Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2008 May 9;4(5):e1000072.
doi: 10.1371/journal.pgen.1000072.

A Genome-Wide Association Study Identifies Protein Quantitative Trait Loci (pQTLs)

Free PMC article

A Genome-Wide Association Study Identifies Protein Quantitative Trait Loci (pQTLs)

David Melzer et al. PLoS Genet. .
Free PMC article


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.

Conflict of interest statement

The authors have declared that no competing interests exist.


Figure 1
Figure 1. Association of SNPs 1Megabase from each cis gene.
For each SNP the X axis represents the distance in base pairs from either the 5′ or 3′ end of the gene. If SNPs occur within the gene, either in introns or exons, they are given a distance of zero. SNPs in IL6R <1×10−25 not shown.
Figure 2
Figure 2. Cis genotype effects.
X axis shows the distance on the relevant chromosome. Left hand Y axis shows the −log10 p values and right hand Y axis shows the recombination rate as calculated from HapMap data.

Similar articles

  • Associations Between Common and Rare Exonic Genetic Variants and Serum Levels of 20 Cardiovascular-Related Proteins: The Tromsø Study.
    Solomon T, Smith EN, Matsui H, Braekkan SK; INVENT Consortium, Wilsgaard T, Njølstad I, Mathiesen EB, Hansen JB, Frazer KA. Solomon T, et al. Circ Cardiovasc Genet. 2016 Aug;9(4):375-83. doi: 10.1161/CIRCGENETICS.115.001327. Epub 2016 Jun 21. Circ Cardiovasc Genet. 2016. PMID: 27329291 Free PMC article.
  • Endometrial vezatin and its association with endometriosis risk.
    Holdsworth-Carson SJ, Fung JN, Luong HT, Sapkota Y, Bowdler LM, Wallace L, Teh WT, Powell JE, Girling JE, Healey M, Montgomery GW, Rogers PA. Holdsworth-Carson SJ, et al. Hum Reprod. 2016 May;31(5):999-1013. doi: 10.1093/humrep/dew047. Epub 2016 Mar 22. Hum Reprod. 2016. PMID: 27005890
  • Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD.
    Sun W, Kechris K, Jacobson S, Drummond MB, Hawkins GA, Yang J, Chen TH, Quibrera PM, Anderson W, Barr RG, Basta PV, Bleecker ER, Beaty T, Casaburi R, Castaldi P, Cho MH, Comellas A, Crapo JD, Criner G, Demeo D, Christenson SA, Couper DJ, Curtis JL, Doerschuk CM, Freeman CM, Gouskova NA, Han MK, Hanania NA, Hansel NN, Hersh CP, Hoffman EA, Kaner RJ, Kanner RE, Kleerup EC, Lutz S, Martinez FJ, Meyers DA, Peters SP, Regan EA, Rennard SI, Scholand MB, Silverman EK, Woodruff PG, O'Neal WK, Bowler RP; SPIROMICS Research Group; COPDGene Investigators. Sun W, et al. PLoS Genet. 2016 Aug 17;12(8):e1006011. doi: 10.1371/journal.pgen.1006011. eCollection 2016 Aug. PLoS Genet. 2016. PMID: 27532455 Free PMC article.
  • Expression quantitative trait loci: present and future.
    Nica AC, Dermitzakis ET. Nica AC, et al. Philos Trans R Soc Lond B Biol Sci. 2013 May 6;368(1620):20120362. doi: 10.1098/rstb.2012.0362. Print 2013. Philos Trans R Soc Lond B Biol Sci. 2013. PMID: 23650636 Free PMC article. Review.
  • eQTL analysis in humans.
    Franke L, Jansen RC. Franke L, et al. Methods Mol Biol. 2009;573:311-28. doi: 10.1007/978-1-60761-247-6_17. Methods Mol Biol. 2009. PMID: 19763935 Review.
See all similar articles

Cited by 191 articles

See all "Cited by" articles


    1. The WTCCC Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447:661–678. - PMC - PubMed
    1. Cheung VG, Spielman RS, Ewens KG, Weber TM, Morley M, et al. Mapping determinants of human gene expression by regional and genome-wide association. Nature. 2005;437:1365–1369. - PMC - PubMed
    1. Moffatt MF, Kabesch M, Liang L, Dixon AL, Strachan D, et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature. 2007;448:470–473. - PubMed
    1. Morley M, Molony CM, Weber TM, Devlin JL, Ewens KG, et al. Genetic analysis of genome-wide variation in human gene expression. Nature. 2004;430:743–747. - PMC - PubMed
    1. Stranger BE, Forrest MS, Clark AG, Minichiello MJ, Deutsch S, et al. Genome-wide associations of gene expression variation in humans. PLoS Genet. 2005;1:e78. - PMC - PubMed

Publication types