach may be cost effective, and may ultimately have more power to detect etiologie genes. Several lines of evidence suggest that a neurodevelopmental defect may play an important role in the etiology of this disorder. Neurodevelopment is a complex process in which genetic and nongenetic factors may interact to create the mature differentiated neuron, with its particular network of synaptic connections. A reasonable chance exists that polymorphisms of the genes that control normal development of the central nervous system (CNS) may produce a slightly altered trajectory of brain development, predisposing individuals to schizophrenia. This assumption has led geneticists to begin to study neurodevelopmental genes in schizophrenia subjects. This article reviews and discusses genetic studies of some developmental genes in schizophrenia. Genetic association and linkage studies of neurotrophic factors (brain-derived neurotrophic factor, or BDNF, and neurotrophin-3, or NT-3), neuronal cell adhesion molecule (NCAM), synapsin, and synaptosome-associated protein with a mass of 25 kd (SNAP-25) have proven to be of most interest.

The genetics of schizophrenia are characterized by a set of complex questions, with few answers forthcoming. However, molecular genetic approaches remain the most promising avenue to the understanding of etiologic mechanisms. Powerful discoveries may arise in the near future from candidate gene studies that are benefiting from the extensive neurobiology research in schizophrenia over the past decades. Furthermore, there are promising new divisions of the phenotype into more manageable subtypes that may make both candidate gene and genome scan studies more revealing. The following review discusses selected highlights of the epidemiology, molecular genetic strategies, candidate genes, and genome scan investigations in schizophrenia.

Genetic anticipation refers to an inheritance pattern within a pedigree showing a decrease in age of onset or an increase in disease severity or both in successive generations. This phenomenon has become the focus of important research in schizophrenia and bipolar mood disorder. The results to date have been controversial and far from conclusive. To attempt to resolve some of the earlier findings, we compared age at onset and disease severity between two generations in 24 Portuguese families ascertained for genetic linkage studies of bipolar mood disorder. There was a significant decrease in age of onset (P<. 00001) and increase in frequency of episodes (P<.0001)from the first to the second generation. This difference was significant under each of the four data-sampling schemes, one of which excluded probands. The second generation experienced onset 12.4 to 15.9 years earlier and illness 2.3 to 2.6 times more severe than did the first generation. We found no evidence for a specific effect in anticipation related to the transmitting parent's sex. Results of the present study, analyzed carefully for a variety of possible biases, suggest evidence for genetic anticipation in these Portuguese bipolar families.

The “Genetics of Obsessive-Compulsive Disorder” session at the Third International Obsessive-Compulsive Disorder Conference focused on the strong evidence of familial transmission of obsessive-compulsive disorder (OCD) and the new strategies available for molecular genetic research in this area. The opportunity to create a truly collaborative approach to the genetic study of OCD with standard methodology and large-scale cooperation among groups was emphasized. The importance of phenotype definition, including systematic subtyping, was discussed in the context of reducing heterogeneity and false-positive results.

Behavioral addictions are considered as the repetitive occurrence of impulsive behaviors without consideration of their potential negative consequences. These addictions represent an increasing cost to society and are an important new field of research in psychiatric genetics. There has been a growing body of evidence on the familial aggregation and genetic influences on the development of behavioral addictions and mainly on pathological gambling. The aim of this article is to critically review findings of family and molecular genetic studies on behavioral addictions, focusing on pathological gambling and commenting on other disorders where appropriate. This review provides a comprehensive approach to genetic studies on behavioral addiction and points out the necessity of expanding the genetic research in this field. Future directions for genetic studies in this field are also discussed.

Clozapine is a prototype atypical antipsychotic drug and displays efficacy in 30% to 60% of schizophrenia patients who do not respond to traditional antipsychotics. There is considerable evidence supporting a concentration-response relationship for clozapine. A plasma clozapine concentration >200 to 420 ng/mL increases the probability of antipsychotic effects. Approximately 70% to 80% of variability in clozapine plasma concentration can be attributed to variability in cytochrome P450 1A2 activity. Measurement of caffeine metabolites in plasma or urine can be used as an in vivo index of cytochrome P450 1A2 activity, since caffeine is primarily eliminated by oxidative metabolism through this cytochrome P450 enzyme. Caffeine-based tests may contribute to individualization of clozapine dosages and optimization of its antipsychotic effects in schizophrenia patieents There are several lines of evidence suggesting the potential involvement of the dopamine D4 receptor in pharmacodynamic effects of clozapine. Clozapine has a 10-fold higher affinity for the dopamine D4 receptor in comparison to the D2 and the D3 receptors. Moreover, the free plasma fluid concentration of clozapine is comparable to its binding affinity for the D4 receptor in vitro. Blockade of the D4 receptor in the mesocorticolimbic region, a brain area implicated in the pathogenesis of schizophrenia, may contribute to efficacy of clozapine in negative symptoms. Moreover, the dopamine D4 receptor gene (DRD4) displays an unusual degree of genetic variation (polymorphism). In a recent preliminary study, investigated the (G)n mononucleotide repeat polymorphism within the first intron of the D4 gene in 50 schizophrenia patients refractory to traditional antipsychotics. These patients were prospectively followed for antipsychotic response during clozapine treatment. Analysis of variance found significant differences in antipsychotic response as demonstrated by mean change in Brief Psychiatric Rating Scale scores among the genotype panels for this polymorphism F[3,49]=4.1 (P=0.01). Future studies investigating the mechanistic basis of variability in response to clozapine should focus on both pharmacokinetic and pharmacodynamic factors.