Anna R. Docherty, Ph.D. - US grants

DESCRIPTION (provided by applicant): The applicant's long-term goal is a successful academic career in clinical psychology. This training grant will enable the applicant to develop a program of research focusing on translational research applying models of genetic vulnerability to research on the treatment-refractory negative symptoms of schizophrenia. There is growing need for association studies targeting endophenotypes in the search for the underlying biological mechanisms of schizophrenia. There evidence that one endophenotype, anhedonia, or the extent to which an individual reports pleasure or interest in social and physical stimuli, is associated with genetic liability to schizophrenia, and with differences in prodromal vulnerability to schizophrenia-spectrum disorders. Anhedonia has been most predictive of schizophrenia-spectrum disorders of any self-reported schizotypal symptom in multiple longitudinal studies. It has also been the only self-reported schizotypal trait to consistently differentiate first-degree relatives of people with schizophrenia from controls. In people with schizophrenia, anhedonia indicates poorer prognosis of the illness and poorer functional outcome. Despite its importance as an endophenotype, it has been unclear how anhedonia might directly relate to the neurobiological substrates of schizophrenia. Currently, there is evidence that anhedonia is associated with differences in emotion processing, specifically with decreased positive affect intensity. However, no one has yet studied this association in patients or their first-degree relatives. In addition, there is evidence for genetic underpinnings of anhedonia in first-degree relatives. First, aberrant dopamine transmission may relate to the processing of positive emotion, and is implicated in symptoms of schizophrenia and in genetic vulnerability to psychosis. One prior study has found that relatives with a high-activity polymorphism of the Val158Met catechol-o-methyl-transferase (COMT) gene, responsible for the inhibition of dopamine, have higher levels of self-reported anhedonia. Second, there is now evidence that anhedonia may be related to disrupted-in- schizophrenia-1 (DISC1) gene expression in humans, a gene that influences hippocampal function. However, possible associations of anhedonia with candidate single nucleotide polymorphisms have rarely been examined in first-degree relatives of people with schizophrenia. It is important to examine both emotion processing in anhedonia and endophenotype-genotype associations, to develop a better understanding of this treatment-refractory symptom. NIMH is currently seeking the unification of advanced statistical methodologies and enhancements in measurement that will facilitate the reduction of heterogeneity and further the search for the genetic basis of psychopathology. This study attempts to address that aim. PUBLIC HEALTH RELEVANCE: The current research has the potential to inform both prevention efforts and treatment for people with schizophrenia. Understanding the relationship between specific genetic mechanisms and subclinical schizotypal symptoms in first-degree family members, as well as the relationship between negative symptoms and affective processing in genetic liability to schizophrenia may impact both psychological and pharmacological treatments for schizophrenia. Moreover, understanding these mechanisms may help to improve functional outcome in people with schizophrenia, since anhedonia has been strongly associated with functional outcome.

? DESCRIPTION (provided by applicant): Schizophrenia (SZ) represents a significant and costly public health burden. Recently, we have witnessed the emergence of the first molecular insights into the etiopathogenic mechanisms of SZ, via the first genome-wide association studies (GWAS) with sufficient case-control sample sizes to detect allelic effects. Importantly, a polygenic signature, which includes genome-wide significant common genetic variants of small effect, has been clearly demonstrated to influence SZ risk. The availability of well-defined risk factors makes it possible, for the first time, to address several critical questions about the genetic architecture of SZ and its component phenotypes and endophenotypes. The overarching goals of this K01 proposal are 1) to test polygenic risk score prediction of dimensional SZ and schizotypy phenotypes across large case, high-density SZ pedigree, and prodromal-aged GWAS samples, and 2) to develop and test, with leaders of the Psychiatric Genomics Consortium, innovative statistical methods to identify and characterize genetic subtypes of SZ. This proposal delineates a series of training and research goals for the candidate that incorporates strengths from phenotypic assessment, statistical genetics, and molecular genetics and combines samples reflecting a broad range of genetic risk. The candidate will capitalize on previously established expertise in schizotypy and clinical risk assessment, as well as expertise in the familial transmission of dimensional traits, to establish a program of translational research wherein the application of statistical genetic/bioinformatic techniques to genetic subtyping analyses will be used to generate promising candidates for further exploration in human genomic data. Empirically-based genetic subtyping methods will be developed and tested in the largest SZ case sample to date, and subtypes will be characterized with respect to dimensional phenotypic traits. Top loci hits in subtype analyses of dimensional symptoms will be validated in secondary analyses of differential gene expression in post-mortem SZ brain. This will allow for a detailed analysis of function at both the SNP and gene levels, and will provide the candidate with substantive training in both statistical and molecular genetics methods. The institutional environment is ideal for the candidate's goal of developing a comprehensive program in SZ research, and the proposed research represents an important contribution toward advancing the understanding of SZ through a combination of clinical, statistical, molecular, and translational methods, consistent with the mission of the NIMH.

PROJECT SUMMARY The current proposal seeks to clarify the mechanisms underlying suicide death. Suicide constitutes a severe and steadily worsening public health crisis, and suicide prevention has become a primary focus of NIMH efforts. Aggregated data across multiple large genetic studies yield heritability estimates of suicide death at approximately 45%. However, research on risk factors to date has been largely confined to epidemiological observations, with a lack of access to molecular genetic data on suicide death. This lack of access has resulted in an overwhelming focus on the genetic study of subthreshold phenotypes?ideation and attempt? which very rarely result in suicide. Currently, positive predictive values for suicide attempt are high (.9), while positive predictive values for suicide death continue to hover near zero. This research team has unprecedented access to DNA from thousands of independent, population-based suicide deaths from the Utah Office of the Medical Examiner. DNA resources are enhanced by a wealth of electronic medical record and environmental exposure data on all suicides, using the Utah Population Database, a unique resource of >10 million residents. Due to the extreme and unambiguous nature of suicide relative to psychiatric phenotypes, genotyping and genome-wide association analysis of the first 3,413 cases and 14,848 matched controls has already resulted in genome-wide significant signals and strong polygenic signal. Five novel, rare missense SNPs are also significantly associated with suicide death in these preliminary data. By genotyping additional and incoming suicide deaths, this project aims to replicate and significantly expand on genetic discoveries. In addition, approximately 20% of the population-based suicides evidence significant ancestry admixture, providing valuable diversity to enhance both discovery and generalizability. This research team will work closely in partnership with the Psychiatric Genomics Consortium and UK Biobank to examine new data on suicide death, test clinically informative risk models, and leverage large external cohorts to model complex suicide etiologies. Some of the high-impact deliverables from this project include a) comprehensive co- morbidity, mode of death, and risk factor statistics from the largest population-based suicide cohort to date, b) the first genome-wide data and summary statistics for suicide death, linked to a wealth of risk phenotypes, polygenic risks, and diagnoses (e.g., ADHD, affective disorders, alcohol use disorder, autism spectrum disorder, pain, mania, metabolic conditions, opiate use, pregnancy, psychosis), c) genetic correlation estimates of suicide death with a range of phenotypes, for the development of genetic risk models, and d) clinically informative genetic and environmental predictors of suicide, accounting for sex, ancestry, and age.