title: Identification of cis-regulatory variation influencing protein abundance levels in human plasma.
abstract: Proteins are central to almost all cellular processes, and dysregulation of expression and function is associated with a range of disorders. A number of studies in human have recently shown that genetic factors significantly contribute gene expression variation. In contrast, very little is known about the genetic basis of variation in protein abundance in man. Here, we assayed the abundance levels of proteins in plasma from 96 elderly Europeans using a new aptamer-based proteomic technology and performed genome-wide local (cis-) regulatory association analysis to identify protein quantitative trait loci (pQTL). We detected robust cis-associations for 60 proteins at a false discovery rate of 5%. The most highly significant single nucleotide polymorphism detected was rs7021589 (false discovery rate, 2.5 × 10(-12)), mapped within the gene coding sequence of Tenascin C (TNC). Importantly, we identified evidence of cis-regulatory variation for 20 previously disease-associated genes encoding protein, including variants with strong evidence of disease association show significant association with protein abundance levels. These results demonstrate that common genetic variants contribute to the differences in protein abundance levels in human plasma. Identification of pQTLs will significantly enhance our ability to discover and comprehend the biological and functional consequences of loci identified from genome-wide association study of complex traits. This is the first large-scale genetic association study of proteins in plasma measured using a novel, highly multiplexed slow off-rate modified aptamer (SOMAmer) proteomic platform.
authors.affiliation: NIHR Biomedical Research Centre for Mental Health, South London, UK. anbarasu.lourdusamy@kcl.ac.uk
authors.forename: Anbarasu
authors.initials: A
authors.lastname: Lourdusamy
authors.forename: Stephan
authors.initials: S
authors.lastname: Newhouse
authors.forename: Katie
authors.initials: K
authors.lastname: Lunnon
authors.forename: Petra
authors.initials: P
authors.lastname: Proitsi
authors.forename: John
authors.initials: J
authors.lastname: Powell
authors.forename: Angela
authors.initials: A
authors.lastname: Hodges
authors.forename: Sally K
authors.initials: SK
authors.lastname: Nelson
authors.forename: Alex
authors.initials: A
authors.lastname: Stewart
authors.forename: Stephen
authors.initials: S
authors.lastname: Williams
authors.forename: Iwona
authors.initials: I
authors.lastname: Kloszewska
authors.forename: Patrizia
authors.initials: P
authors.lastname: Mecocci
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.forename: Magda
authors.initials: M
authors.lastname: Tsolaki
authors.forename: Bruno
authors.initials: B
authors.lastname: Vellas
authors.forename: Simon
authors.initials: S
authors.lastname: Lovestone
authors.forename: Richard
authors.initials: R
authors.lastname: Dobson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D052157:Aptamers, Nucleotide; D001798:Blood Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D040901:Proteomics / Q000379:methods; D040641:Quantitative Trait Loci; D012045:Regulatory Sequences, Nucleic Acid
chemical_list: D052157:Aptamers, Nucleotide; D001798:Blood Proteins