Proteogenomic analysis integrated with electronic health records data reveals disease-associated variants in Black Americans

Abstract

BACKGROUNDMost GWAS of plasma proteomics have focused on White individuals of European ancestry, limiting biological insight from other ancestry-enriched protein quantitative loci (pQTL).METHODSWe conducted a discovery GWAS of approximately 3,000 plasma proteins measured by the antibody-based Olink platform in 1,054 Black adults from the Jackson Heart Study (JHS) and validated our findings in the Multi-Ethnic Study of Atherosclerosis (MESA). The genetic architecture of identified pQTLs was further explored through fine mapping and admixture association analysis. Finally, using our pQTL findings, we performed a phenome-wide association study (PheWAS) across 2 large multiethnic electronic health record (EHR) systems in All of Us and BioMe.RESULTSWe identified 1,002 pQTLs for 925 protein assays. Fine mapping and admixture analyses suggested allelic heterogeneity of the plasma proteome across diverse populations. We identified associations for variants enriched in African ancestry, many in diseases that lack precise biomarkers, including cis-pQTLs for cathepsin L (CTSL) and Siglec-9, which were linked with sarcoidosis and non-Hodgkin's lymphoma, respectively. We found concordant associations across clinical diagnoses and laboratory measurements, elucidating disease pathways, including a cis-pQTL associated with circulating CD58, WBC count, and multiple sclerosis.CONCLUSIONSOur findings emphasize the value of leveraging diverse populations to enhance biological insights from proteomics GWAS, and we have made this resource readily available as an interactive web portal.FUNDINGNIH K08 HL161445-01A1; 5T32HL160522-03; HHSN268201600034I; HL133870.

Keywords: Genetic diseases; Genetics; Immunology; Population genetics; Proteomics.

Figure 1. Study design.

We performed discovery GWAS of 2,881 plasma proteins in the JHS (n = 1,040) and validated associations in the MESA (n = 2,120). pQTLs were interrogated in 2 biobanks of diverse individuals for phenotype associations through PheWAS. AoU, All of Us research program.

Figure 2. Genetic associations with plasma abundance of 2,881 proteins in Black individuals from the JHS (Manhattan plot).

Significance thresholds reflect genome-wide significance for cis-pQTLs (P < 5 × 10^–8) or Bonferroni’s significance for trans-pQTLs (P < 7.7 × 10^-11). pQTLs enriched in African ancestry (NFEs MAF < 1% based on gnomAD) are colored in red. Trans-pQTLs are labeled with the protein name and gene name.

Figure 3. Genetic architecture of plasma pQTLs.

(A) The number of proteins significantly associated with each sentinel pQTL. (B) Distance of the sentinel variant from the transcription start site versus the effect size of the variant on protein abundance for cis pQTL loci. (C)Minor allele frequency of pQTLs in JHS versus estimated effect size. Points are colored based on genomic location (exonic or intronic). (D)pQTL MAF in NFEs and MAF in individuals of African ancestry. Points are colored based on genomic location (exonic or intronic) as denoted in the label.

Figure 4. Miami plot representing pQTL associations with binary phecodes and continuous laboratory measurements in BioMe and All of Us.

Top: pQTL associations with binary phecodes. Bottom: continuous laboratory measurements. Each point represents a unique phenotypic association for a given pQTL; points colored in red are those with MAF in NFE of less than 1%. Red lines represent FDR significance.