Genetic Risk for Developmental Expression of Neuropsychiatric Intermediate Traits

University Of California Los Angeles, Los Angeles CA

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Abstract

? DESCRIPTION (provided by applicant): There is growing evidence that neurodevelopmental factors play a key role in the susceptibility to severe neuropsychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BP) that typically have full symptomatic onset in late adolescence or early adulthood. Identifying the earliest biomarkers of these illnesses is particularly critical, given that overt symptom onset may be a late manifestation of the actual disease processes. The Philadelphia Neurodevelopmental Cohort (PNC), an ethnically diverse, population-based sample of over 9,000 youth ages 8-21 from the greater Philadelphia area, offers a unique resource in which to investigate the genetics of neurodevelopmental intermediate phenotypes of psychiatric disorders in children and adolescents. Here, our first aim is to leverage data from the largest studies of the Psychiatric Genomics Consortium - a platform for major discoveries of genetic risk factors for these neuropsychiatric disorders - in order to investigate the shared genetic burden of SCZ and BP in adults with psychotic and mood spectrum disorders that present in youth, and with neurobehavioral (endo)phenotype data in the PNC. We will then define risk groups based on polygenic risk scores for SCZ and BP, in order to investigate the developmental time-course of the expression of traits associated with genetic liability to these disorders. Given the ethnic heterogeneity of the PNC cohort, we will also apply novel population genetics methods to examine the effect of genetic admixture on polygenic risk, and its association with intermediate phenotypes. In our second aim we will apply new methods for estimating genetic distance between unrelated individuals to determine the genetic and environmental covariance between neurocognitive traits and clinical symptoms in PNC cohort members. We will then investigate the stability of genetic and environmental contributions to overall trait variance in pre- and post-adolescent age groups, to provide insight regarding developmental epochs in which environmental factors may play a greater role. Finally, we will utilize the resources of the Encyclopedia of DNA Elements (ENCODE), NIH Epigenomics Roadmap, and expression QTL data of many different cell types from the Genotype-Tissue Expression (GTEx) Consortium, in order to obtain functional genomic insights about the most genetically informative candidate traits in the PNC. Using these resources we will identify specific functional pathways and cell types that play a critical role in the etiology of these trais.