title: Quantitative variability of 342 plasma proteins in a human twin population.
abstract: The degree and the origins of quantitative variability of most human plasma proteins are largely unknown. Because the twin study design provides a natural opportunity to estimate the relative contribution of heritability and environment to different traits in human population, we applied here the highly accurate and reproducible SWATH mass spectrometry technique to quantify 1,904 peptides defining 342 unique plasma proteins in 232 plasma samples collected longitudinally from pairs of monozygotic and dizygotic twins at intervals of 2-7 years, and proportioned the observed total quantitative variability to its root causes, genes, and environmental and longitudinal factors. The data indicate that different proteins show vastly different patterns of abundance variability among humans and that genetic control and longitudinal variation affect protein levels and biological processes to different degrees. The data further strongly suggest that the plasma concentrations of clinical biomarkers need to be calibrated against genetic and temporal factors. Moreover, we identified 13 cis-SNPs significantly influencing the level of specific plasma proteins. These results therefore have immediate implications for the effective design of blood-based biomarker studies.
authors: Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland liu@imsb.biol.ethz.ch aebersold@imsb.biol.ethz.ch.
authors: Yansheng
authors: Y
authors: Liu
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors: Alfonso
authors: A
authors: Buil
authors: Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
authors: Ben C
authors: BC
authors: Collins
authors: Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
authors: Ludovic C J
authors: LC
authors: Gillet
authors: Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
authors: Lorenz C
authors: LC
authors: Blum
authors: Department of Statistics and Department of Computer Science, Purdue University, West Lafayette, IN, USA.
authors: Lin-Yang
authors: LY
authors: Cheng
authors: Department of Statistics and Department of Computer Science, Purdue University, West Lafayette, IN, USA.
authors: Olga
authors: O
authors: Vitek
authors: Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
authors: Jeppe
authors: J
authors: Mouritsen
authors: Department of Twin Research and Genetic Epidemiology, King's College London St Tomas' Hospital Campus, London, UK.
authors: Genevieve
authors: G
authors: Lachance
authors: Department of Twin Research and Genetic Epidemiology, King's College London St Tomas' Hospital Campus, London, UK.
authors: Tim D
authors: TD
authors: Spector
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors: Emmanouil T
authors: ET
authors: Dermitzakis
authors: Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland Faculty of Science, University of Zurich, Zurich, Switzerland liu@imsb.biol.ethz.ch aebersold@imsb.biol.ethz.ch.
authors: Ruedi
authors: R
authors: Aebersold
mesh_terms: D000328:Adult; D000368:Aged; D001798:Blood Proteins / Q000235:genetics*; D019295:Computational Biology; D030541:Databases, Genetic; D005069:Evaluation Studies as Topic; D005260:Female; D005819:Genetic Markers; D006801:Humans; D016014:Linear Models; D008137:Longitudinal Studies; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D040901:Proteomics; D040641:Quantitative Trait Loci; D014429:Twins, Dizygotic / Q000235:genetics; D014430:Twins, Monozygotic / Q000235:genetics; D044465:White People
chemical_list: D001798:Blood Proteins; D005819:Genetic Markers
keywords: SWATH‐MS; heritability; longitudinal variability; plasma biomarkers; twin study
references: J Proteome Res. 2005 Jul-Aug;4(4):1104-9
references: 16083259
references: Twin Res. 2001 Dec;4(6):464-77
references: 11780939
references: Sci Data. 2014;1:140031
references: 25977788
references: Nat Biotechnol. 2014 Mar;32(3):219-23
references: 24727770
references: Anal Chem. 2002 Oct 15;74(20):5383-92
references: 12403597
references: Nat Genet. 2012 Oct;44(10):1084-9
references: 22941192
references: J Natl Cancer Inst. 2010 Jan 6;102(1):26-38
references: 20042715
references: J Proteome Res. 2009 Dec;8(12):5674-8
references: 19848406
references: Eur Heart J. 2014 Aug 1;35(29):1917-24
references: 24917639
references: Mol Syst Biol. 2011;7:525
references: 21878913
references: Nucleic Acids Res. 2012 Jul;40(Web Server issue):W65-70
references: 22544707
references: Proteomics. 2007 Mar;7(5):655-67
references: 17295354
references: PLoS Genet. 2008 May;4(5):e1000072
references: 18464913
references: Bioinformatics. 2007 May 15;23(10):1294-6
references: 17384015
references: Nature. 2012 Nov 1;491(7422):56-65
references: 23128226
references: Sci Transl Med. 2012 Jul 11;4(142):142ra94
references: 22786679
references: Proteomics. 2013 Apr;13(8):1247-56
references: 23322582
references: Proteomics. 2012 Apr;12(8):1111-21
references: 22577012
references: Nat Biotechnol. 2007 Jan;25(1):125-31
references: 17195840
references: Proteome Sci. 2011 Nov 17;9:73
references: 22093360
references: Eur J Hum Genet. 2008 Nov;16(11):1372-9
references: 18560444
references: Cancer Inform. 2005;1:98-104
references: 19305635
references: Hum Mol Genet. 2012 Aug 15;21(16):3719-26
references: 22595970
references: Nat Commun. 2014;5:4684
references: 25147954
references: Nat Genet. 2015 Jan;47(1):88-91
references: 25436857
references: Nature. 2008 Mar 27;452(7186):423-8
references: 18344981
references: N Engl J Med. 2000 Jul 13;343(2):78-85
references: 10891514
references: J Proteome Res. 2014 Jul 24;:null
references: 25058407
references: Nat Rev Genet. 2008 Apr;9(4):255-66
references: 18319743
references: Circulation. 2000 Apr 4;101(13):1546-51
references: 10747348
references: J Hum Genet. 2004;49(1):24-8
references: 14661079
references: J Thromb Haemost. 2007 Apr;5(4):700-7
references: 17408404
references: Mol Cell Proteomics. 2011 Sep;10(9):M110.006353
references: 21632744
references: Stroke. 2004 Aug;35(8):1795-9
references: 15232129
references: Twin Res Hum Genet. 2013 Feb;16(1):144-9
references: 23088889
references: Metabolism. 2014 Mar;63(3):365-71
references: 24333007
references: Am J Hum Genet. 2013 Nov 7;93(5):876-90
references: 24183450
references: Nat Methods. 2013 Dec;10(12):1246-53
references: 24162925
references: Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9440-5
references: 12883005
references: Int J Cancer. 2011 Jul 1;129(1):133-42
references: 20824709
references: Expert Rev Mol Diagn. 2013 Nov;13(8):811-25
references: 24138574
references: Genetics. 2007 Sep;177(1):577-85
references: 17660554
references: Cancer Sci. 2009 Dec;100(12):2396-401
references: 19737146
references: Nat Rev Genet. 2009 Feb;10(2):109-21
references: 19139765
references: J Proteomics. 2012 May 17;75(9):2745-52
references: 22498883
references: Mol Cell Proteomics. 2012 Mar;11(3):M111.013987
references: 22101334
references: Mol Cell Proteomics. 2012 Jun;11(6):O111.016717
references: 22261725
references: J Lipid Res. 2013 Oct;54(10):2575-85
references: 23434634
references: Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):10852-7
references: 16043703
references: Anal Chem. 1995 Apr 15;67(8):1426-36
references: 7741214
references: Nat Genet. 2014 Jun;46(6):543-50
references: 24816252
references: Am J Hum Genet. 1998 May;62(5):1198-211
references: 9545414
references: Bioinformatics. 2010 Apr 1;26(7):966-8
references: 20147306
references: J Clin Invest. 1992 Jul;90(1):52-60
references: 1386087
references: Nat Biotechnol. 2014 Mar;32(3):223-6
references: 24727771
references: Nat Genet. 2014 May;46(5):430-7
references: 24728292
references: Nat Methods. 2007 Mar;4(3):207-14
references: 17327847
references: Diabetes. 2012 Dec;61(12):3304-13
references: 22872235
references: JAMA. 2009 Jun 10;301(22):2331-9
references: 19509380
references: BMC Cancer. 2010;10:114
references: 20346108
references: Proc Natl Acad Sci U S A. 2011 Feb 22;108(8):3342-7
references: 21300890
references: Arterioscler Thromb Vasc Biol. 1999 Dec;19(12):2826-34
references: 10591657
references: Mol Syst Biol. 2005;1:2005.0017
references: 16729052
references: Mol Cell Proteomics. 2007 Jan;6(1):64-71
references: 17030953
references: Bioinformatics. 2008 Nov 1;24(21):2534-6
references: 18606607
references: Mol Syst Biol. 2008;4:222
references: 18854821
references: Nat Protoc. 2009;4(1):44-57
references: 19131956
references: Nat Genet. 2007 Oct;39(10):1217-24
references: 17873874
references: JAMA. 2009 Jul 1;302(1):37-48
references: 19567438
references: Mol Cell Proteomics. 2014 Jul;13(7):1753-68
references: 24741114
references: Nature. 2013 Feb 14;494(7436):266-70
references: 23334424
references: Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4673-8
references: 23487758
references: J Proteome Res. 2013 Apr 5;12(4):1628-44
references: 23391308
references: Nature. 2013 Jul 4;499(7456):79-82
references: 23676674
references: Mol Cell Proteomics. 2013 Jan;12(1):132-44
references: 23082029
references: PLoS Genet. 2009 Jun;5(6):e1000529
references: 19543373
references: Clin Chem. 2010 Feb;56(2):177-85
references: 19884488
references: Nat Genet. 1997 Dec;17(4):387-92
references: 9398838