Abstract 19062: Genome-Wide Association Study of the Human Proteome in a Community-Based Cohort
Introduction: Circulating proteins play key roles as markers and effectors of cardiometabolic diseases, though the genetic determinants of relatively few circulating proteins have been defined. We hypothesized that the integration of plasma proteomic data with genome-wide scans would refine our understanding of the genetic architecture that underlies the human proteome.
Methods: Proteomic profiling of 1,129 analytes in plasma samples from 923 Framingham Heart Study (FHS) Offspring participants was performed using the aptamer-based Somascan platform. Genome wide association studies (GWAS) were performed on the top 75 plasma proteins associated with the FHS cardiovascular disease 10-year risk score. Genotyping was conducted using the Affymetrix 500K mapping array and the Affymetrix 50K gene-focused MIP array. Imputation of 2.5 million SNPs was performed using a hidden Markov model. The association of genetic variants and log-transformed protein levels was tested using linear mixed effects models.
Results: We identified more than 500 gene-protein associations with high levels of significance (P<5x10-8). Fifty-one of the 75 proteins analyzed had at least one genetic association with P<5x10-8. Approximately one-third of the plasma proteins analyzed were associated with loci that mapped to the cognate gene for the protein itself. For example, plasma levels of the membrane associated phospholipase A2 protein were highly associated with the PLA2G2A gene (P=6x10-48). As expected, a subset of associations represented locus-protein pairs of high biological plausibility. For example, complement component 1S protein was highly associated with the CFH gene that encodes the complement control protein Factor H (P=2x10-22). By contrast, we identified many novel locus-protein associations. Plasma Apolipoprotein E (ApoE) protein levels were highly associated with the ApoE gene (P=6x10-14), as well as sixteen additional genetic loci (P<5x10-8). Several of these novel loci mapped to genes that encode proteins known to play key roles in transcriptional regulation and intracellular trafficking.
Conclusions: Our GWAS of 75 plasma proteins offers potential insight into the genetic architecture of these key protein markers of cardiometabolic disease.
Author Disclosures: M.D. Benson: None. Q. Yang: None. M.J. Keyes: None. D. Ngo: None. J. O’Sullivan: None. D. Shen: None. J. Morningstar: None. X. Shi: None. L. Farrell: None. S. Sinha: None. R.S. Vasan: None. T.J. Wang: None. R.E. Gerszten: None.
- © 2016 by American Heart Association, Inc.