Friday, December 27, 2024
12/27/2024
¿ DESCRIPTION (provided by applicant): Obsessive-compulsive behaviors (OCB) are common in children and adolescents. In addition to being the core features of obsessive-compulsive disorder (OCD), OCB are often associated in youth with tic, grooming, generalized anxiety, and autistic spectrum disorders. This competitive renewal application combines the unique clinical assessment, magnetic resonance imaging, and genetics expertise of three performance sites: Wayne State University (WSU), University of Michigan (UM), and the Hospital for Sick Children, affiliated with the University of Toronto (UT). The overall goal of this project - which extends prior and existing NIMH-funded research including Drs. Rosenberg and Diwadkar's neurodiagnostic imaging-genetic studies (K24MH02037; R01MH59299), Dr. Hanna's family, molecular genetic, and action monitoring studies (R01MH53876; R01MH59299; K20MH01065; R01MH101493) and Dr. Arnold and colleagues' extensive genetic studies in pediatric OCD (R01MH59299; R01MH101493) - is to exploit the emerging field of imaging genetics to 1) determine the relationship between alterations in functional connectivity of fronto-striatal-thalamic circuitry (FSTC) as measured by task and resting state functional magnetic resonance imaging (fMRI) and childhood OCB; 2) identify common, rare, and novel genetic variants associated with alterations in connectivity of FSTC as measured by fMRI; 3) clarify whether fMRI measured alterations in FSTC are potential intermediate phenotypes of OCB by determining whether they mediate the effects of genetic variants on OCB; and 4) combine structural MRI data from this study and our previous imaging genetics study to identify genetic variants associated with anterior cingulate volume and other FSTC structures in 1000 youth. The Child Behavior Checklist Obsessive-Compulsive Scale (CBCL-OCS) shows substantial heritability in pediatric twin studies. Heritability of structural and functional abnormalities in STC has also been demonstrated in OCD patients and their unaffected relatives. By using a research design consistent with the Research Domain Criteria (RDoC), targeted high field (3 Tesla) fMRI at WSU will be combined with comprehensive genomic assessment in 200 child psychiatric outpatients with CBCL-OCS scores = 5, 200 child psychiatric outpatients with CBL-OCS scores < 5, and 200 matched healthy controls aged 8-18 years. We will examine for common and rare genomic variants associated with FSTC dysregulation and conduct whole genome sequencing (WGS) in 60 subjects with FSTC dysregulation in the highest 10% of the distribution and compare to 60 subjects with FSTC dysregulation in the lowest 10% of the distribution to identify rare and novel variants of possible clinical significance. This unique study enacts the call for translational approaches to mental illness outlined in PAR- 14-165 by examining multiple genomic variants in FSTC in a spectrum of common, but understudied disorders in youth. Our work will provide a better understanding of the impact of genetic variants on FSTC dysregulation in the pathogenesis of OCB and lead to new diagnostic, treatment, and prevention strategies.
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