NIMH Diversity Supplement Parent grant: 5R01MH130609-02 Principal Investigator: Christopher Pittenger MD PhD Trainee: Enock B. Teefe MD PROJECT SUMMARY: Obsessive-Compulsive Disorder (OCD) and tic disorders, including Tourette Syndrome (TS) are severe neuropsychiatric conditions thought to involve disrupted dopamine signaling within cortico-basal ganglia neural circuits. Despite this association, existing neuroimaging research on D2 and D3 dopamine receptor binding has yielded inconsistent results, possibly owing to poorly understood genetic variations that affect dopamine function. This proposed supplement aims to fill this knowledge gap by augmenting an existing parent grant (5R01MH130609), which utilizes positron emission tomography (PET) with 11C-PHNO to study D2/D3 receptor binding in adults with OCD and tics (15 OCD, 15 OCD+tics, 15 tics, 15 controls). In Aim 1, the supplement proposes whole-genome sequencing for all study participants, enabling the calculation of polygenic risk scores specifically for OCD and TS. This will allow for investigations into the association between common genetic risk factors and D2/D3 receptor binding potential. Aim 2 involves generating dopamine receptor polygenic co- expression indices based on post-mortem human brain gene expression data. This will enable us to test whether co-expression modules involving dopamine receptor genes (DRD2 and DRD3) affect dopamine binding within basal ganglia regions. Aim 3 will focus on understanding the distinct impact of genetic variants within canonical dopamine-related genes on D2/D3 receptor binding. Additionally, exploratory analyses will be conducted to examine the contributions of rare genetic variants to D2/D3 receptor binding. Overall, this supplemental study employs an innovative imaging-genetics integration approach, leveraging whole-genome sequencing to understand the complex genetic factors that influence dopamine receptor alterations pertinent to OCD and tic pathophysiology. The findings are expected to inform the development of much needed novel, targeted therapeutic interventions. Concurrently, the study will offer specialized mentoring and training in statistical genetics and multi-omic data integration, providing the trainee with valuable skills essential for a productive career in translational neurogenetics research.