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PMID: 18464913 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

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

PLoS genetics ·Vol. 4 ·No. 5 ·2008-05-09 ·Pages e1000072

Melzer D, Perry JR, 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, Newman AB, 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

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.

MeSH Terms
Adult Aged Aged, 80 and over Blood Proteins/genetics,metabolism Female Gene Dosage Genetic Linkage Genetic Variation Genome, Human Genotype Humans Male Middle Aged Polymorphism, Single Nucleotide Quantitative Trait Loci Transcription, Genetic
Chemicals
Blood Proteins
Authors & Affiliations
37 authors, click to expand affiliations / ORCID
Melzer David
Department of Epidemiology and Public Health, Institute of Biomedical and Clinical Sciences, Peninsula College of Medicine and Dentistry, University of Exeter, Devon, United Kingdom.
Perry John R B
Hernandez Dena
Corsi Anna-Maria
Stevens Kara
Rafferty Ian
Lauretani Fulvio
Murray Anna
Gibbs J Raphael
Paolisso Giuseppe
Rafiq Sajjad
Simon-Sanchez Javier
Lango Hana
Scholz Sonja
Weedon Michael N
Arepalli Sampath
Rice Neil
Washecka Nicole
Hurst Alison
Britton Angela
Henley William
van de Leemput Joyce
Li Rongling
Newman Anne B
Tranah Greg
Harris Tamara
Panicker Vijay
Dayan Colin
Bennett Amanda
McCarthy Mark I
Ruokonen Aimo
Jarvelin Marjo-Riitta
Guralnik Jack
Bandinelli Stefania
Frayling Timothy M
Singleton Andrew
Ferrucci Luigi
Conflict of Interest

The authors have declared that no competing interests exist.

References (47)
47 references, click to expand
  1. A sampling of the yeast proteome.
    Mol Cell Biol. 1999 Nov;19(11):7357-68 PMID: 10523624
  2. An interleukin-18 polymorphism is associated with reduced serum concentrations and better physical functioning in older people.
    J Gerontol A Biol Sci Med Sci. 2007 Jan;62(1):73-8 PMID: 17301041
  3. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.
    Science. 2007 May 11;316(5826):889-94 PMID: 17434869
  4. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma.
    Nature. 2007 Jul 26;448(7152):470-3 PMID: 17611496
  5. A genome-wide association study of global gene expression.
    Nat Genet. 2007 Oct;39(10):1202-7 PMID: 17873877
  6. Statistical significance for genomewide studies.
    Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9440-5 PMID: 12883005
  7. A common variant of the interleukin 6 receptor (IL-6r) gene increases IL-6r and IL-6 levels, without other inflammatory effects.
    Genes Immun. 2007 Oct;8(7):552-9 PMID: 17671508
  8. Genome-wide associations of gene expression variation in humans.
    PLoS Genet. 2005 Dec;1(6):e78 PMID: 16362079
  9. Early life factors and blood pressure at age 31 years in the 1966 northern Finland birth cohort.
    Hypertension. 2004 Dec;44(6):838-46 PMID: 15520301
  10. Identification of class-mu glutathione transferase genes GSTM1-GSTM5 on human chromosome 1p13.
    Am J Hum Genet. 1993 Jul;53(1):220-33 PMID: 8317488
  11. Endotoxemia, inflammation, and atrial fibrillation.
    Am J Cardiol. 2007 Sep 15;100(6):986-8 PMID: 17826383
  12. The number of identical kringle IV repeats in apolipoprotein(a) affects its processing and secretion by HepG2 cells.
    J Biol Chem. 1996 Dec 13;271(50):32403-10 PMID: 8943305
  13. Genetic analysis of genome-wide variation in human gene expression.
    Nature. 2004 Aug 12;430(7001):743-7 PMID: 15269782
  14. 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease?
    Int J Epidemiol. 2003 Feb;32(1):1-22 PMID: 12689998
  15. Genetic variation in the CCL18-CCL3-CCL4 chemokine gene cluster influences HIV Type 1 transmission and AIDS disease progression.
    Am J Hum Genet. 2006 Jul;79(1):120-8 PMID: 16773571
  16. A common variant of HMGA2 is associated with adult and childhood height in the general population.
    Nat Genet. 2007 Oct;39(10):1245-50 PMID: 17767157
  17. Subsystems contributing to the decline in ability to walk: bridging the gap between epidemiology and geriatric practice in the InCHIANTI study.
    J Am Geriatr Soc. 2000 Dec;48(12):1618-25 PMID: 11129752
  18. The human glutathione S-transferase supergene family, its polymorphism, and its effects on susceptibility to lung cancer.
    Environ Health Perspect. 1992 Nov;98:87-94 PMID: 1486868
  19. Variant in sex hormone-binding globulin gene and the risk of prostate cancer.
    Cancer Epidemiol Biomarkers Prev. 2007 Jan;16(1):165-8 PMID: 17220347
  20. The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility.
    Science. 2005 Mar 4;307(5714):1434-40 PMID: 15637236
  21. Interrelating different types of genomic data, from proteome to secretome: 'oming in on function.
    Genome Res. 2001 Sep;11(9):1463-8 PMID: 11544189
  22. The relationship between ABO histo-blood group, factor VIII and von Willebrand factor.
    Transfus Med. 2001 Aug;11(4):343-51 PMID: 11532189
  23. Admixture mapping of an allele affecting interleukin 6 soluble receptor and interleukin 6 levels.
    Am J Hum Genet. 2007 Apr;80(4):716-26 PMID: 17357077
  24. Sequence variation at the human ABO locus.
    Ann Hum Genet. 2002 Jan;66(Pt 1):1-27 PMID: 12014997
  25. Human genetics: an expression of interest.
    Nature. 2004 Aug 12;430(7001):733-4 PMID: 15306793
  26. Correlation between protein and mRNA abundance in yeast.
    Mol Cell Biol. 1999 Mar;19(3):1720-30 PMID: 10022859
  27. Mapping expression in randomized rodent genomes.
    Nat Genet. 2005 Mar;37(3):209-10 PMID: 15731750
  28. The longitudinal study of the northern Finland birth cohort of 1966.
    Paediatr Perinat Epidemiol. 1988 Jan;2(1):59-88 PMID: 2976931
  29. Partial substitution of thyroxine (T4) with tri-iodothyronine in patients on T4 replacement therapy: results of a large community-based randomized controlled trial.
    J Clin Endocrinol Metab. 2005 Feb;90(2):805-12 PMID: 15585551
  30. Mapping determinants of human gene expression by regional and genome-wide association.
    Nature. 2005 Oct 27;437(7063):1365-9 PMID: 16251966
  31. Population genomics of human gene expression.
    Nat Genet. 2007 Oct;39(10):1217-24 PMID: 17873874
  32. No association between insulin gene variation and adult metabolic phenotypes in a large Finnish birth cohort.
    Diabetologia. 2005 May;48(5):886-91 PMID: 15834700
  33. Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations.
    J Clin Invest. 1992 Jul;90(1):52-60 PMID: 1386087
  34. Circulating levels of inflammatory markers and cancer risk in the health aging and body composition cohort.
    Cancer Epidemiol Biomarkers Prev. 2005 Oct;14(10):2413-8 PMID: 16214925
  35. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.
    Nature. 2007 Jun 7;447(7145):661-78 PMID: 17554300
  36. Discovery of expression QTLs using large-scale transcriptional profiling in human lymphocytes.
    Nat Genet. 2007 Oct;39(10):1208-16 PMID: 17873875
  37. The soluble human IL-6 receptor. Mutational characterization of the proteolytic cleavage site.
    J Immunol. 1994 May 15;152(10):4958-68 PMID: 8176214
  38. The blood groups in relation to peptic ulceration and carcinoma of colon, rectum, breast, and bronchus; an association between the ABO groups and peptic ulceration.
    Br Med J. 1954 Aug 7;2(4883):315-21 PMID: 13182205
  39. Common genetic variation in the gene encoding interleukin-1-receptor antagonist (IL-1RA) is associated with altered circulating IL-1RA levels.
    Genes Immun. 2007 Jun;8(4):344-51 PMID: 17443229
  40. Polymorphisms associated with circulating sex hormone levels in postmenopausal women.
    J Natl Cancer Inst. 2004 Jun 16;96(12):936-45 PMID: 15199113
  41. C-reactive protein and its role in metabolic syndrome: mendelian randomisation study.
    Lancet. 2005 Dec 3;366(9501):1954-9 PMID: 16325697
  42. The apolipoprotein (a) gene: a transcribed hypervariable locus controlling plasma lipoprotein (a) concentration.
    Hum Genet. 1992 Nov;90(3):220-30 PMID: 1336760
  43. Genetic basis of proteome variation in yeast.
    Nat Genet. 2007 Nov;39(11):1369-75 PMID: 17952072
  44. Principal components analysis corrects for stratification in genome-wide association studies.
    Nat Genet. 2006 Aug;38(8):904-9 PMID: 16862161
  45. Single nucleotide polymorphisms in exons of the apo(a) kringles IV types 6 to 10 domain affect Lp(a) plasma concentrations and have different patterns in Africans and Caucasians.
    Hum Mol Genet. 2001 Apr 1;10(8):815-24 PMID: 11285247
  46. Fibrinogen and coronary heart disease: test of causality by 'Mendelian randomization'.
    Int J Epidemiol. 2006 Aug;35(4):935-43 PMID: 16870675
  47. CCL2 polymorphisms are associated with serum monocyte chemoattractant protein-1 levels and myocardial infarction in the Framingham Heart Study.
    Circulation. 2005 Aug 23;112(8):1113-20 PMID: 16116069
Article Info
Journal
PLoS genetics
Abbr.
PLoS Genet
ISSN
1553-7404
DOI
10.1371/journal.pgen.1000072
Published
2008-05-09
Epub
2008-00-09
Pages
e1000072
Language
English
Region
United States
NLM ID
101239074
PMCID
PMC2362067
Subset
IM
Grants
NIA NIH HHS · N01-AG-6-2101 · United States
NIA NIH HHS · R01 AG24233-01 · United States
NIA NIH HHS · N01-AG-6-2103 · United States
NIA NIH HHS · R01 AG024233 · United States
Intramural NIH HHS · United States
NIA NIH HHS · N01-AG-6-2106 · United States
External Links
PubMed source DOI: 10.1371/journal.pgen.1000072 PMC Full Text View journal details
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