title: Identification of genetic variants influencing the human plasma proteome.
abstract: Genetic variants influencing the transcriptome have been extensively studied. However, the impact of the genetic factors on the human proteome is largely unexplored, mainly due to lack of suitable high-throughput methods. Here we present unique and comprehensive identification of genetic variants affecting the human plasma protein profile by combining high-throughput and high-resolution mass spectrometry (MS) with genome-wide SNP data. We identified and quantified the abundance of 1,056 tryptic-digested peptides, representing 163 proteins in the plasma of 1,060 individuals from two population-based cohorts. The abundance level of almost one-fifth (19%) of the peptides was found to be heritable, with heritability ranging from 0.08 to 0.43. The levels of 60 peptides from 25 proteins, 15% of the proteins studied, were influenced by cis-acting SNPs. We identified and replicated individual cis-acting SNPs (combined P value ranging from 3.1 × 10(-52) to 2.9 × 10(-12)) influencing 11 peptides from 5 individual proteins. These SNPs represent both regulatory SNPs and nonsynonymous changes defining well-studied disease alleles such as the ε4 allele of apolipoprotein E (APOE), which has been shown to increase risk of Alzheimer's disease. Our results show that high-throughput mass spectrometry represents a promising method for large-scale characterization of the human proteome, allowing for both quantification and sequencing of individual proteins. Abundance and peptide composition of a protein plays an important role in the etiology, diagnosis, and treatment of a number of diseases. A better understanding of the genetic impact on the plasma proteome is therefore important for evaluating potential biomarkers and therapeutic agents for common diseases.
authors.affiliation: Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, SciLifeLab, Uppsala University, 75185 Uppsala, Sweden.
authors.forename: Åsa
authors.initials: Å
authors.lastname: Johansson
authors.forename: Stefan
authors.initials: S
authors.lastname: Enroth
authors.forename: Magnus
authors.initials: M
authors.lastname: Palmblad
authors.forename: André M
authors.initials: AM
authors.lastname: Deelder
authors.forename: Jonas
authors.initials: J
authors.lastname: Bergquist
authors.forename: Ulf
authors.initials: U
authors.lastname: Gyllensten
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D015415:Biomarkers / Q000097:blood; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D020543:Proteome / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D001798:Blood Proteins; D005819:Genetic Markers; D020543:Proteome