Neurogenetic Investigations of Obsessive-Compulsive Disorder

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Obsessive-compulsive disorder (OCD) is a disabling early-onset neuropsychiatric disorder with unclear underlying pathophysiology, which has hindered the development of new treatments and interventions. While there is a clear genetic contribution to OCD risk, decades of investigations have yet to yield reproducible, statistically significant findings that have identified high-confidence risk genes. Progress in leveraging genetics to clarify biology has likely been impeded by multiple factors, including a narrow focus on common genetic variants with small effect sizes, underpowered study designs, general uncertainty about the spectrum of genetic variation that should be queried, and limited attention to downstream gene expression and associated epigenetic signatures that drive gene expression in relevant tissue. There is a critical need for further efforts using alternate approaches to identify and confirm risk genes that will provide insights into OCD biology. The overall objective of the current proposal is to use high-throughput sequencing approaches to identify OCD risk genes, detect gene expression differences in OCD, and determine epigenetic signatures driving gene expression in OCD brain. This will be accomplished by pursuing three specific aims. Aim 1 proposes to (a) identify high-confidence risk genes by whole-exome sequencing and de novo genetic variant detection in 500 OCD parent-child trios and 500 control trios; (b) replicate these analyses with collaborator data from 475 OCD trios and 1,000 OCD probands; and (c) integrate OCD risk genes into systems analyses to identify enriched gene networks, pathways, and spatiotemporal expression patterns. Aim 2 proposes to identify somatic mosaic variants in exome sequencing data from all OCD and control trios, and from peripheral blood and brain tissue from 10 OCD subjects. Aim 3 proposes identification of differentially expressed genes and chromatin signatures in brain tissue from 10 OCD and 10 matched control subjects using RNA-seq, ChIP-seq, and ATAC-seq. The proposed research attempts to close gaps in our knowledge of OCD biology by a series of studies that specifically addresses Objective 1 of the NIMH Strategic Plan (defining the mechanisms of complex behaviors). If successful, this research will transform our understanding of the underlying mechanisms of OCD and identify points of traction for mechanistic studies in model systems, ultimately leading to novel therapeutics, and reducing the significant morbidity and mortality associated with this disabling illness. Furthermore, insights gained in these studies can inform gene discovery approaches to other complex neuropsychiatric disorders.