Molecular and Cellular Subtyping of Response to Drugs of Abuse in Co-morbid Psychiatric Disorders

PROJECT SUMMARY Substance use disorders (SUDs) are notoriously difficult to treat, especially when co-occurring with psychiatric conditions. However, pharmacologic treatment that effectively targets SUDs and psychiatric disorders simultaneously are lacking, and the shared mechanistic underpinnings of comorbid SUDs and psychiatric disorders remained to be elucidated. This proposal introduces an innovative framework to address this gap by systematically examining how psychiatric genetic risk factors and substances of abuse interact at molecular and cellular levels. The central questions are: (1) How are the cellular responses to drugs of abuse affected by genetic loading for psychiatric disorders? (2) Can we identify distinct molecular subtypes of SUDs arising from gene-drug interactions? These questions are driven by decades of genetic studies, including recent GWAS’s, that show overlapping genetic risk across SUDs and psychiatric disorders, pointing to pleiotropy and shared pathophysiology. Our overarching hypothesis is that genetic variants linked to SUDs and psychiatric disorders cluster into distinct “profiles” of drug response, which could serve as the molecular correlates of clinical subtypes of SUDs. This research represents a paradigm shift in addiction research by systematically interrogating the combined molecular and cellular effects of substance use and genetic loading for psychiatric risk rather than treating them separately, with greater real-world relevance. To identify molecular and cellular endophenotypes that reflect addiction subtypes, we use two complementary approaches. First, in a gene-centric approach, we will introduce specific mutations linked to SUDs and/or psychiatric disorders into isogenic iPSC-derived brain cell types and expose them to panels of drugs of abuse, as well as to soluble factors associated with these drugs. We then assess cellular response through high-dimensional assays, including molecular (e.g., chromatin state and epigenetic marks) and functional (e.g., neurotransmission) readouts. Second, in a clinical phenotype-centric approach, we will take patient cells with known SUDs and deep clinical phenotyping data. We identify “subtypes” of patients with similar cellular drug response profiles and search for genetic and molecular features that define these subtypes. This study brings high-dimensional phenotypic profiling—which has been successfully used in cancer research to develop biomarkers and predict drug response—to substance use research.