Large Bi-Ethnic Study of Plasma Proteome Leads to Comprehensive Mapping of cis-pQTL and Models for Proteome-wide Association Studies

Zhang, Jingning; Dutta, Diptavo; Köttgen, Anna; Tin, Adrienne; Schlosser, Pascal; Grams, Morgan E.; Harvey, Benjamin; Yu, Bing; Boerwinkle, Eric; Coresh, Josef; Chatterjee, Nilanjan

Improved understanding of genetic regulation of proteome can facilitate the identification of causal mechanisms for complex traits. We analyzed data on 4,657 plasma proteins from 7,213 European American (EA) and 1,871 African American individuals from the ARIC study, and further replicated findings on 467 AA individuals from the AASK study. We identified 2,004 plasma proteins in EA and 1,618 in AA, with majority overlapping, which showed significant genetic associations with common variants in cis-regions. Availability of AA sample led to smaller credible sets and identification of a significant number of population-specific cis-pQTLs. Estimates of cis-heritability for proteins were similar across EA and AA (median cis-h2=0.09 for EA and 0.10 for AA) and tended to be lower than those of gene expressions. Elastic-net-based algorithms produced high accuracy for protein prediction in each population, but models developed in AA were more transportable to EA than conversely. An illustrative application of proteome-wide association studies (PWAS) to serum urate and gout, implicated several proteins, including IL1RN, revealing the promise of the drug anakinra to treat acute gout flares. Our study demonstrates the value of large and diverse ancestry study for understanding genetic mechanisms of molecular phenotypes and their relationship with complex traits.