Stephen V. Faraone - US grants

DESCRIPTION (Adapted from applicant's abstract): Despite increasing media attention, adult Attention-deficit-hyperactivity disorder (ADHD) has not been systematically studied in large samples. As a result, there has been a debate in the field about the validity of ADHD in adults presenting at mental health clinics. To shed light on this debate, we propose to test hypothesis in one domain of adult ADHD that has received scant attention: its genetic epidemiology. As we review in the background section, there have been only two small pilot studies of the genetic epidemiology of ADHD. Such data are essential to validating the syndrome, creating developmentally appropriate diagnostic algorithms and laying the clinical foundation for genetic linkage studies. To fill this gap in the research literature, we will address the validity of adult ADHD from the genetic epidemiological perspective by testing the following hypothesis for the five main aims of our proposal: 1) Assessing the Familial Transmission of Adult ADHD; 2) Validating Adult ADHD with Molecular Genetic Data; 3) Assessing the Divergent Validity of Adult ADHD; 4) Using Family Study Data to Validate Diagnostic Models of Adult ADHD; AND 5) Creating a Resource for Future Follow-up and Molecular Genetic Studies of Adult ADHD. To acheive these aims, we will complete a double- blind family study of 140 ADHD families and 120 control families. We view our family study strategy as being a valuable investment for several reasons. A large double-blind study of adult ADHD has never been done before. Moreover, because consistent positive associations have been reported between childhood ADHD and two dopamine related genes, the collection of molecular genetic data will allow us to validate adult ADHD at the molecular level. Because we are collecting data about lifetime psychiatric diagnoses, we will be able to determine if other disorders can account for the familial transmission of ADHD or its molecular genetic associations. We will also be able to assess what age at onset criterion and what set of symptom thresholds should be used for the diagnosis of adult ADHD and will be able to define phenotypes and sample selection rules that will maximize the yield of future linkage studies. To maximize the scientific yield of this proposal, we will create a resource for future molecular genetic and follow-up studies of adult ADHD. We will set the stage for these studies by 1) providing a comprehensive baseline assessment for a follow-up study and 2) clarifying the nature of phenotypes and the sample sizes that will be needed for molecular genetic studies. Thus, if founded, we expect that the proposed work will lead to a program of research that can both clarify the nosological complexities of adult ADHD and clarify the nature of genes that are risk factors for the disorder.

The main goal of the proposed program of research is to use specific gene variants and environmental measures to clarify the nature of gene-environment interactions in Attention Deficit Hyperactivity Disorder (ADHD) and to improve our ability to predict which children require preventive interventions for ADHD and its associated adverse outcomes. We will accomplish this goal by collecting DNA samples from subjects who have already participated in two ongoing longitudinal family studies of ADHD. Our basic strategy is to use the ecogenetic approach described by Khoury et al. This method improves risk prediction by examining genetically mediated differences in susceptibility to environmental agents. In the proposed work, we will collect DNA samples from the ADHD proband and their family members who have participated in our two longitudinal family studies comprising 1,040 subjects in families ascertained through ADHD children. The proposal has three main aims: 1) to predict adverse outcomes among ADHD children and their siblings; 2) to assess the accuracy of risk prediction and 3) to create a genetics resource for ecogenetic studies. There can be little doubt that ADHD is caused by the confluence of genes and environment. Because some susceptibility genes have been found and some environmental causes identified, ADHD is an ideal disorder for the application of ecogenetic models. Moreover, because ADHD children are at high risk for multiple adverse outcomes, they are a clinically meaningful target group for prevention studies seeking to prevent these outcomes. Predicting adverse outcomes among ADHD children has clinical, scientific and public health implications. Such efforts can help identify etiologic risk factors associated with more impaired outcome in ADHD and can characterize early predictors of persistence and morbidity of this disorder. Moreover, predicting the course of ADHD could help design improved secondary prevention programs aimed at reducing the morbidity of ADHD throughout childhood and adolescence. From a public health perspective, the ability to predict course and clinical complications could help focus societal resources on those at higher risk for persistent illness with complicated outcomes. One strength of the proposed study is that we have also collected data on the siblings of ADHD probands. Using ecogenetic methods, we will be able to predict which siblings are at highest risk for ADHD. Such data would be useful for clinicians faced with parents of ADHD children who are concerned with the future of their non-ADHD children. Ecogenetic prediction models could one day provide a rational method for clinicians to recommend preventive interventions for siblings of ADHD children. Although longitudinal studies of ADHD have provided some evidence that outcome can be predicted from clinical assessments, the accuracy of prediction is low, suggesting that variables from other domains should be entered into the prediction equation. Our plan is to use genes as new predictors of outcome is innovative because no prior studies have used specific gene variants to predict course and outcome among ADHD children. Furthermore, no studies have used an ecogenetic approach to sharpen the accuracy of risk prediction.

We are proposing a multi-year conference grant which seeks to establish forum for researcher to pursue collaborative studies of the molecular genetics of attention deficit hyperactivity disorder (ADHD). This application was conceived in response to a recent call from the NIMH for researchers to establish mechanisms for pooling molecular genetic and clinical data in a manner that would facilitate the detection of genes predisposing to psychiatric disorders. Although these preliminary results are encouraging, several considerations suggest that fully clarifying the genetic architecture of ADHD will require large samples. The field's experience with studies of schizophrenia and bipolar disorder show that the sample sizes collected by individual investigators can provide evidence for linkage but are not sufficient to clone disease genes. This is consistent with statistical considerations regarding the power to locate genes and the likely genetic complexity of psychiatric disorders. These considerations suggest that coordinated collaboration among investigators is needed to share findings and pool samples. The main aim of the proposed conference grant is to overcome the hurdles to collaboration by establishing yearly conferences among investigators studying the genetics of ADHD. These conferences win be held in conjunction with the annual meeting of the International Society of Psychiatric Genetics. The main goal of the conference is to establish a network of investigators who are studying or plan to study the molecular genetics of ADHD. Subgoals of these conferences are: 1. To standardize data collection methods across sites to facilitate pooling of diagnostic data.: 2. To facilitate joint submissions of large collaborative projects.; 3. To standardize DNA marker sets across sites to facilitate the pooling of genotypic data.: 4. To create a mechanism for pooling samples so that potential findings from one group can be cross-validated on the pooled data from the remaining groups.; 5. To establish rules for sharing genotypes and DNA across sites that will preserve the academic independence of each site and foster junior investigators while allowing for the pooled analysis and publication of data.; 6. To encourage women and minorities to pursue molecular genetic studies of ADHD. There are three reasons why the field needs a series of conferences to foster collaborative studies of the molecular genetics of ADHD: 1) family, twin and adoption studies show that much of the susceptibility to ADHD is mediated by genes. Hence, molecular genetic studies are justified; 2) ADHD is likely to have a complex genetic etiology which includes multiple genes that act in an additive or interactive fashion and 3) no such meeting has ever own held. Statistical considerations indicate that no one investigator is likely to have access to a sample that is sufficient to detect and clone disease genes.

data collection methodology /evaluation; disease /disorder etiology

[unreadable] DESCRIPTION (provided by applicant): Attention Deficit Hyperactivity Disorder (ADHD) is a common disorder of childhood associated with school failure, psychiatric comorbidity and psychosocial disability. Because family and twin studies suggest that ADHD has a substantial genetic component, several research groups have now begun molecular genetic studies of the disorder. These studies have already produced two replicated findings: one showing an association between ADHD and the D4 dopamine receptor gene and the other between ADHD and the dopamine transporter gene. Another well replicated feature of ADHD is its pattern of cognitive dysfunction along with structural and functional abnormalities in frontal-subcortical neural networks. Notably, the areas of cognitive deficit seen in ADHD are moderately heritable, as are the volumes of implicated brain structures. We are thus proposing a networking grant which seeks to establish collaborative partnerships among scientists who study basic behavioral processes associated with attention deficit hyperactivity disorder (ADHD) and those who study the genetics of the disorder. Thus, there are three main facts that underlie the present proposal: 1) ADHD is heritable; 2) it is associated with a pattern of cognitive dysfunction; and 3) it is associated with structural and functional brain abnormalities. These facts lead us to believe that it will be fruitful to create a network of researchers studying these domains of inquiry. The main aims of the proposed network are: 1) to provide a venue for basic and clinical investigators to initiate and explore the potential of research collaborations that focus on genetics and cognition in ADHD; 2) to identify cognitive phenotypes suitable for molecular genetic studies of ADHD; 3) to identify neuroimaging phenotypes suitable for molecular genetic studies of ADHD; 4) to design research projects aimed at finding genes that mediate the neuropsychological and neuroimaging abnormalities associated with ADHD; 5) to identify candidate genes that mediate these phenotypes; 6) to design protocols that use neuropsychological and neuroimaging methods to clarify the functional significance of gene variants implicated in the etiology of ADHD; and 7) to encourage junior investigators to develop research careers that integrate the domains of genetics, cognition and neuroimaging in ADHD.

DESCRIPTION (provided by applicant): Two domains have been robustly implicated in the etiology and pathophysiology of attention deficit hyperactivity disorder (ADHD). First, family, twin, and adoption studies have demonstrated that genetic factors play a substantial role in its etiology. Segregation analysis and molecular genetic studies have provided further support for a significant genetic component in ADHD. Second, although the details of ADHD?s pathophysiology have yet to be worked out, numerous studies have demonstrated biological abnormalities among ADHD patients. These abnormalities have been demonstrated both indirectly, as in neuropsychological assessment, and directly as in neuroimaging studies. The available data strongly suggest that a substantial component of ADHD?s etiology is mediated by gene expression in the central nervous system. However, a detailed understanding of the genetics of ADHD must overcome several hurdles. Paramount among these are the potential for genetic heterogeneity among ADHD and the likelihood that subforms of the disorder have a complex mode of inheritance. The main goal of the proposed research is to detect one or more genes responsible for the genetic transmission of ADHD. The main strategy of this proposal is to perform quantitative trait locus (QTL) sibling pair analysis using 400 microsatellite markers (simple sequence repeats, SSRs) which span the genome at 10 centimorgan (cm) intervals. This is expected to identify regions in the human genome containing QTLs for ADHD and to lay the foundations for fine mapping to identify one or more genes that mediate the susceptibility to ADHD. The three aims of the proposal are to ascertain a large sample of sib-pairs concordant and discordant for ADHD, to apply QTL linkage mapping approach to ADHD, and to create a resource for the fine mapping of ADHD genes. The project will make use of a collaborative framework in order to ascertain a total of 800 sibling pairs in eight countries. The collection of such a large international sample will provide the statistical power needed to detect the expected size of gene effects, and will create a resource of 800 nuclear families suitable for future family-based association studies and for subsequent fine mapping and genomewide association mapping of ADHD genes.

[unreadable] DESCRIPTION (provided by applicant): Attention Deficit Hyperactivity Disorder (ADHD) is a common disorder of childhood associated with school failure, psychiatric co-morbidity and psychosocial disability. Family and twin studies suggest that ADHD has a substantial genetic component and, unlike other psychiatric conditions that have produced an array of conflicting results, molecular genetic research into ADHD has produced a body of work implicating several genes in the etiology of the disorder. In the first funding cycle of this grant, we have used a family- based association study to search for variants that result in increased susceptibility to ADHD for the DRD4, SLC6A3, DRD5, SNAP25 and HTR1B genes. That work has found evidence for haplotypes of the HTR1B and SNAP25 genes as increasing susceptibility to ADHD. We have resequenced the risk haplotypes in 48 ADHD affecteds, resequencing a total of 115kb identifying a total of 350 SNPs of which 200 are novel. In this proposed renewal, we plan to confirm and extend the haplotype association results for HTR1B, SLC6A3 and SNAP25 using family-based and case-control samples. Identifying true causal variants after observing haplotypic associations presents a challenge because the SNPs sampled in a given haplotype block are correlated and may not include the causal polymorphisms of interest. Our search for susceptibility variants will focus on the following genes which show sufficient evidence for association with ADHD in our sample: SLC6A3, SNAP25, and HTR1B. We will extend our project to test the hypothesis that additional genes are associated with ADHD. For each of these genes we will: 1. Select htSNPs that characterize the haplotype structure of each gene as well as SNPs reported to be associated with ADHD in previous studies; 2. Genotype these htSNPs in our ADHD samples. 3. Perform family-based and haplotype-based analyses that are resistant to population stratification biases; and 4. Perform exploratory studies of ADHD phenotypes, gene-gene interaction and gene- environment interaction. We view our proposal as significant because, should we find gene variants that mediate susceptibility to ADHD, they will likely provide clues to the etiology and pathophysiology of the disorder. That, in turn, should facilitate the search for newer, more effective treatments for the disorder. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This is a response to RFA-DA-04-005, which requests proposals for studies that describe and evaluate innovative drug abuse phenotypes that will inform and refine investigations into genetic risk. The overall goal of this proposal is to use a multigenerational perspective and an extensive assessment of multiple domains of functioning to systematically and precisely develop familial SUD phenotypes that can be informative to genetic studies. Future molecular genetic studies may thus be more fruitful if they focus on these alternative phenotypes explicitly developed to maximize their power to detect genes. Within the context of families ascertained from a referred ADHD youth, we will determine what clinical and functional phenotypic features are more common among subjects with SUDs than those without SUDs, and whether these features are stable over time. We will then examine whether these phenotypes are transmitted through families and if the strength of this transmission is related to SUDs. We will also investigate the familial association between SUDs and comorbid mood and antisocial disorders. We will then assess the specificity of these findings by replicating these analyses in families ascertained by youth with bipolar disorder. Throughout this research, we will test the effect of gender on the expression and familiality of these novel phenotypes. Following the recommendation of the RFA, we will capitalize on existing data sources that will provide us with ample statistical power, considerable cost-effectiveness and broad generalizability. We will use several identically designed case-control family-genetic studies of youth ascertained by a diagnosis of ADHD or bipolar disorder. All studies used structured psychiatric diagnostic interviews, cognitive and neuropsychological tests and psychosocial and global functioning measures to assess the probands and their first-degree relatives. State of the art statistical techniques will be employed.

[unreadable] DESCRIPTION (provided by applicant): The GAIN program will complete a 600,000 tag SNP genome-wide association scan of 956 parent-child trios from the PI's International Multi-site ADHD Genetics (IMAGE) project. In this proposal we are requesting funds for the analysis of these data. The overarching aim of this proposal is to complete a comprehensive analysis of the whole genome scan (WGAS) data in a manner that will provide insights into the genetic etiology of ADHD and associated features. We will do this by completing the following: 1) assessing the association of GAIN SNP's with the ADHD diagnostic phenotype, 2) Imputing genotypes for siblings in the GAIN trio families, 3) Assessing the association of GAIN SNP's with the quantitative ADHD phenotypes, 4) conducting copy number analyses, 5) assessing parent of origin effects; 6) assessing season of birth effects and 7) testing for epistasis. The IMAGE project is now in the process of creating an international resource for molecular genetic studies of ADHD by sharing the study's clinical and genetic data with the scientific community through the NIMH genetic data repositories. All clinical and DNA data from our samples has been sent to the NIMH DNA and clinical data repositories for release to the scientific community. All genotype data generated by the GAIN whole genome association scan will be made available to the scientific community by GAIN as soon as the genotypes are completed. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): This application consists of five collaborative R01s submitted in response to NIMH RFA-MH-08-121, "Limited Competition for Data Deposition and Analyses of Genome Wide Association Studies of Mental Disorders (Collaborative R01)". These applications are from the Psychiatric GWAS Consortium (PGC). By the end of 2008, there will be GWAS data on 47 samples of individuals with either attention-deficit hyperactivity disorder (ADHD), autism (AUT), bipolar disorder (BIP), major depressive disorder (MDD), or schizophrenia (SCZ). Taken together, these GWAS constitute the largest biological experiment ever conducted in psychiatry - over 80,000 subjects (59,000 independent cases/controls and over 7700 family trios), ~500,000 SNP genotypes per subject, and ~40 billion total genotypes. Although the availability of GWAS data is highly attractive, there is a real risk of conflicting claims and confusion. GWAS meta-analysis for any disease is complex and requires considerable care and expertise in order to be done validly. Given the urgent need to know if there are replicable genotype-phenotype associations, a new type of collaboration is required. To accomplish these ends, we initiated the PGC in early 2007 to conduct rigorous and comprehensive within- and cross- disorder GWAS meta-analyses. The overall philosophy of the PGC is to be as inclusive, democratic, and rapid as possible. The PGC is well-underway with a coordinating committee, five disease working groups, a cross-disorder group, statistical analysis group, and a cluster computer for data warehousing and statistical analysis. 101 scientists from 11 countries and 48 institutions. It is remarkable that all but one eligible study is participating and that no one who has joined the PGC has left. The Specific Aims of the PGC are: (1) Within-disorder meta-analyses: conduct separate meta-analyses of all available GWAS data for ADHD, AUT, BIP, MDD, and SCZ to attempt to identify convincing genotype-phenotype associations. (2) Cross-disorder analyses: it is widely suspected that the clinically-derived DSM-IV and ICD-10 definitions may not have "carved nature at the joint" with respect to the fundamental genetic architecture. There are two sub-aims: (2a) Conduct meta-analysis to attempt to identify convincing genotype-phenotype associations that are common to =2 of ADHD, AUT, BIP, MDD, and SCZ. (2b) Convene an expert working group to convert epidemiological and genetic epidemiological evidence into rigorous and explicit hypotheses about overlap amongst these disorders. The analytic plan abides to current best practices for GWAS quality control and meta-analysis, particularly in its attention to investigating sources of heterogeneity. Statistical power should be superior to any prior study in psychiatric genetics. Results will be made available as soon as possible. Finally, the PGC proposes to abide as fully as possible with the NIH's GWAS data sharing policies and we provide a detailed data sharing plan and timetable. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): The proposed work addresses a key goal of NIMH Program Announcement PA-07-312, which seeks to enhance scientific understanding about the etiology of psychopathology related to violence and trauma". The almost 4000 missiles that fell within Northern Israel in the summer of 2006, the damage suffered by property and persons, and the confinement of many families in bomb shelters during the terror period created a unique 'naturalistic' laboratory for assessing the effects of PTSD caused by exposure to a circumscribed period of terror. Within this context, we will examine the health and behavior of fetuses and birth parameters of pregnant women who were residents of the North at the time of the war and test for gene and environmental moderation of fetal and birth measures. We will study two groups: (1) 150 women who are residents of cities attacked during the "war" and who meet full criteria for posttraumatic stress disorder (PTSD) as a result of their exposure to attacks, and (2) 150 women from the same cohort, who show no symptoms of PTSD. The study will be the first study to examine fetal health and behavior in pregnant women with PTSD and the first study to test for gene-based vulnerabilities and Gene x Environment on these measures. The study speaks to the impact of terror induced PTSD on fetal development, the potential transmission of biological events associated with PTSD from mother to fetus, and environmental and genetic factors that may exacerbate fetal risk. The specific aims of the study are: Aim 1. Fetal health and behavior will be adversely affected by maternal PTSD. Hypothesis 1 asserts that fetuses of mothers exposed to terror and suffer from PTSD will show signs of poorer health (stunted fetal growth measures, atypical reactivity and regulation of heart rate and torso/limb movement to challenge, and complications) and poorer birth/neonatal parameters (birth weight, head circumference, gestational age at delivery, and complications) than women who were exposed to terror, but who do not develop PTSD. We also predict an association between posttraumatic stress symptoms and outcome measures, across the sample. Aim 2. Psychosocial stresses and maternal depression predict fetal health, behavior, and stress reactivity and regulation. Hypothesis 2 posits that, among women with PTSD, psychosocial stressors (life events, chronic stressors) and maternal depression will add significant risk to their fetus. Hypothesis 3 predicts that, in the full sample, psychosocial stress and maternal depression will moderate the effects of maternal PTSD. Aim 3. Analyses of candidate gene associations with fetal/neonatal outcomes. We will evaluate the association between offspring's genotype (indexed by a battery of candidate genes) and fetal/neonatal outcomes. Hypothesis 4 predicts that variants of these genes will have main effects on infant outcomes. Hypothesis 5 predicts we will find gene-environment interactions as follows: a) risk variants implicated in hypothesis 4 will moderate the impact that mothers' PTSD and mother's psychosocial stress each have on fetal/neonatal outcomes (i.e., we expect to observe gene-environment interactions). [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE PARAGRAPH: The violence outside the home, as experienced in some US communities (sporadic and frequent) can affect anyone near by. Information regarding the relation between exposure to violence and PTSD on fetal development and birth outcome is important for understanding the processes that can promote developmental risk in communities with such violence. In this regard, the distribution of adverse reproductive health outcomes in the US and other developed nations is characterized by large racial/ethic disparities (Anachebe 2003). In the US, an almost two-fold disparity persists in the rate of premature birth between African American and non-Hispanic White women, even after accounting for obstetric, socio demographic, and behavioral risk factors (Collins & Hammond 1996; MacDorman et al 2002); and it has been suggested that differences in risk may be related to variations in stress and stress physiology (Wadwa et al 2001). The results of the proposed study, which examines genetic and environmental risk in relation to fetal health, can further understanding of individual differences in psycho- neuroendocrine processes that underlie or contribute to the risk of pre maturity and adverse neurodevelopment, and both represent major public health issues in the US. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): We are proposing to continue a multi-year conference grant that has provided a forum for researchers to pursue collaborative studies of the molecular genetics of attention deficit hyperactivity disorder (ADHD). The original application was conceived in response to a call from the NIMH for researchers to establish mechanisms for collaborating in a manner that would facilitate the detection of genes predisposing to psychiatric disorders. ADHD is a common disorder of childhood associated with school failure, psychiatric comorbidity and psychosocial disability. Because family and twin studies suggest that ADHD has a substantial genetic component, several research groups have been pursuing molecular genetic studies of the disorder. These studies have already produced several meta-analytic findings implicating the DRD4, DAT1, DRD5, SNAP-25, and 5HT1B genes in the etiology of ADHD. Although these findings are intriguing, they have not led to new pathways for treatment. Because genomewide linkage studies have been equivocal and a genomewide association scan of 938 ADHD trios found no genomewide significant associations, susceptibility genes for ADHD must, individually, have very small effects. Thus, discovering replicated associations for ADHD will require large samples and collaborative efforts. Collaborative strategies have been successful for diabetes, Crohn's disease and other complex disorders, but they required very large samples. Despite the need for collaboration, collaboration can be difficult. Many investigators are concerned that large collaborative studies will dilute the scientific impact of their work and will make it difficult for junior investigators to establish independent reputations. Moreover, when collaborations are considered, they frequently face hurdles that cannot be surmounted. For example, clinical traditions at each site often clash regarding what diagnostic instruments are appropriate for use. This leads to the creation of data sets that are not easily combined with one another. Although we have begun to work out many of these issues at prior conferences, we need to continue the series to build upon those achievements and to complete the collaborative plans laid out in prior conferences. Attention deficit hyperactivity disorder (ADHD) is the most common psychiatric disorder of childhood, affecting 8 to 12 percent of youth. The disorder creates impairments in multiple life domains including school failure, substance abuse, antisocial behavior, traffic accidents, increased non-psychiatric health care utilization, relationship difficulties and occupational failure. Although several pharmacologic and psychosocial treatments are available, these are palliative, not curative and no available treatment leads to remission of symptoms and impairments for most patients. Genetic studies are one method of discovering new biological pathways for treatment. But, because ADHD is a complex genetic disorder caused by many genes, large collaborative studies are needed for gene discovery. Thus, the goal of the proposed conference series is to overcome hurdles to collaboration by bringing ADHD genetics researchers together in a manner that promotes collaborative work.

The NIMH Research Domain Criteria (RDoC) project is intended to further a long-range goal of contributing to diagnostic systems as informed by research on genetics, neuroscience, and behavior. The Request for Applications to which we are responding encourages applications to study RDoC Constructs that cut across traditional diagnostic categories. Because RDoC Constructs are theoretical entities instantiated by behavioral and neurobiologic assessments, their validation (in the absence of a known gold standard) requires an empirical framework. This proposal seeks to apply such a framework to RDoC Constructs of the Positive Valence Systems. We will apply an updated version of the validation system proposed by Robins and Guze, which has been used for many decades as a tool for validating psychiatric constructs. We will focus on four of the five questions asked by this method: Is the Construct coherent? Is it familial? Is it associated with neurobiologic measures? Is it stable over time? Our work will answer the first three questions and will set the stage for a longitudinal study to answer the fourth. In the RDoC spirit, we will take an agnostic approach regarding nosology by ascertaining families having a child with any psychiatric disorder through referrals to our general child psychiatry clinic. We will also sample non-psychiatric comparison subjects from the community to assure that we have a wide range of scores on the RDoC Constructs represented in our study and to assess the clinical significance of Construct measures. We are adopting a clinic-based approach with appropriately matched community controls because, although the RDoC Domains are not intended to define particular disorders, any study of these domains should be more powerful when studying a sample enriched for individuals with extreme values on these traits (i.e., those with or without psychiatric disorders).2 As a consequence, we can simultaneously evaluate RDoC constructs and the predominant traditionally defined childhood psychiatric disorders in one study. Our approach is also clearly relevant to the target population of NIMH and the RDoC initiative; i.e., children and adults exhibiting impairing psychiatric symptoms. Using this sample, we will accomplish the following Specific Aims: 1) Determine if Constructs in the Positive Valence System Domains proposed by the NIMH Working Groups are homogenous theoretical Constructs; 2) Determine if Positive Valence System Constructs are familial; 3) Determine if Positive Valence System Constructs predict psychopathology and impairment; 4) Determine if Positive Valence System Constructs are associated with Construct candidate genes, with recently identified genome-wide significant cross-disorder candidate genes, and with cross-disorder polygenic scores; and 5) Establish a database of enrolled families and maintain annual contact with them to ensure the viability of longitudinal follow-up analyses.