| dc.description.abstract | High prevalence of dyslipidemia in the United States results in elevated risk of cardiovascular disease. Identifying genetic factors associated with serum lipid regulation may improve treatment and prevention of cardiovascular diseases. The high heritability of serum lipids has motivated many large-scale genetic association studies to identify genes impacting blood lipid levels. Although numerous lipid-associated genes have been identified, much of heritability of serum lipids is still unexplained. In this study, I leveraged two novel but emerging approaches, identity by descent (IBD) mapping and genetically regulated expression (GReX) association, to investigate the genetic variation that impacts serum lipid regulation. Genomic segments shared due to a recent common ancestor can be detected, and represent an untapped opportunity to identify genes that harbor low frequency, large effect variants, which were undetectable in previous studies. In addition, based on GReX, transcriptome-wide association studies (TWAS) aggregate effects of individual variants that are known to regulate gene expression, and enhance our ability to find novel lipid-associated genes. I applied these methods in two populations, a large-scale biobank with linked electronic health records (EHR) at Vanderbilt University Medical Center (BioVU) and an epidemiological study of an underrepresented population, the Hispanic Community Health Study / Study of Latinos (HCHS/SOL). Using the results of my discovery analyses, I then conducted an enrichment analysis to understand the broader clinical consequences of the identified serum lipid-related genes. I identified two significant regions enriched with IBD sharing within dyslipidemia case pairs compared to case-control pairs in BioVU (chr 5:169-171MB, and chr 22: 49.3-49.6MB), and another region in HCHS/SOL (chr1:147-152MB). From GReX-based TWAS, 776 previously reported genes were replicated, and 303 novel genes were identified. With the set of 1,079 identified genes, 68 clinical phenotypes were significantly enriched with serum lipid genes, including diabetes, heart diseases, suicide attempt and others. In summary, these resulted in novel gene discovery while highlighting the importance of innovative computational genetic approaches, especially in understudied and disproportionately affected populations. | |
