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A genome-wide association study identifies protein quantitative trait loci (pQTLs)

Melzer, D and Perry, JRB and Hernandez, D and Corsi, AM and Stevens, K and Rafferty, I and Lauretani, F and Murray, A and Gibbs, JR and Paolisso, G and Rafiq, S and Simon-Sanchez, J and Lango, H and Scholz, S and Weedon, MN and Arepalli, S and Rice, N and Washecka, N and Hurst, A and Britton, A and Henley, W and Van De Leemput, J and Li, R and Newman, AB and Tranah, G and Harris, T and Panicker, V and Dayan, C and Bennett, A and McCarthy, MI and Ruokonen, A and Jarvelin, MR and Guralnik, J and Bandinelli, S and Frayling, TM and Singleton, A and Ferrucci, L (2008) A genome-wide association study identifies protein quantitative trait loci (pQTLs). PLoS Genetics, 4 (5). ISSN 1553-7390

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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 = 1.8×10 -57), CCL4L1 (p = 3.9×10-21), IL18 (p = 6.8×10-13), LPA (p = 4.4×10-10), GGT1 (p = 1.5×10-7), SHBG (p = 3.1×10-7), CRP (p = 6.4×10-6) and IL1RN (p = 7.3×10-6) 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 = 6.8×10-40), 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. © 2008 Melzer et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Melzer, D
Perry, JRB
Hernandez, D
Corsi, AM
Stevens, K
Rafferty, I
Lauretani, F
Murray, A
Gibbs, JR
Paolisso, G
Rafiq, S
Simon-Sanchez, J
Lango, H
Scholz, S
Weedon, MN
Arepalli, S
Rice, N
Washecka, N
Hurst, A
Britton, A
Henley, W
Van De Leemput, J
Li, R
Tranah, G
Harris, T
Panicker, V
Dayan, C
Bennett, A
McCarthy, MI
Ruokonen, A
Jarvelin, MR
Guralnik, J
Bandinelli, S
Frayling, TM
Singleton, A
Ferrucci, L
ContributionContributors NameEmailPitt UsernameORCID
Date: 1 May 2008
Date Type: Publication
Journal or Publication Title: PLoS Genetics
Volume: 4
Number: 5
DOI or Unique Handle: 10.1371/journal.pgen.1000072
Schools and Programs: School of Public Health > Epidemiology
Refereed: Yes
ISSN: 1553-7390
PubMed ID: 18464913
Date Deposited: 18 Jul 2012 20:34
Last Modified: 22 Jun 2021 15:55


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