Project description:The Institute for Personalized Medicine (IPM) Biobank Project is a consented, EMR-linked medical care setting biorepository of the Mount Sinai Medical Center (MSMC) drawing from a population of over 70,000 inpatients and 800,000 outpatient visits annually. MSMC serves diverse local communities of upper Manhattan, including Central Harlem (86% African American), East Harlem (88% Hispanic Latino), and Upper East Side (88% Caucasian/white) with broad health disparities. IPM Biobank populations include 28% African American (AA), 38% Hispanic Latino (HL) predominantly of Caribbean origin, 23% Caucasian/White (CW). IPM Biobank disease burden is reflective of health disparities with broad public health impact: average body mass index of 28.9 and frequencies of hypertension (55%), hypercholesterolemia (32%), diabetes (30%), coronary artery disease (25%), chronic kidney disease (23%), among others. Biobank operations are fully integrated in clinical care processes, including direct recruitment from clinical sites, waiting areas and phlebotomy stations by dedicated Biobank recruiters independent of clinical care providers, prior to or following a clinician standard of care visit. Recruitment currently occurs at a broad spectrum of over 30 clinical care sites. Minorities are strikingly underrepresented in GWAS, including Coronary Artery Disease (CAD) and Chronic Kidney Disease; multigenic genetic risk scores for CAD have been recently validated in European ancestry populations, but not in AA or HL populations. Several important opportunities exist for extending additional GWAS to minority populations with a shared risk spectrum of CAD and CKD. For example, progressive CKD is a major and independent risk factor for CVD with an inverse relationship between estimated GFR (eGFR), and risk for mortality and cardiovascular events. This increased risk is only partially explained by the prevalence of cardiovascular risk factors among these patients. We conducted a GWAS of CAD and CKD related phenotypes in IPM Biobank with the primary objective to explore the genetics of overlapping CAD and CKD predominantly in minority populations characterized by increased risk.

Project description:Genome-wide association studies (GWAS) have discovered thousands of risk loci for common, complex diseases, each of which could point to genes and gene programs that influence disease. For some diseases, it has been observed that GWAS signals converge on a smaller number of biological programs, and that this convergence can help to identify causal genes. However, identifying such convergence remains challenging: each GWAS locus can have 2-20 candidate genes, the cellular programs a gene participates in are difficult to define in an unbiased fashion, and it remains unclear which genes and programs would be likely to influence disease risk. Here, we explored a new approach to address this challenge, by creating an unbiased catalog of gene programs and their regulators in endothelial cells to link variants to functions for coronary artery disease (CAD). To do so, we applied CRISPRi-Perturb-seq to knock down all expressed genes within 500 Kb of all CAD GWAS loci (2,285 genes in total) and measure their effects on the transcriptome using single-cell RNA-seq. We used consensus non-negative matrix factorization to define 60 gene expression programs—including core cellular programs, such as ribosome biogenesis, and endothelial cell-specific programs, such as flow response and angiogenesis—and link these programs to upstream regulators including transcription factors, chromatin regulators, metabolic enzymes, and signaling cascades. By combining this gene-to-program catalog with variant-to-gene maps, we find that candidate CAD genes converge onto 6 interrelated gene programs, together involving known and novel genes in 39 of 229 CAD GWAS loci. Analysis of these programs revealed that the cerebral cavernous malformations (CCM) complex—whose potential connection to CAD has not been previously explored—acts upstream to regulate other CAD genes involved in cytoskeletal organization, extracellular matrix remodeling, and cell migration. The strongest regulator of these programs is TLNRD1, a highly conserved but poorly studied gene that we show acts in the CCM pathway and regulates actin organization and endothelial cell barrier function. Together, our study nominates new genes that likely influence risk for CAD, identifies convergence of CAD risk loci into certain gene programs in endothelial cells, and demonstrates a generalizable strategy to catalog gene programs to connect disease variants to functions.

Dataset Information

Charles R. Bronfman Institute for Personalized Medicine (IPM) BioBank Genome Wide Association Study of Cardiovascular, Renal and Metabolic Phenotypes

Publications

Genetic background of patients from a university medical center in Manhattan: implications for personalized medicine.

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