Wednesday, January 15, 2025
1/15/2025
DESCRIPTION (provided by applicant): The International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome (22q11DS) is a collaborative RO1 of 22 institutions, with one genomic and four phenotyping leading sites. The collaboration combines genomic with neuropsychiatric and neurobehavioral paradigms to advance the understanding of the pathogenesis of schizophrenia (SZ) and related phenotypes. The Consortium provides the largest available sample to date of 1000 genetically and phenotypically characterized individuals with 22q11DS. There is a substantial risk for developing SZ in adolescents and young adults with 22q11DS (~25-30%), with illness presentation and course similar to SZ in the general population (~1%). Consortium sites have established collaborations with extensive experience in applying integrative genomic and brain-behavior strategies to study 22q11DS and SZ across the lifespan. We will examine neuropsychiatric features through an integrated consensus focusing on SZ and emergence of psychosis. Neurobehavioral measures will be investigated across domains, establishing their relation to psychosis (Specific Aim 1). We will conduct whole genome sequencing (WGS) on 600 individuals with 22q11DS to uncover genetic variation that may contribute to the heterogeneity of neuropsychiatric and neurobehavioral phenotypes of SZ and psychosis. The convergence of phenotypic and genomic measures in adult and pediatric populations will permit examination of shared genetic variants that influence the expression of SZ and early psychosis. We will perform WGS on 300 adults using phenotypic "extremes": 150 22q11DS individuals with SZ and 150 22q11DS individuals without psychotic symptoms, as well as 300 pediatric participants with 22q11DS phenotyped by cognitive decline and psychosis proneness. This will be followed by association analysis on all common SNPs and CNVs in the entire sample. The discovered genomic variation will be followed in non-deleted SZ GWAS (Specific Aim 2). As diverse approaches and instruments are applied in assessing neuropsychiatric and neurobehavioral phenotypes in 22q11DS, the Consortium can advance the field by developing and piloting common measures that tap major dimensions of psychopathology and brain function. This will enhance the integration of phenotypic and genomic data, lay the foundation for a systematic approach internationally and provide a framework for longitudinal studies. This approach will cohere with RDoC and integration of genomic and neuroscience paradigms (Specific Aim 3). The resource built by the international Consortium will be a platform for data sharing as tools created, specimens collected and high fidelity data are placed in the public domain (Specific Aim 4). The proposed project will be an unprecedented international initiative to examine a common deletion associated with SZ and elucidate its genomic and behavioral substrates. Beyond the potential for yielding a better understanding of a severe manifestation of 22q11DS, the results will help identify pathways leading to SZ in the general population in a way that will inform novel treatments.
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