title: A genome-wide association study identifies protein quantitative trait loci (pQTLs).
abstract: There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts - cis effects, and elsewhere in the genome - trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8x10(-57)), CCL4L1 (p = 3.9x10(-21)), IL18 (p = 6.8x10(-13)), LPA (p = 4.4x10(-10)), GGT1 (p = 1.5x10(-7)), SHBG (p = 3.1x10(-7)), CRP (p = 6.4x10(-6)) and IL1RN (p = 7.3x10(-6)) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8x10(-40)), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways.
authors.affiliation: Department of Epidemiology and Public Health, Institute of Biomedical and Clinical Sciences, Peninsula College of Medicine and Dentistry, University of Exeter, Devon, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Melzer
authors.forename: John R B
authors.initials: JR
authors.lastname: Perry
authors.forename: Dena
authors.initials: D
authors.lastname: Hernandez
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Corsi
authors.forename: Kara
authors.initials: K
authors.lastname: Stevens
authors.forename: Ian
authors.initials: I
authors.lastname: Rafferty
authors.forename: Fulvio
authors.initials: F
authors.lastname: Lauretani
authors.forename: Anna
authors.initials: A
authors.lastname: Murray
authors.forename: J Raphael
authors.initials: JR
authors.lastname: Gibbs
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Paolisso
authors.forename: Sajjad
authors.initials: S
authors.lastname: Rafiq
authors.forename: Javier
authors.initials: J
authors.lastname: Simon-Sanchez
authors.forename: Hana
authors.initials: H
authors.lastname: Lango
authors.forename: Sonja
authors.initials: S
authors.lastname: Scholz
authors.forename: Michael N
authors.initials: MN
authors.lastname: Weedon
authors.forename: Sampath
authors.initials: S
authors.lastname: Arepalli
authors.forename: Neil
authors.initials: N
authors.lastname: Rice
authors.forename: Nicole
authors.initials: N
authors.lastname: Washecka
authors.forename: Alison
authors.initials: A
authors.lastname: Hurst
authors.forename: Angela
authors.initials: A
authors.lastname: Britton
authors.forename: William
authors.initials: W
authors.lastname: Henley
authors.forename: Joyce
authors.initials: J
authors.lastname: van de Leemput
authors.forename: Rongling
authors.initials: R
authors.lastname: Li
authors.forename: Anne B
authors.initials: AB
authors.lastname: Newman
authors.forename: Greg
authors.initials: G
authors.lastname: Tranah
authors.forename: Tamara
authors.initials: T
authors.lastname: Harris
authors.forename: Vijay
authors.initials: V
authors.lastname: Panicker
authors.forename: Colin
authors.initials: C
authors.lastname: Dayan
authors.forename: Amanda
authors.initials: A
authors.lastname: Bennett
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Aimo
authors.initials: A
authors.lastname: Ruokonen
authors.forename: Marjo-Riitta
authors.initials: MR
authors.lastname: Jarvelin
authors.forename: Jack
authors.initials: J
authors.lastname: Guralnik
authors.forename: Stefania
authors.initials: S
authors.lastname: Bandinelli
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001798:Blood Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018628:Gene Dosage; D008040:Genetic Linkage; D014644:Genetic Variation; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D014158:Transcription, Genetic
chemical_list: D001798:Blood Proteins