James J. Crowley - US grants

DESCRIPTION (provided by applicant): In this project, the candidate proposes to elucidate the genetic basis of important antidepressant response phenotypes in a pre-clinical system, recombinant-inbred intercrosses (RIX) from the Collaborative Cross (CC) mouse lines. Experiments will be performed using fluoxetine (Prozac), a highly prescribed antidepressant. While fluoxetine does not have major side effects, only about 50% of patients experience a therapeutic response. First, we will expose adult male RIX to human-like steady state concentrations of fluoxetine (250 exposed, 250 control cage mates) and assess changes in two phenotypes relevant to antidepressant response in rodents: behavioral despair in the tail suspension test and quantitative measures of hippocampal neurogenesis. For each of these traits, we will use existing genomic data to conduct genome-wide association mapping and pathway analysis. Second, we refine these associations using new and powerful ways to assess the hippocampal dentate gyrus transcriptome and methylome (next generation sequencing technologies). Third, we test the predictive validity of these genetic and molecular biomarkers by generating novel animals expected to show high or low fluoxetine sensitivity (N=10 RIX each). This pre-clinical systems pharmacogenomics project is powered to identify key genes regulating response to fluoxetine in mice. Follow- up work will then examine these candidate genes in human clinical trial samples.

DESCRIPTION (provided by applicant): Schizophrenia (SCZ) is a highly heritable psychiatric disorder with an elusive pathophysiology and few novel treatments under development. Our understanding of the biological basis of SCZ would be greatly accelerated by the isolation of a substantial number of precise causal mutations that influence risk. Copy number variants (CNVs) are an attractive source for causative mutations since, by altering gene dosage or structure, they provide a clear direction of effect and molecular mechanism. We propose to leverage the power of multiple technologies and large samples used in the Large-Scale Swedish Schizophrenia Association Study funded by NIMH to identify gene- and exon-level CNVs associated with SCZ. Our overarching goal is to discover risk loci resulting from changes in copy number in specific genes that could lead to improved understanding of SCZ. First, we will combine multiple CNV call sets from complimentary technologies to identify gene- and exon-level CNVs nominally associated with SCZ. Data available include genome-wide SNP, exome genotyping arrays and exome sequencing in 5,001 SCZ cases and 6,234 controls. Second, we will integrate the normalized raw data from all three datasets to construct a virtual array and use a specialized hidden Markov model (VAMM) to survey genic CNVs to yield high-density CNV calls. Third, we will create a prioritized list of gene/exon level CNV associations with SCZ and validate 50 putative CNVs using a precise and high sensitivity independent methodology. Finally, we will evaluate whether validated CNV regions associate with SCZ beyond chance by querying existing genomic data available from a distinct set of 20,000 cases and 20,000 controls. To date, only a few specific genes have been implicated via CNV analysis, all of which provided novel insights into SCZ pathophysiology. We contend that these genes are the tip of an iceberg and the current deficiency is simply attributed to the lack of methods for gene-focused CNV evaluation. If this R21 study can identify even one new exon- or gene-level CNV whose dosage alters SCZ risk, it will represent an important advance in our understanding of the biological basis of SCZ. Any identified CNV would provide the basis for an R01 application to understand the mechanisms linking its dosage to SCZ risk.

DESCRIPTION (provided by applicant): Here we seek to understand how genetic and environmental factors jointly influence the risk of developing two highly co-morbid neuropsychiatric disorders, Tourette's Syndrome (TS) and Obsessive- Compulsive Disorder (OCD). These disorders are of major public health importance owing to their profound personal and societal costs. Little is known for certain about their etiology, and treatment, detection and prevention strategies are not optimal or directed by knowledge of pathophysiology. In other psychiatric disorders (e.g., schizophrenia, bipolar disorder and autism), genomics has begun to deliver fundamental knowledge about genetic architecture, identify specific loci for biological follow-up and localize pathways altered in disease. We intend to realize these same advances for TS and OCD by markedly increasing the worldwide sample size for genomic analysis of both disorders, in a first step toward elucidating the fundamental biology of these related conditions. Four overlapping areas will be investigated in this project. First, we will discover genomic loci harboring common and rare variation associated with TS and OCD. We propose to quadruple the sample size of published TS and OCD genome-wide association studies (GWAS), in a rapid and cost-effective manner by utilizing archived blood spots from Denmark. Second, we will discover replicable structural variants (CNVs) associated with TS and OCD. Disease-associated CNVs are attractive causative mutations since, by altering gene dosage or structure, they provide a direction of effect and molecular mechanism. Third, we will identify shared genetic risk factors for TS, OCD and its major comorbidities. Here we test whether clinical comorbidity equates to genetic comorbidity. Finally, we will identify gene by environment interactions predisposing individuals to TS and OCD. We have access to a wealth of longitudinal medical registry data for every individual that will be genotyped in this study. This creates an extraordinary opportunity to identify gene by environment interactions. In sum, this project could add a high-impact understanding of how genetic and environmental factors jointly influence risk of TS and OCD, and lead to new mechanistic hypotheses.

PROJECT SUMMARY In this study we seek to understand how genetic and environmental factors jointly influence both the risk of developing Obsessive-Compulsive Disorder (OCD) and the outcome of treatment interventions. OCD and related disorders are of major public health importance owing to their profound personal and societal costs. Little is known for certain about their etiology, and treatment, detection and prevention strategies are not optimal or directed by knowledge of pathophysiology. In other psychiatric disorders (e.g., schizophrenia, bipolar disorder and autism), genomics has begun to deliver fundamental knowledge about genetic architecture, identify specific loci for biological follow-up and localize pathways altered in disease. We intend to realize these same advances for OCD by markedly increasing the worldwide sample size for genomic analysis, in a first step toward elucidating the fundamental biology of this condition. Three overlapping areas will be investigated in this project. First, we will collect the world's largest richly phenotyped sample of OCD cases (N = 10,000). To do this in an efficient and cost-effective manner, we will take advantage of an ongoing nationwide OCD treatment study in Norway and a network of active OCD clinics in Sweden. The phenotypes will include a detailed clinical characterization (e.g., comorbidities, symptom dimensions, treatment response) and links to the Swedish and Norwegian registers, facilitating gene by environment interaction studies. Second, we will genotype all 10,000 samples on the PsychChip GWAS array (genotypes for >30,000 matched controls are already available). This will allow us to discover genomic loci harboring common and rare variation associated with OCD. We will also incorporate a novel comparative genomic approach to interpret these genomic data, capitalizing on an animal model with high face and construct validity: canine compulsive disorder. Third, we will calculate individual risk profile scores (GRS) as a measure of genetic liability to OCD and test for interactions between genetic liability and a range of clinical (e.g., response to treatment), epidemiological (e.g., paternal age, obstetric complications, early life adversity, socioeconomic status) and genetic epidemiological (e.g., family history) variables from the Swedish and Norwegian registers. We expect this study to improve our understanding of the causal mechanisms implicated in OCD, with a view towards improving clinical outcomes and reducing chronicity and societal costs.

PROJECT SUMMARY Recent research has indicated that individuals diagnosed with a major psychiatric disorder are more likely than healthy individuals to select a mate with their own or an alternative psychiatric condition. What role this nonrandom mating may play in the transmission of psychiatric illness, however, remains unclear. Where parents are homotypic for a disorder (e.g., both parents have a diagnosis of schizophrenia), offspring will receive genetic variants from each parent that are related to that disorder ? placing them at particularly high genetic risk for that condition's development. However, this type of compounded genetic risk may also occur in heterotypic pairings (e.g., one parent having schizophrenia, the other bipolar disorder), as many psychiatric conditions share genetic risks. With prior research suggesting that such heterotypic pairings are pervasive in psychiatric populations, understanding the degree to which risks are sustained in these offspring is an important question. The primary goal of this proposal is, therefore, to leverage the unique scale of data available in the Swedish Medical Registers to determine the change in risk for major psychiatric diagnoses, among the offspring of parents who are homotypic or heterotypic for major psychiatric diagnoses, relative to the risk in offspring of single affected or healthy parents. Parents with any of eight major psychiatric diagnoses - attention deficit hyperactivity disorder, bipolar disorder, generalized anxiety disorder, major depressive disorder, obsessive- compulsive disorder, schizophrenia, social phobia, and substance abuse ? will be considered in this work, with the incidence of these conditions in their offspring compared to the incidence in matched population controls. In addition to describing these risks, this project also proposes to examine the degree of overlap in risk variants for a particular condition ? schizophrenia ? among the parents of offspring diagnosed with this condition. If found, this type of molecular correlation would signal a clear mechanism by which a disorder may arise in offspring of homo- or heterotypic pairs, while its absence could suggest a stronger role for environment in shaping these added risks.

PROJECT SUMMARY In this study we seek to understand how genetic factors influence the risk of developing obsessive-compulsive disorder (OCD) in Latin American individuals. OCD and related disorders are of major public health importance owing to their profound personal and societal costs. Little is known for certain about their etiology, and treatment, detection and prevention strategies are not optimal or directed by knowledge of pathophysiology. In other psychiatric disorders (e.g., schizophrenia, bipolar disorder, and autism), genomics has begun to deliver fundamental knowledge about genetic architecture, identify specific loci for biological follow-up and localize pathways altered in disease. We intend to realize these same advances for OCD by markedly increasing and diversifying the worldwide sample size for genomic analysis, in a first step toward elucidating the fundamental biology of this condition. Three overlapping areas will be investigated in this project. First, we will collect the world?s largest ancestrally- diverse sample of OCD cases (N = 5,000 individuals from Latin America). To do this in an efficient and cost- effective manner, we will take advantage of a network of OCD clinics we have established across Latin America, in addition to clinics in the USA and web-based recruitment. The phenotypic data collected will include a detailed clinical characterization including comorbidities and OCD symptom dimensions. Second, we will genotype all 5,000 samples on the Illumina Global Screening Array (genotypes for >10,000 matched controls will be available). This will allow us to, in collaboration with the Psychiatric Genomics Consortium, discover genomic loci harboring common variation associated with OCD. Third, we will fine-map genome-wide significant loci and calculate individual polygenic risk scores (PRS) as a measure of genetic liability to OCD. We expect the new inclusion of ancestrally diverse samples to improve our fine-mapping ability, to yield more accurate PRS in non-European samples and ultimately to reduce health disparities when OCD genomic findings are used clinically. Overall, this study will improve our understanding of the causal mechanisms implicated in OCD, with a view towards improving clinical outcomes and reducing chronicity and societal costs.

Project Summary In this study we seek to understand how rare genetic variation in all protein coding genes (the exome) influences the risk of developing obsessive-compulsive disorder (OCD). OCD is of major public health importance owing to its profound personal and societal costs. Little is known for certain about its etiology, and treatment, detection and prevention strategies are not optimal or directed by knowledge of pathophysiology. In other psychiatric disorders (e.g., autism, intellectual disability, schizophrenia, ADHD), whole exome sequencing (WES) in large numbers of subjects has begun to deliver fundamental knowledge about genetic architecture, identify specific loci for biological follow-up and localize pathways altered in disease. We intend to realize these same advances for OCD by markedly increasing the worldwide number of OCD subjects with WES data, in a first step toward elucidating the fundamental biology of this condition. Three overlapping areas will be investigated in this project. First, we will produce WES data from 5,100 OCD subjects and 3,000 ancestry-matched controls, all from Sweden and Norway. Sequencing individuals from these countries provides the substantial advantage of knowing about co-morbid conditions. We will call rare genetic variation from the sequencing data. Second, we will combine these new data with existing WES data for ~1,400 OCD cases and ~8,000 controls. This will increase power to identify OCD risk genes, which we will do using a combination of existing and novel analytical methods. Third, we will further refine our understanding of the genetic architecture of OCD, focusing on the relationship of OCD risk to risk for other neurodevelopmental disorders, including tic disorders, autism, ADHD, schizophrenia and bipolar disorder. Combining WES data from multiple large studies will enhance power to identify shared loci and begin to identify loci with greater specificity for OCD. Overall, we believe this study will improve our understanding of genetic risk factors for OCD, with a view towards improving clinical outcomes and reducing chronicity and societal costs.