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dc.contributor.authorMelzer, Den
dc.contributor.authorPerry, JRBen
dc.contributor.authorHernandez, Den
dc.contributor.authorCorsi, A-Men
dc.contributor.authorStevens, Ken
dc.contributor.authorRafferty, Ien
dc.contributor.authorLauretani, Fen
dc.contributor.authorMurray, Aen
dc.contributor.authorGibbs, JRen
dc.contributor.authorPaolisso, Gen
dc.contributor.authorRafiq, Sen
dc.contributor.authorSimon-Sanchez, Jen
dc.contributor.authorLango, Hen
dc.contributor.authorScholz, Sen
dc.contributor.authorWeedon, MNen
dc.contributor.authorArepalli, Sen
dc.contributor.authorRice, Nen
dc.contributor.authorWashecka, Nen
dc.contributor.authorHurst, Aen
dc.contributor.authorBritton, Aen
dc.contributor.authorHenley, Wen
dc.contributor.authorvan de Leemput, Jen
dc.contributor.authorLi, Ren
dc.contributor.authorNewman, ABen
dc.contributor.authorTranah, Gen
dc.contributor.authorHarris, Ten
dc.contributor.authorPanicker, Ven
dc.contributor.authorDayan, Cen
dc.contributor.authorBennett, Aen
dc.contributor.authorMcCarthy, MIen
dc.contributor.authorRuokonen, Aen
dc.contributor.authorJarvelin, M-Ren
dc.contributor.authorGuralnik, Jen
dc.contributor.authorBandinelli, Sen
dc.contributor.authorFrayling, TMen
dc.contributor.authorSingleton, Aen
dc.contributor.authorFerrucci, Len

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.

dc.format.extente1000072 - ?en
dc.subjectAged, 80 and overen
dc.subjectBlood Proteinsen
dc.subjectGene Dosageen
dc.subjectGenetic Linkageen
dc.subjectGenetic Variationen
dc.subjectGenome, Humanen
dc.subjectMiddle Ageden
dc.subjectPolymorphism, Single Nucleotideen
dc.subjectQuantitative Trait Locien
dc.subjectTranscription, Geneticen
dc.titleA genome-wide association study identifies protein quantitative trait loci (pQTLs).en
dc.typeJournal Article
plymouth.publication-statusPublished onlineen
plymouth.journalPLoS Geneten
plymouth.organisational-group/Plymouth/00 Groups by role
plymouth.organisational-group/Plymouth/00 Groups by role/Academics
plymouth.organisational-group/Plymouth/Faculty of Medicine and Dentistry
plymouth.organisational-group/Plymouth/Faculty of Medicine and Dentistry/Collaboration for the Advancement of Medical Education Research Assessment
plymouth.organisational-group/Plymouth/Faculty of Medicine and Dentistry/Medical Statistics
plymouth.organisational-group/Plymouth/Faculty of Medicine and Dentistry/Medical Statistics/RC Reporting group Medical Statistics
plymouth.organisational-group/Plymouth/Faculty of Medicine and Dentistry/Peninsula Medical School
plymouth.organisational-group/Plymouth/Research Groups
plymouth.organisational-group/Plymouth/Research Groups/Institute of Health and Community
dc.publisher.placeUnited Statesen
dc.rights.embargoperiodNot knownen
rioxxterms.typeJournal Article/Reviewen

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