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 4,035 independent associations between genetic variants and 2,091 serum proteins, of which 36% 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 protein’s 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.

A proteogenomic signature of age-related macular degeneration in blood

“…To determine if any of the 28 AMD-associated proteins might be causally related to the disease, a two-sample Mendelian randomization (MR) study was performed using cis -acting genetic variants as instruments. BPIFB1, CFHR1, CFHR5, FUT5, and GHR were found to have such instruments 13 . However, the genetic instruments for BPIFB1 and GHR do not overlap with previously known risk loci for AMD (Table 2 ).…”

“…b Reported P -values are two-sided derived from sex and age-adjusted linear regression analysis. The effect alleles for each corresponding pQTL 13 are shown in Supplementary Data 8 and 9 . To account for multiple comparisons, significant associations with P -values of <1 × 10 −6 are reported.…”

“…7b–d ). Because the loci containing the genes encoding CFHR1, CFHR5, and FUT5 are saturated with multiple independent variants for both AMD (Supplementary Data 7 ) and proteins 13 , 14 , colocalization analysis becomes difficult and thus inconclusive 38 , 39 . As a result, colocalization analyses were omitted from the current study.…”

“…We applied linear regression using an additive genetic model for all single-point SNP association analyses for different disease-related outcomes as well as for proteins. The results of associating genetic variants with serum protein levels were obtained using a GWAS of 4782 human proteins measured in serum using 7,506,463 assayed and imputed genetic variants from 5368 AGES-RS individuals 13 .…”

Integration ofCandida albicans-induced single-cell gene expression data and circulatory protein concentrations reveal genetic regulators of inflammation

“…Larger-scale candidemia GWAS studies would be useful to disentangle these possibilities. Supporting this argument, a recent powered study evaluating the relationship between pQTLs and GWAS loci of 81 diseases and other clinical traits found 69 out of 76 (number of phenotypes associated with the genome-wide significant loci investigated) representing 90.8% of the tested genetic associations with phenotypes were also associated with at least one protein with strong evidence of colocalization (Gudjonsson et al, 2022).…”