Abstract
Identifying genetic variants associated with circulating protein concentrations (protein quantitative trait loci; pQTLs) and integrating them with variants from genome-wide association studies (GWAS) may illuminate the proteome’s causal role in disease and bridge a knowledge gap regarding SNP-disease associations. We provide the results of GWAS of 71 high-value cardiovascular disease proteins in 6861 Framingham Heart Study participants and independent external replication. We report the mapping of over 16,000 pQTL variants and their functional relevance. We provide an integrated plasma protein-QTL database. Thirteen proteins harbor pQTL variants that match coronary disease-risk variants from GWAS or test causal for coronary disease by Mendelian randomization. Eight of these proteins predict new-onset cardiovascular disease events in Framingham participants. We demonstrate that identifying pQTLs, integrating them with GWAS results, employing Mendelian randomization, and prospectively testing protein-trait associations holds potential for elucidating causal genes, proteins, and pathways for cardiovascular disease and may identify targets for its prevention and treatment.
Highlights
ResultsSeventy-one proteins, selected a priori based on prior evidence of association with CVD, were measured in 7333 FHS participants (Supplementary Data 1)
Using a multistage strategy, we discovered over 16,000 pQTL variants associated with 57 out of 71 proteins that were selected a priori as high-value plasma proteins for CVD
Integration of pQTL variants with CHD risk variants from genome-wide association studies (GWAS) revealed nine proteins with pQTL variants that coincided with CHD risk variants from prior GWAS (Table 1), and Mendelian randomization (MR) analyses implicated six proteins as causal for CHD (Supplementary Data 15)
Summary
Seventy-one proteins, selected a priori based on prior evidence of association with CVD, were measured in 7333 FHS participants (Supplementary Data 1). The sample size available for GWAS of the 71 proteins was up to 6861 participants (mean age 50 years, 53% women); clinical characteristics of the discovery sample are summarized in Supplementary Data 2. GWAS of 71 proteins yielded 16,602 pQTL variants (11,806 cis; 4796 trans) representing 103 loci (40 cis, 63 trans) for 57 proteins. 36 cis-loci and 60 trans-loci (associated with 51 proteins) were previously unreported. 75% of cis-loci and 60% of Independent external replication trans-loci replicated. PQTL variants are enriched for intergenic and intronic regions, and linked to known CHD risk pathways. 210 pQTL variants (9 proteins) coincided with CHD-related SNPs from GWAS. Longitudinal association of 13 proteins with CHD/CVD events identified eight at P
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