Expression quantitative trait locus analysis for translational medicine

Expression quantitative trait locus analysis has emerged as an important component of efforts to understand how genetic polymorphisms influence disease risk and is poised to make contributions to translational medicine. Here we review how expression quantitative trait locus analysis is aiding the identification of which gene(s) within regions of association are causal for a disease or phenotypic trait; the narrowing down of the cell types or regulators involved in the etiology of disease; the characterization of drivers and modifiers of cancer; and our understanding of how different environments and cellular contexts can modify gene expression. We also introduce the concept of transcriptional risk scores as a means of refining estimates of individual liability to disease based on targeted profiling of the transcripts that are regulated by polymorphisms jointly associated with disease and gene expression.

[1]  M. DePamphilis,et al.  HUMAN DISEASE , 1957, The Ulster Medical Journal.

[2]  Alex E. Lash,et al.  Gene Expression Omnibus: NCBI gene expression and hybridization array data repository , 2002, Nucleic Acids Res..

[3]  R. Stoughton,et al.  Genetics of gene expression surveyed in maize, mouse and man , 2003, Nature.

[4]  D. Pe’er,et al.  Module networks: identifying regulatory modules and their condition-specific regulators from gene expression data , 2003, Nature Genetics.

[5]  D. Kleinjan,et al.  Long-range control of gene expression: emerging mechanisms and disruption in disease. , 2005, American journal of human genetics.

[6]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[7]  L. Kruglyak,et al.  Genetics of global gene expression , 2006, Nature Reviews Genetics.

[8]  Jingyuan Fu,et al.  Mapping Determinants of Gene Expression Plasticity by Genetical Genomics in C. elegans , 2006, PLoS genetics.

[9]  G. Gibson,et al.  Quantitative trait transcripts for nicotine resistance in Drosophila melanogaster , 2007, Nature Genetics.

[10]  A. Barabasi,et al.  The human disease network , 2007, Proceedings of the National Academy of Sciences.

[11]  Helen E. Parkinson,et al.  ArrayExpress—a public database of microarray experiments and gene expression profiles , 2006, Nucleic Acids Res..

[12]  Francis S. Collins,et al.  Identifiability in Genomic Research , 2007, Science.

[13]  Francisco S. Roque,et al.  A large-scale analysis of tissue-specific pathology and gene expression of human disease genes and complexes , 2008, Proceedings of the National Academy of Sciences.

[14]  Joshua M. Korn,et al.  Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2008, Nature.

[15]  Scott A. Rifkin,et al.  Revealing the architecture of gene regulation: the promise of eQTL studies. , 2008, Trends in genetics : TIG.

[16]  Virginia Pascual,et al.  A modular analysis framework for blood genomics studies: application to systemic lupus erythematosus. , 2008, Immunity.

[17]  Eric E Schadt,et al.  Accuracy of Genome-wide Imputation of Untyped Markers and Impacts on Statistical Power for Association Studies , 2009 .

[18]  H. Stefánsson,et al.  Genetics of gene expression and its effect on disease , 2008, Nature.

[19]  N. Schork,et al.  Prediction of cancer driver mutations in protein kinases. , 2008, Cancer research.

[20]  L. Liang,et al.  Mapping complex disease traits with global gene expression , 2009, Nature Reviews Genetics.

[21]  L. Hood,et al.  Systems medicine: the future of medical genomics and healthcare , 2009, Genome Medicine.

[22]  M. Daly,et al.  Identifying Relationships among Genomic Disease Regions: Predicting Genes at Pathogenic SNP Associations and Rare Deletions , 2009, PLoS genetics.

[23]  Silke Szymczak,et al.  Genetics and Beyond – The Transcriptome of Human Monocytes and Disease Susceptibility , 2010, PloS one.

[24]  Olle Melander,et al.  From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus , 2010, Nature.

[25]  E. Dermitzakis,et al.  Candidate Causal Regulatory Effects by Integration of Expression QTLs with Complex Trait Genetic Associations , 2010, PLoS genetics.

[26]  N. Cox,et al.  Trait-Associated SNPs Are More Likely to Be eQTLs: Annotation to Enhance Discovery from GWAS , 2010, PLoS genetics.

[27]  Tsun-Po Yang,et al.  Genevar: a database and Java application for the analysis and visualization of SNP-gene associations in eQTL studies , 2010, Bioinform..

[28]  D. Pe’er,et al.  An Integrated Approach to Uncover Drivers of Cancer , 2010, Cell.

[29]  Sharon R Grossman,et al.  Integrating common and rare genetic variation in diverse human populations , 2010, Nature.

[30]  Wei Chen,et al.  Gene Expression in Skin and Lymphoblastoid Cells: Refined Statistical Method Reveals Extensive Overlap in Cis-eqtl Signals , 2022 .

[31]  Russell D. Wolfinger,et al.  Geographical Genomics of Human Leukocyte Gene Expression Variation in Southern Morocco , 2009, Nature Genetics.

[32]  Jacek Majewski,et al.  The study of eQTL variations by RNA-seq: from SNPs to phenotypes. , 2011, Trends in genetics : TIG.

[33]  M. Daly,et al.  Proteins Encoded in Genomic Regions Associated with Immune-Mediated Disease Physically Interact and Suggest Underlying Biology , 2011, PLoS genetics.

[34]  Alkes L. Price,et al.  Single-Tissue and Cross-Tissue Heritability of Gene Expression Via Identity-by-Descent in Related or Unrelated Individuals , 2011, PLoS genetics.

[35]  J. Shendure,et al.  Exome sequencing as a tool for Mendelian disease gene discovery , 2011, Nature Reviews Genetics.

[36]  Miles Parkes,et al.  Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis. , 2011, The Journal of clinical investigation.

[37]  Benjamin J. Raphael,et al.  Integrated Genomic Analyses of Ovarian Carcinoma , 2011, Nature.

[38]  Bin Zhang,et al.  A survey of the genetics of stomach, liver, and adipose gene expression from a morbidly obese cohort. , 2011, Genome research.

[39]  Damian Szklarczyk,et al.  The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored , 2010, Nucleic Acids Res..

[40]  Jingyuan Fu,et al.  Trans-eQTLs Reveal That Independent Genetic Variants Associated with a Complex Phenotype Converge on Intermediate Genes, with a Major Role for the HLA , 2011, PLoS genetics.

[41]  Simon C. Potter,et al.  The Architecture of Gene Regulatory Variation across Multiple Human Tissues: The MuTHER Study , 2011, PLoS genetics.

[42]  F. Vannberg,et al.  GENETICS OF GENE EXPRESSION IN PRIMARY IMMUNE CELLS IDENTIFIES CELL-SPECIFIC MASTER REGULATORS AND ROLES OF HLA ALLELES , 2012, Nature Genetics.

[43]  P. Deloukas,et al.  Patterns of Cis Regulatory Variation in Diverse Human Populations , 2012, PLoS genetics.

[44]  Xihong Lin,et al.  Population Differences in Transcript-Regulator Expression Quantitative Trait Loci , 2012, PloS one.

[45]  Nicholas Eriksson,et al.  Comparison of Family History and SNPs for Predicting Risk of Complex Disease , 2012, PLoS genetics.

[46]  Simon C. Potter,et al.  Mapping cis- and trans-regulatory effects across multiple tissues in twins , 2012, Nature Genetics.

[47]  Steven J. M. Jones,et al.  Comprehensive molecular characterization of human colon and rectal cancer , 2012, Nature.

[48]  P. Awadalla,et al.  Evidence for additive and interaction effects of host genotype and infection in malaria , 2012, Proceedings of the National Academy of Sciences.

[49]  Joseph B Hiatt,et al.  Massively parallel functional dissection of mammalian enhancers in vivo , 2012, Nature Biotechnology.

[50]  Matthew Stephens,et al.  The Contribution of RNA Decay Quantitative Trait Loci to Inter-Individual Variation in Steady-State Gene Expression Levels , 2012, PLoS genetics.

[51]  Data production leads,et al.  An integrated encyclopedia of DNA elements in the human genome , 2012 .

[52]  P. Visscher,et al.  Genetic control of gene expression in whole blood and lymphoblastoid cell lines is largely independent. , 2012, Genome research.

[53]  P. Visscher,et al.  Five years of GWAS discovery. , 2012, American journal of human genetics.

[54]  S. Batzoglou,et al.  Linking disease associations with regulatory information in the human genome , 2012, Genome research.

[55]  Maxwell D. Sanderford,et al.  Evolutionary meta-analysis of association studies reveals ancient constraints affecting disease marker discovery. , 2012, Molecular biology and evolution.

[56]  Shane J. Neph,et al.  Systematic Localization of Common Disease-Associated Variation in Regulatory DNA , 2012, Science.

[57]  Greg Gibson,et al.  Using Blood Informative Transcripts in Geographical Genomics: Impact of Lifestyle on Gene Expression in Fijians , 2012, Front. Gene..

[58]  ENCODEConsortium,et al.  An Integrated Encyclopedia of DNA Elements in the Human Genome , 2012, Nature.

[59]  John C. Marioni,et al.  Deciphering the genetic architecture of variation in the immune response to Mycobacterium tuberculosis infection , 2012, Proceedings of the National Academy of Sciences.

[60]  Tanya M. Teslovich,et al.  Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes , 2012, Nature Genetics.

[61]  David C. Wilson,et al.  Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease , 2012, Nature.

[62]  Eurie L. Hong,et al.  Annotation of functional variation in personal genomes using RegulomeDB , 2012, Genome research.

[63]  Ara Darzi,et al.  Preparing for precision medicine. , 2012, The New England journal of medicine.

[64]  Manolis Kellis,et al.  HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants , 2011, Nucleic Acids Res..

[65]  M. Peters,et al.  Systematic identification of trans eQTLs as putative drivers of known disease associations , 2013, Nature Genetics.

[66]  Jonathan K. Pritchard,et al.  Identification of Genetic Variants That Affect Histone Modifications in Human Cells , 2013, Science.

[67]  P. Visscher,et al.  Pitfalls of predicting complex traits from SNPs , 2013, Nature Reviews Genetics.

[68]  M. Stephens,et al.  A Statistical Framework for Joint eQTL Analysis in Multiple Tissues , 2012, PLoS genetics.

[69]  Pedro G. Ferreira,et al.  Transcriptome and genome sequencing uncovers functional variation in humans , 2013, Nature.

[70]  M. Clyde,et al.  Functional annotation signatures of disease susceptibility loci improve SNP association analysis , 2013, bioRxiv.

[71]  H. Hakonarson,et al.  Large sample size, wide variant spectrum, and advanced machine-learning technique boost risk prediction for inflammatory bowel disease. , 2013, American journal of human genetics.

[72]  Mathieu Blanchette,et al.  The relationship between DNA methylation, genetic and expression inter-individual variation in untransformed human fibroblasts , 2014, Genome Biology.

[73]  Jong-Keuk Lee,et al.  Large-scale profiling and identification of potential regulatory mechanisms for allelic gene expression in colorectal cancer cells. , 2013, Gene.

[74]  Greg Gibson,et al.  Blood-Informative Transcripts Define Nine Common Axes of Peripheral Blood Gene Expression , 2013, PLoS genetics.

[75]  Joseph E. Powell,et al.  Congruence of Additive and Non-Additive Effects on Gene Expression Estimated from Pedigree and SNP Data , 2013, PLoS genetics.

[76]  Jonathan K. Pritchard,et al.  Primate Transcript and Protein Expression Levels Evolve Under Compensatory Selection Pressures , 2013, Science.

[77]  E. Dermitzakis,et al.  Genetic and epigenetic regulation of human lincRNA gene expression. , 2013, American journal of human genetics.

[78]  Jiang Li,et al.  Large Scale Comparison of Gene Expression Levels by Microarrays and RNAseq Using TCGA Data , 2013, PloS one.

[79]  Jason M. Torres,et al.  Inter-ethnic differences in lymphocyte sensitivity to glucocorticoids reflect variation in transcriptional response , 2011, The Pharmacogenomics Journal.

[80]  Jaana M. Hartikainen,et al.  Large-scale genotyping identifies 41 new loci associated with breast cancer risk , 2013, Nature Genetics.

[81]  Leighton J. Core,et al.  Coordinated Effects of Sequence Variation on DNA Binding, Chromatin Structure, and Transcription , 2013, Science.

[82]  Jingyuan Fu,et al.  Human Disease-Associated Genetic Variation Impacts Large Intergenic Non-Coding RNA Expression , 2013, PLoS genetics.

[83]  Ellen T. Gelfand,et al.  The Genotype-Tissue Expression (GTEx) project , 2013, Nature Genetics.

[84]  Joshua M. Stuart,et al.  The Cancer Genome Atlas Pan-Cancer analysis project , 2013, Nature Genetics.

[85]  Joseph E. Powell,et al.  Detection and replication of epistasis influencing transcription in humans , 2014, Nature.

[86]  John D. Blischak,et al.  Methylation QTLs Are Associated with Coordinated Changes in Transcription Factor Binding, Histone Modifications, and Gene Expression Levels , 2014, bioRxiv.

[87]  M. Peters,et al.  Cell specific eQTL analysis without sorting cells , 2014, bioRxiv.

[88]  A. Singleton,et al.  Genetic variability in the regulation of gene expression in ten regions of the human brain , 2014, Nature Neuroscience.

[89]  P. Visscher,et al.  Another Explanation for Apparent Epistasis , 2014 .

[90]  Daphne Koller,et al.  Polarization of the Effects of Autoimmune and Neurodegenerative Risk Alleles in Leukocytes , 2014, Science.

[91]  P. Sullivan,et al.  Heritability and Genomics of Gene Expression in Peripheral Blood , 2014, Nature Genetics.

[92]  Han Xu,et al.  Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. , 2014, American journal of human genetics.

[93]  Richard Durbin,et al.  Genetic interactions affecting human gene expression identified by variance association mapping , 2014, eLife.

[94]  C. Spencer,et al.  Biological Insights From 108 Schizophrenia-Associated Genetic Loci , 2014, Nature.

[95]  Daniel J. Gaffney,et al.  Genetic Background Drives Transcriptional Variation in Human Induced Pluripotent Stem Cells , 2014, PLoS genetics.

[96]  C. Gieger,et al.  Mapping the Genetic Architecture of Gene Regulation in Whole Blood , 2014, PloS one.

[97]  M. Lupien,et al.  Combinatorial effects of multiple enhancer variants in linkage disequilibrium dictate levels of gene expression to confer susceptibility to common traits , 2014, Genome research.

[98]  Manolis Kellis,et al.  Common Genetic Variants Modulate Pathogen-Sensing Responses in Human Dendritic Cells , 2014, Science.

[99]  G. Gibson Cancer: Directions for the drivers , 2014, Nature.

[100]  John D. Storey,et al.  Gene expression profiles associated with acute myocardial infarction and risk of cardiovascular death , 2014, Genome Medicine.

[101]  J. Knight,et al.  Approaches for establishing the function of regulatory genetic variants involved in disease , 2014, Genome Medicine.

[102]  Takahisa Kawaguchi,et al.  Large-Scale East-Asian eQTL Mapping Reveals Novel Candidate Genes for LD Mapping and the Genomic Landscape of Transcriptional Effects of Sequence Variants , 2014, PloS one.

[103]  C. Wallace,et al.  Bayesian Test for Colocalisation between Pairs of Genetic Association Studies Using Summary Statistics , 2013, PLoS genetics.

[104]  Xavier Solé,et al.  Identification of candidate susceptibility genes for colorectal cancer through eQTL analysis. , 2014, Carcinogenesis.

[105]  Joseph K. Pickrell Joint analysis of functional genomic data and genome-wide association studies of 18 human traits , 2013, bioRxiv.

[106]  Emmanouil T. Dermitzakis,et al.  Putative cis-regulatory drivers in colorectal cancer , 2014, Nature.

[107]  J. Shendure,et al.  A general framework for estimating the relative pathogenicity of human genetic variants , 2014, Nature Genetics.

[108]  Jun S. Liu,et al.  Genetics of rheumatoid arthritis contributes to biology and drug discovery , 2013 .

[109]  R. Andrews,et al.  Innate Immune Activity Conditions the Effect of Regulatory Variants upon Monocyte Gene Expression , 2014, Science.

[110]  Chun Jimmie Ye,et al.  Intersection of population variation and autoimmunity genetics in human T cell activation , 2014, Science.

[111]  A. Lusis,et al.  Systems genetics approaches to understand complex traits , 2013, Nature Reviews Genetics.

[112]  Xiaoquan Wen,et al.  Cross-Population Joint Analysis of eQTLs: Fine Mapping and Functional Annotation , 2014, bioRxiv.

[113]  L. Kruglyak,et al.  The role of regulatory variation in complex traits and disease , 2015, Nature Reviews Genetics.

[114]  Kristin Reiche,et al.  Dissecting the genetics of the human transcriptome identifies novel trait-related trans-eQTLs and corroborates the regulatory relevance of non-protein coding loci† , 2015, Human molecular genetics.

[115]  Jun S. Liu,et al.  The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans , 2015, Science.

[116]  Richard Durbin,et al.  Gene-gene and gene-environment interactions detected by transcriptome sequence analysis in twins , 2014, Nature Genetics.

[117]  M. Daly,et al.  Genetic and Epigenetic Fine-Mapping of Causal Autoimmune Disease Variants , 2014, Nature.

[118]  John Quackenbush,et al.  Genetic control of gene expression at novel and established chronic obstructive pulmonary disease loci. , 2015, Human molecular genetics.

[119]  Jingyuan Fu,et al.  Cell Specific eQTL Analysis without Sorting Cells , 2014, bioRxiv.

[120]  F. Collins,et al.  A new initiative on precision medicine. , 2015, The New England journal of medicine.

[121]  Tomas W. Fitzgerald,et al.  Large-scale discovery of novel genetic causes of developmental disorders , 2014, Nature.

[122]  Alexis Battle,et al.  Impact of regulatory variation from RNA to protein , 2015, Science.

[123]  C. Spencer,et al.  A contribution of novel CNVs to schizophrenia from a genome-wide study of 41,321 subjects: CNV Analysis Group and the Schizophrenia Working Group of the Psychiatric Genomics Consortium , 2016, bioRxiv.