A genome-wide association study of serum proteins reveals shared loci with common diseases

Abstract

With the growing number of genetic association studies, the genotype-phenotype atlas has become increasingly more complex, yet the functional consequences of most disease associated alleles is not understood. The measurement of protein level variation in solid tissues and biofluids integrated with genetic variants offers a path to deeper functional insights. Here we present a large-scale proteogenomic study in 5,368 individuals, revealing 4,113 independent associations between genetic variants and 2,099 serum proteins, of which 37% are previously unreported. The majority of both cis- and trans-acting genetic signals are unique for a single protein, although our results also highlight numerous highly pleiotropic genetic effects on protein levels and demonstrate that a proteins genetic association profile reflects certain characteristics of the protein, including its location in protein networks, tissue specificity and intolerance to loss of function mutations. Integrating protein measurements with deep phenotyping of the cohort, we observe substantial enrichment of phenotype associations for serum proteins regulated by established GWAS loci, and offer new insights into the interplay between genetics, serum protein levels and complex disease.

Positioning imatinib for pulmonary arterial hypertension: A phase I/II design comprising dose finding and single‐arm efficacy

“…In two studies of 3301 and 5368 individuals, respectively, the same sentinel variant (rs2304058) was detected with an effect on circulating PDGFRB levels; each minor allele was associated with one standard deviation in plasma PDGFRB levels. 27,28 The effect of this common variant on the circulating proteins levels was independent of protein-altering, germ-line variants in PDGFRB. 27 PDGFRB expression is upregulated in lung tissue from PAH patients 12 and may be involved in the pharmacological effect of Imatinib on pulmonary vascular tissue; the IC 50 of Imatinib for PDGFRB is around 600 nM, 37 a concentration exceeded by trough plasma levels (averaging 700 ng.ml À1 ) in IMPRES.…”

“…24,25 Of note here, three separate population-based studies have identified a cis-acting protein quantitative trait locus (pQTL) located close to PDGFRB, influencing circulating levels of PDGFRB, that reaches genome-wide significance. [26][27][28] If PDGFRB is an important target for Imatinib in PAH, common genetic variants influencing PDGFRB protein levels may affect therapeutic response, or at least the dose required to elicit a response, and the risk of dose-limiting adverse effects.…”

Multiallelic Copy Number Variation in ORM1 is Associated with Plasma Cell-Free DNA Levels as an Intermediate Phenotype for Venous Thromboembolism

“…44 Specifically, rs10982156 and rs3762056 have been previously associated with coagulation factor X levels. 45 46 47 Recently, rs10982156 has also been associated with serum levels of tissue factor pathway inhibitor and serine protease inhibitor Kazal-type 2, 46 the latter being associated with stroke, 48 mean platelet volume, and platelet count, 49 among others. In addition, rs150611042 has been associated with thrombin generation.…”

Evaluating the Causal Effects of Circulating Proteome on the Risk of Sepsis and Related Outcomes

“…5,6 The human plasma proteome comprises an intricate network of proteins, either secreted or shed into the bloodstream, facilitating essential functions and intertissue communication. 7 Dysregulation of these proteins often signals disease, positioning them as crucial targets for pharmacological intervention. 8 Given the ease of blood collection compared to other tissues, circulating proteins offer a promising resource for identifying diseasespecific molecular signatures in large population cohorts.…”

“…8 Given the ease of blood collection compared to other tissues, circulating proteins offer a promising resource for identifying diseasespecific molecular signatures in large population cohorts. 7 Advancements in proteomic methods now allow researchers to simultaneously quantify numerous circulating proteins in large-scale study populations. 9 Genome-wide association studies (GWAS) assessing the levels of these proteins facilitate the identification of protein quantitative trait loci (pQTLs), enhancing our understanding of the genetic architecture governing protein expression.…”