title: Identification and validation of genetic variants that influence transcription factor and cell signaling protein levels.
abstract: Many genetic variants associated with human disease have been found to be associated with alterations in mRNA expression. Although it is commonly assumed that mRNA expression changes will lead to consequent changes in protein levels, methodological challenges have limited our ability to test the degree to which this assumption holds true. Here, we further developed the micro-western array approach and globally examined relationships between human genetic variation and cellular protein levels. We collected more than 250,000 protein level measurements comprising 441 transcription factor and signaling protein isoforms across 68 Yoruba (YRI) HapMap lymphoblastoid cell lines (LCLs) and identified 12 cis and 160 trans protein level QTLs (pQTLs) at a false discovery rate (FDR) of 20%. Whereas up to two thirds of cis mRNA expression QTLs (eQTLs) were also pQTLs, many pQTLs were not associated with mRNA expression. Notably, we replicated and functionally validated a trans pQTL relationship between the KARS lysyl-tRNA synthetase locus and levels of the DIDO1 protein. This study demonstrates proof of concept in applying an antibody-based microarray approach to iteratively measure the levels of human proteins and relate these levels to human genome variation and other genomic data sets. Our results suggest that protein-based mechanisms might functionally buffer genetic alterations that influence mRNA expression levels and that pQTLs might contribute phenotypic diversity to a human population independently of influences on mRNA expression.
authors.affiliation: Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL 60637, USA; Committee on Genetics, Genomics and Systems Biology, University of Chicago, Chicago, IL 60637, USA; Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Hause
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Stark
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Nirav N
authors.initials: NN
authors.lastname: Antao
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Lidija K
authors.initials: LK
authors.lastname: Gorsic
authors.affiliation: Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Sophie H
authors.initials: SH
authors.lastname: Chung
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Brown
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Shan S
authors.initials: SS
authors.lastname: Wong
authors.affiliation: Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Gill
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Myers
authors.affiliation: Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Lida Anita
authors.initials: LA
authors.lastname: To
authors.affiliation: Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL 60637, USA; Committee on Genetics, Genomics and Systems Biology, University of Chicago, Chicago, IL 60637, USA; Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: White
authors.affiliation: Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL 60637, USA; Committee on Genetics, Genomics and Systems Biology, University of Chicago, Chicago, IL 60637, USA; Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, IL 60637, USA. Electronic address: edolan@medicine.bsd.uchicago.edu.
authors.forename: M Eileen
authors.initials: ME
authors.lastname: Dolan
authors.affiliation: Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL 60637, USA; Committee on Genetics, Genomics and Systems Biology, University of Chicago, Chicago, IL 60637, USA; Ben May Department for Cancer Research, University of Chicago, Chicago, IL 60637, USA; Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, IL 60637, USA. Electronic address: richardbjones@gmail.com.
authors.forename: Richard Baker
authors.initials: RB
authors.lastname: Jones
mesh_terms: D000906:Antibodies / Q000235:genetics / Q000276:immunology; D001483:Base Sequence; D002460:Cell Line; D002874:Chromosome Mapping; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D015870:Gene Expression; D014644:Genetic Variation; D015894:Genome, Human / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008957:Models, Genetic; D040081:Protein Array Analysis; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D020543:Proteome / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics
chemical_list: D000906:Antibodies; C518584:DIDO1 protein, human; D004268:DNA-Binding Proteins; D011506:Proteins; D020543:Proteome; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors
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