The purpose of this postdoctoral fellowship proposal is to support the applicant?s research goal of elucidating the nature of the shared genomic underpinnings of alcohol use disorder (AUD) and schizophrenia (SCZ). This will be accomplished by facilitating training in advanced statistical genetic and bioinformatics methods, as well as building a deeper clinical understanding of the etiology of problematic alcohol use, SCZ, and their comorbidity. SCZ is a rare but serious mental illness that is associated with significant personal and societal burden. AUD is more common in individuals with SCZ than in the general population and complicates the course of SCZ. Common genetic variants contribute to this comorbidity. There remain large gaps in the literature concerning the nature of the putative genetic and biological overlap between these disorders. This F32 proposal aims to (1) characterize the genome-wide genetic correlation between SCZ and AUD, examining whether their shared polygenic liability is enriched in certain categories of variation (e.g. rare vs. common alleles, regions of the genome conserved across species, genes expressed in certain tissues); (2) identify genetic variants significantly associated with both SCZ and AUD (via a cross-disorder genome-wide association study (GWAS)), and examine whether those loci are enriched in genes that show tissue-specific expression patterns or aggregate within particular biological pathways; (3) parse which aspects of alcohol use (e.g. casual drinking frequency vs. binge drinking, individual criteria related to negative emotionality vs. salience) are most associated with polygenic risk for SCZ, and investigate whether incorporating biological annotations improves the predictive accuracy of polygenic risk scores. In parallel with these research aims, this fellowship application proposes the following training objectives: (1) gain a better understanding of the genetic etiology and clinical features of AUD (including phenotype distinctions across the range of AUD symptoms), SCZ, and dual diagnosis, building a clinical knowledge base to complement the applicant?s methods-focused graduate training; (2) focused, mentored training in the latest statistical genetic and bioinformatics approaches, including cross-disorder GWAS, partitioned whole-genome heritability methods, and pathway analyses; (3); training in the responsible conduct of research (RCR); and (4) general career development including preparation of a future K01 application. The applicant will be attending courses/workshops to accomplish this training, as well as one-on-one discussions with her mentoring team, which includes two co-sponsors with addiction genetics expertise and four consultants with specific expertise in schizophrenia neurobiology and genetics, statistical genetics and bioinformatics methods development and troubleshooting, and translational genetics. The ultimate goal of this proposal is to enrich the field?s understanding of the shared genetic etiology of AUD and SCZ and position the applicant to develop into an independent investigator with the skills to build a research program at the interface of alcohol genetics and psychopathology, including schizophrenia.
Both alcohol use disorder and schizophrenia are heritable psychiatric conditions with severe negative consequences, both for the individual and society. This proposal aims to better understand which aspects of alcohol use are most related to genetic risk for schizophrenia, and what categories of genetic variation and common biological pathways underlie both disorders. The ultimate goal of this line of research is to contribute knowledge about the genetic etiology of these frequently-comorbid disorders, a key step in the advancement of therapeutic approaches, and to train the applicant in the use of multiple statistical genetic and bioinformatics approaches to study psychiatric comorbidity.
