Although genome-wide association studies (GWAS) have been extremely successful in identifying numerous germline variants associated to risk for schizophrenia and bipolar disorder, at the vast majority of these loci, the causal mechanism between genetic variation and disease risk remains unknown. This limits the development of novel drug targets and/or personalized treatments. Schizophrenia and bipolar disorder share many genetic risk loci thus motivating approaches to gain insights into the shared molecular basis of these two diseases. Post-GWAS studies are experiencing a ?big data? revolution driven by the exponentially decreasing costs of high-throughput genomic assays, including transcriptome levels, epigenetic modifications, and localization of tissue-specific regulatory sites, which are being collected in increasingly large cohorts of individuals. Here we propose a rigorous framework aimed at loci where shared or disease-specific risk for schizophrenia and bipolar disorder is mediated through alteration in gene expression levels, regulated via epigenetic control. To increase power for discovery while also facilitating validation of new findings, we will generate new disease-specific expression and chromatin variation data in subjects with known disease status. We propose to examine risk loci for schizophrenia and bipolar disorder to prioritize causal variants and genes and to validate them in functional assays.

Public Health Relevance

Genetic studies of schizophrenia and bipolar disorder have been tremendously successful in identifying regions in the genome harboring genetic susceptibility for disease but the underlying biological mechanisms remain elusive. In this proposal we will develop and apply new statistical and experimental methods to identify causal risk alleles and genes with their underlying mechanisms that contribute to the shared and disease- specific risk of these common neuropsychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH115676-03
Application #
9852552
Study Section
Behavioral Genetics and Epidemiology Study Section (BGES)
Program Officer
Koester, Susan E
Project Start
2018-04-01
Project End
2023-01-31
Budget Start
2020-04-07
Budget End
2021-01-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Freund, Malika Kumar; Burch, Kathryn S; Shi, Huwenbo et al. (2018) Phenotype-Specific Enrichment of Mendelian Disorder Genes near GWAS Regions across 62 Complex Traits. Am J Hum Genet 103:535-552