PROJECT SUMMARY/ABSTRACT Trichotillomania (hair pulling) and excoriation (skin picking) disorder are debilitating, difficult-to-treat obsessive-compulsive disorder (OCD) spectrum conditions with no first-line pharmacologic interventions. Previous work supports the role of shared genetic factors in the development of these body-focused repetitive behaviors (BFRBs), but progress in identifying BFRB risk genes and biological pathways has been slow. The scientific objective of this K08 award application is to use a series of complementary, unbiased state-of-art neurogenetic approaches to advance our understanding of the genes and pathways that underly BFRBs, which is an important step towards developing improved treatments. Completion of this K08 proposal will provide Dr. Olfson with critical new training in several key areas to achieve her long-term career goal of becoming an independent investigator in neurogenomics. Our central hypothesis is that damaging DNA sequence and structural variants are enriched in individuals with BFRBs compared to controls, and iSPC brain organoids can shed light on convergent neurodevelopmental mechanisms. Guided by strong preliminary data generated by Dr. Olfson from whole-exome DNA sequencing (WES) in BFRB parent-child trios, this hypothesis will be examined in 3 specific aims. In Aim 1, we propose expanding our BFRB cohort to conduct WES in 200 parent-child trios. We will (i) compare de novo and rare inherited WES mutation rates between case and control trios, (ii) examine shared sequence variant genetic risk across the OCD spectrum using 400 previously sequenced OCD trios, and (iii) integrate systems analyses to identify biologic pathways, gene networks, and expression patterns. In Aim 2, Dr. Olfson will develop new skills in analyzing copy-number variants (CNVs) by conducting the first genome-wide CNV study of BFRB parent-child trios. We will (i) compare the de novo and rare inherited CNV burden in the BFRB and control trios, (ii) examine CNVs across the OCD spectrum, and (iii) integrate CNV data with results from Aim 1 for recurrence and enrichment in systems analyses. In Aim 3, Dr. Olfson will expand her skill set in iPSC brain organoids to assess early neurodevelopmental mechanisms of BFRBs. We will characterize iPSC brain organoids derived from 4 patients and unaffected sex-matched first- degree relatives to compare (i) neural differentiation and (ii) transcriptomics by single-cell RNA-sequencing. Overall, this K08 proposal will not only improve our fundamental knowledge of BFRB neurobiology, but also provide Dr. Olfson with vital training necessary to develop an independent neurogenomics research program to continue her investigations of BFRBs and other neuropsychiatric conditions. This training plan involves a multi-disciplinary mentoring team based primarily at the Yale Child Study Center with expertise in genomics (Dr. Fernandez and Dr. Scharf), iSPC brain organoids (Dr. Vaccarino and Dr. Fernandez), an...