从表达QTLs到个体转录组的进展
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摘要
建立表达数量性状位点(eQTLs)与全基因组关联研究(GWAS)相结合的方法,可以为人类复杂疾病的病因学和复杂性状研究提供进一步的功能信息。在探索疾病的转录组,细胞的生长动态过程,人群的起源和多样化拟表型方面,这一方法,也为人们提供了一种较好的,有助于理解疾病发生机制和人类基因调控格局的研究手段。本综述将介绍在基因组时代eQTLs的应用及其意义。
Approaches that combine expression quantitative trait loci( eQTLs) and genome-wide association( GWA) studies are offering further functional information about the aetiology of complex human diseases and complex traits. These approaches-which take into account technological advances in resolving the transcriptome,cell history and state,population of origin and diverse endophenotypes-are providing better reach teqchniques to help us understand the architecture of disease and the landscape of gene regulation in humans. This review will introduce the application and significance of eQTLs on genome era.
Approaches that combine expression quantitative trait loci( eQTLs) and genome-wide association( GWA) studies are offering further functional information about the aetiology of complex human diseases and complex traits. These approaches-which take into account technological advances in resolving the transcriptome,cell history and state,population of origin and diverse endophenotypes-are providing better reach teqchniques to help us understand the architecture of disease and the landscape of gene regulation in humans. This review will introduce the application and significance of eQTLs on genome era.
引文
1 De Vienne,D.,Leonardi,A.&Damerval,C.Genetic aspects of variation of protein amounts in maize and pea[J].Electrophoresis,1988,9:742-750.
2 Damerval,C.,Maurice,A.,Josse,J.M.&de Vienne,D.Quantitative trait loci underlying gene product variation:a novel perspective for analyzing regulation of genome expression[J].Genetics,1994,137:《中国老年保健医学》杂志2014年第12卷第1期·综述·289-301.
3 Michaelson,J.J.,Loguercio,S.&Beyer,A.Detection and interpretation of expression quantitative trait loci(eQTL)[J].Methods,2009,48:265-276.
4 Cookson,W.,Liang,L.,Abecasis,G.,Moffatt,M.&Lathrop,M.Mapping complex disease traits with global gene expression[J].Nat Rev Genet,2009,10:184-194.
5 Nicolae,D.L.et al.Trait-associated SNPs are more likely to be eQTLs:annotation to enhance discovery from GWAS[J].PLoS Genet,2010,6:e1000888.
6 Gamazon,E.R.,Huang,R.S.,Cox,N.J.&Dolan,M.E.Chemotherapeutic drug susceptibility associated SNPs are enriched in expression quantitative trait loci[J].Proc Natl Acad Sci U S A,2010,107:9287-9292.
7 Lee,S.I.et al.Learning a prior on regulatory potential from eQTL data[J].PLoS Genet,2009,5:e1000358.
8 Manolio,T.A.et al.Finding the missing heritability of complex diseases[J].Nature,2009,461:747-753.
9 Manolio,T.A.Genomewide association studies and assessment of the risk of disease[J].N Engl J Med,2010,363:166-176.
10 Nica,A.C.et al.Candidate causal regulatory effects by integration of expression QTLs with complex trait genetic associations[J].PLoS Genet,2010,6:e1000895.
11 Montgomery,S.B.et al.Transcriptome genetics using second generation sequencing in a Caucasian population[J].Nature,2010,464:773-777.
12 Pickrell,A.M.&Moraes,C.T.What role does mitochondrial stress play in neurodegenerative diseases?[J].Methods Mol Biol,2010,648:63-78.
13 Kwan,T.et al.Tissue effect on genetic control of transcript isoform variation[J].PLoS Genet,2009,5:e1000608.
14 Altshuler,D.M.et al.Integrating common and rare genetic variation in diverse human populations[J].Nature,2010,467:52-58.
15 Zaitlen,N.,Pasaniuc,B.,Gur,T.,Ziv,E.&Halperin,E.Leveraging genetic variability across populations for the identification of causal variants[J].Am J Hum Genet,2010,86:23-33.
16 Moffatt,M.F.et al.Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma[J].Nature,2007,448:470-473.
17 Emilsson,V.et al.Genetics of gene expression and its effect on disease[J].Nature,2008,452:423-428.
18 Stranger,B.E.et al.Population genomics of human gene expression[J].Nat Genet,2007,39:1217-1224.
19 Dimas,A.S.et al.Common regulatory variation impacts gene expression in a cell type-dependent manner[J].Science,2009,325:1246-1250.
20 Birney,E.et al.Identification and analysis of functional elements in 1%of the human genome by the ENCODE pilot project[J].Nature,2007,447:799-816.
21 van Nas,A.et al.Expression quantitative trait loci:replication,tissueand sex-specificity in mice[J].Genetics,2010,185:1059-1068.
22 Gerrits,A.et al.Expression quantitative trait loci are highly sensitive to cellular differentiation state[J].PLoS Genet,2009,5:e1000692.
23 Nica,A.C.et al.The architecture of gene regulatory variation across multiple human tissues:the MuTHER study[J].PLoS Genet,2011,7:e1002003.
24 Gilad,Y.,Rifkin,S.A.&Pritchard,J.K.Revealing the architecture of gene regulation:the promise of eQTL studies[J].Trends Genet,2008,24:408-415.
25 Cheung,V.G.et al.Polymorphic cis-and trans-regulation of human gene expression[J].PLoS Biol,2010:8.
26 Petretto,E.et al.New insights into the genetic control of gene expression using a Bayesian multi-tissue approach[J].PLoS Comput Biol,2010,6:e1000737.
27 Fehrmann,R.S.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[J].PLoS Genet,2011,7:e1002197.
28 Grundberg,E.et al.Mapping cis-and trans-regulatory effects across multiple tissues in twins[J].Nat Genet,2012,44:1084-1089.
29 Breitling,R.et al.Genetical genomics:spotlight on QTL hotspots[J].PLoS Genet,2008,4:e1000232.
30 Sun,W.,Yu,T.&Li,K.C.Detection of eQTL modules mediated by activity levels of transcription factors[J].Bioinformatics,2007,23:2290-2297.
31 Wu,C.et al.Gene set enrichment in eQTL data identifies novel annotations and pathway regulators[J].PLoS Genet,2008,4:e1000070.
32 Ghazalpour,A.et al.Integrating genetic and network analysis to characterize genes related to mouse weight[J].PLoS Genet,2006,2:e130.
33 Ren,X.,Zhou,X.,Wu,L.Y.&Zhang,X.S.An information-flowbased model with dissipation,saturation and direction for active pathway inference[J].BMC Syst Biol,2010,4:72.
34 Li,S.,Lu,Q.&Cui,Y.A systems biology approach for identifying novel pathway regulators in eQTL mapping[J].J Biopharm Stat,2010,20:373-400.
35 Lee,E.&Bussemaker,H.J.Identifying the genetic determinants of transcription factor activity[J].Mol Syst Biol,2010,6:412.
36 Sun,W.&Hu,Y.eQTL Mapping Using RNA-seq Data[J].Stat Biosci,2013,5:198-219.
37 Sun,W.A statistical framework for eQTL mapping using RNA-seq data[J].Biometrics,2012,68:1-11.
38 Pickrell,J.K.et al.Understanding mechanisms underlying human gene expression variation with RNA sequencing[J].Nature,2010,464:768-72.
39 McDaniell,R.et al.Heritable individual-specific and allele-specific chromatin signatures in humans[J].Science,2010,328:235-239.
40 Dubois,P.C.et al.Multiple common variants for celiac disease influencing immune gene expression[J].Nat Genet,2010,42:295-302.
41 Speliotes,E.K.et al.Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index[J].Nat Genet,2010,42:937-948.
42 Anttila,V.et al.Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1[J].Nat Genet,2010,42:869-873.
43 Teslovich,T.M.et al.Biological,clinical and population relevance of 95 loci for blood lipids[J].Nature,2010,466:707-713.
44 Musunuru,K.et al.From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus[J].Nature,2010,466:714-719.
45 Li,Q.et al.Integrative eQTL-based analyses reveal the biology of breast cancer risk loci[J].Cell,2013,152:633-641.
46 Libioulle,C.et al.Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4[J].PLoS Genet,2007,3:e58.
47 Heid,I.M.et al.Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution[J].Nat Genet,2010,42:949-960.
48 Lango Allen,H.et al.Hundreds of variants clustered in genomic loci and biological pathways affect human height[J].Nature,2010,467:832-838.
49 Wheeler,H.E.et al.Sequential use of transcriptional profiling,expression quantitative trait mapping,and gene association implicates MMP20 in human kidney aging[J].PLoS Genet,2009,5:e1000685.
50 Cunnington,M.S.,Santibanez Koref,M.,Mayosi,B.M.,Burn,J.&Keavney,B.Chromosome 9p21 SNPs Associated with Multiple Disease Phenotypes Correlate with ANRIL Expression[J].PLoS Genet,2010,6:e1000899.
51 Hsu,Y.H.et al.An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility Loci for osteoporosis-related traits[J].PLoS Genet,2010,6:e1000977.
52 Rivadeneira,F.et al.Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies[J].Nat Genet,2009,41:1199-206.
53 Hamza,T.H.et al.Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease[J].Nat Genet,2010,42:781-785.
54 Simon-Sanchez,J.et al.Genome-wide association study reveals genetic risk underlying Parkinson's disease[J].Nat Genet,2009,41:1308-1312.
55 Stuart,P.E.et al.Genome-wide association analysis identifies three psoriasis susceptibility loci[J].Nat Genet,2010,42:1000-1004.
56 Sotoodehnia,N.et al.Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction[J].Nat Genet,2010,42:1068-1076.
57 Dupuis,J.et al.New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk[J].Nat Genet,2010,42:105-16.
58 Voight,B.F.et al.Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis[J].Nat Genet,2010,42:579-589.
59 Cheng,Y.,Quinn,J.F.&Weiss,L.A.An eQTL mapping approach reveals that rare variants in the SEMA5A regulatory network impact autism risk[J].Hum Mol Genet,2013,22:2960-2972.
60 Kabakchiev,B.&Silverberg,M.S.Expression quantitative trait Loci analysis identifies associations between genotype and gene expression in human intestine[J].Gastroenterology,2013,144:1488-1496.
61 Soubrier,F.From an ACE polymorphism to genome-wide searches for eQTL[J].J Clin Invest,2013,123:111-112.
62 Yamanaka,S.&Blau,H.M.Nuclear reprogramming to a pluripotent state by three approaches[J].Nature,2010,465:704-712.
63 Abecasis,G.R.et al.A map of human genome variation from population-scale sequencing[J].Nature,2010,467:1061-1073.
64 Wen,Y.et al.An eQTL-based method identifies CTTN and ZMAT3 as pemetrexed susceptibility markers[J].Hum Mol Genet,2012,21:1470-1480.
65 Glubb,D.M.,Dholakia,N.&Innocenti,F.Liver expression quantitative trait loci:a foundation for pharmacogenomic research[J].Front Genet,2012,3:153.
2 Damerval,C.,Maurice,A.,Josse,J.M.&de Vienne,D.Quantitative trait loci underlying gene product variation:a novel perspective for analyzing regulation of genome expression[J].Genetics,1994,137:《中国老年保健医学》杂志2014年第12卷第1期·综述·289-301.
3 Michaelson,J.J.,Loguercio,S.&Beyer,A.Detection and interpretation of expression quantitative trait loci(eQTL)[J].Methods,2009,48:265-276.
4 Cookson,W.,Liang,L.,Abecasis,G.,Moffatt,M.&Lathrop,M.Mapping complex disease traits with global gene expression[J].Nat Rev Genet,2009,10:184-194.
5 Nicolae,D.L.et al.Trait-associated SNPs are more likely to be eQTLs:annotation to enhance discovery from GWAS[J].PLoS Genet,2010,6:e1000888.
6 Gamazon,E.R.,Huang,R.S.,Cox,N.J.&Dolan,M.E.Chemotherapeutic drug susceptibility associated SNPs are enriched in expression quantitative trait loci[J].Proc Natl Acad Sci U S A,2010,107:9287-9292.
7 Lee,S.I.et al.Learning a prior on regulatory potential from eQTL data[J].PLoS Genet,2009,5:e1000358.
8 Manolio,T.A.et al.Finding the missing heritability of complex diseases[J].Nature,2009,461:747-753.
9 Manolio,T.A.Genomewide association studies and assessment of the risk of disease[J].N Engl J Med,2010,363:166-176.
10 Nica,A.C.et al.Candidate causal regulatory effects by integration of expression QTLs with complex trait genetic associations[J].PLoS Genet,2010,6:e1000895.
11 Montgomery,S.B.et al.Transcriptome genetics using second generation sequencing in a Caucasian population[J].Nature,2010,464:773-777.
12 Pickrell,A.M.&Moraes,C.T.What role does mitochondrial stress play in neurodegenerative diseases?[J].Methods Mol Biol,2010,648:63-78.
13 Kwan,T.et al.Tissue effect on genetic control of transcript isoform variation[J].PLoS Genet,2009,5:e1000608.
14 Altshuler,D.M.et al.Integrating common and rare genetic variation in diverse human populations[J].Nature,2010,467:52-58.
15 Zaitlen,N.,Pasaniuc,B.,Gur,T.,Ziv,E.&Halperin,E.Leveraging genetic variability across populations for the identification of causal variants[J].Am J Hum Genet,2010,86:23-33.
16 Moffatt,M.F.et al.Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma[J].Nature,2007,448:470-473.
17 Emilsson,V.et al.Genetics of gene expression and its effect on disease[J].Nature,2008,452:423-428.
18 Stranger,B.E.et al.Population genomics of human gene expression[J].Nat Genet,2007,39:1217-1224.
19 Dimas,A.S.et al.Common regulatory variation impacts gene expression in a cell type-dependent manner[J].Science,2009,325:1246-1250.
20 Birney,E.et al.Identification and analysis of functional elements in 1%of the human genome by the ENCODE pilot project[J].Nature,2007,447:799-816.
21 van Nas,A.et al.Expression quantitative trait loci:replication,tissueand sex-specificity in mice[J].Genetics,2010,185:1059-1068.
22 Gerrits,A.et al.Expression quantitative trait loci are highly sensitive to cellular differentiation state[J].PLoS Genet,2009,5:e1000692.
23 Nica,A.C.et al.The architecture of gene regulatory variation across multiple human tissues:the MuTHER study[J].PLoS Genet,2011,7:e1002003.
24 Gilad,Y.,Rifkin,S.A.&Pritchard,J.K.Revealing the architecture of gene regulation:the promise of eQTL studies[J].Trends Genet,2008,24:408-415.
25 Cheung,V.G.et al.Polymorphic cis-and trans-regulation of human gene expression[J].PLoS Biol,2010:8.
26 Petretto,E.et al.New insights into the genetic control of gene expression using a Bayesian multi-tissue approach[J].PLoS Comput Biol,2010,6:e1000737.
27 Fehrmann,R.S.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[J].PLoS Genet,2011,7:e1002197.
28 Grundberg,E.et al.Mapping cis-and trans-regulatory effects across multiple tissues in twins[J].Nat Genet,2012,44:1084-1089.
29 Breitling,R.et al.Genetical genomics:spotlight on QTL hotspots[J].PLoS Genet,2008,4:e1000232.
30 Sun,W.,Yu,T.&Li,K.C.Detection of eQTL modules mediated by activity levels of transcription factors[J].Bioinformatics,2007,23:2290-2297.
31 Wu,C.et al.Gene set enrichment in eQTL data identifies novel annotations and pathway regulators[J].PLoS Genet,2008,4:e1000070.
32 Ghazalpour,A.et al.Integrating genetic and network analysis to characterize genes related to mouse weight[J].PLoS Genet,2006,2:e130.
33 Ren,X.,Zhou,X.,Wu,L.Y.&Zhang,X.S.An information-flowbased model with dissipation,saturation and direction for active pathway inference[J].BMC Syst Biol,2010,4:72.
34 Li,S.,Lu,Q.&Cui,Y.A systems biology approach for identifying novel pathway regulators in eQTL mapping[J].J Biopharm Stat,2010,20:373-400.
35 Lee,E.&Bussemaker,H.J.Identifying the genetic determinants of transcription factor activity[J].Mol Syst Biol,2010,6:412.
36 Sun,W.&Hu,Y.eQTL Mapping Using RNA-seq Data[J].Stat Biosci,2013,5:198-219.
37 Sun,W.A statistical framework for eQTL mapping using RNA-seq data[J].Biometrics,2012,68:1-11.
38 Pickrell,J.K.et al.Understanding mechanisms underlying human gene expression variation with RNA sequencing[J].Nature,2010,464:768-72.
39 McDaniell,R.et al.Heritable individual-specific and allele-specific chromatin signatures in humans[J].Science,2010,328:235-239.
40 Dubois,P.C.et al.Multiple common variants for celiac disease influencing immune gene expression[J].Nat Genet,2010,42:295-302.
41 Speliotes,E.K.et al.Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index[J].Nat Genet,2010,42:937-948.
42 Anttila,V.et al.Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1[J].Nat Genet,2010,42:869-873.
43 Teslovich,T.M.et al.Biological,clinical and population relevance of 95 loci for blood lipids[J].Nature,2010,466:707-713.
44 Musunuru,K.et al.From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus[J].Nature,2010,466:714-719.
45 Li,Q.et al.Integrative eQTL-based analyses reveal the biology of breast cancer risk loci[J].Cell,2013,152:633-641.
46 Libioulle,C.et al.Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4[J].PLoS Genet,2007,3:e58.
47 Heid,I.M.et al.Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution[J].Nat Genet,2010,42:949-960.
48 Lango Allen,H.et al.Hundreds of variants clustered in genomic loci and biological pathways affect human height[J].Nature,2010,467:832-838.
49 Wheeler,H.E.et al.Sequential use of transcriptional profiling,expression quantitative trait mapping,and gene association implicates MMP20 in human kidney aging[J].PLoS Genet,2009,5:e1000685.
50 Cunnington,M.S.,Santibanez Koref,M.,Mayosi,B.M.,Burn,J.&Keavney,B.Chromosome 9p21 SNPs Associated with Multiple Disease Phenotypes Correlate with ANRIL Expression[J].PLoS Genet,2010,6:e1000899.
51 Hsu,Y.H.et al.An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility Loci for osteoporosis-related traits[J].PLoS Genet,2010,6:e1000977.
52 Rivadeneira,F.et al.Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies[J].Nat Genet,2009,41:1199-206.
53 Hamza,T.H.et al.Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease[J].Nat Genet,2010,42:781-785.
54 Simon-Sanchez,J.et al.Genome-wide association study reveals genetic risk underlying Parkinson's disease[J].Nat Genet,2009,41:1308-1312.
55 Stuart,P.E.et al.Genome-wide association analysis identifies three psoriasis susceptibility loci[J].Nat Genet,2010,42:1000-1004.
56 Sotoodehnia,N.et al.Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction[J].Nat Genet,2010,42:1068-1076.
57 Dupuis,J.et al.New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk[J].Nat Genet,2010,42:105-16.
58 Voight,B.F.et al.Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis[J].Nat Genet,2010,42:579-589.
59 Cheng,Y.,Quinn,J.F.&Weiss,L.A.An eQTL mapping approach reveals that rare variants in the SEMA5A regulatory network impact autism risk[J].Hum Mol Genet,2013,22:2960-2972.
60 Kabakchiev,B.&Silverberg,M.S.Expression quantitative trait Loci analysis identifies associations between genotype and gene expression in human intestine[J].Gastroenterology,2013,144:1488-1496.
61 Soubrier,F.From an ACE polymorphism to genome-wide searches for eQTL[J].J Clin Invest,2013,123:111-112.
62 Yamanaka,S.&Blau,H.M.Nuclear reprogramming to a pluripotent state by three approaches[J].Nature,2010,465:704-712.
63 Abecasis,G.R.et al.A map of human genome variation from population-scale sequencing[J].Nature,2010,467:1061-1073.
64 Wen,Y.et al.An eQTL-based method identifies CTTN and ZMAT3 as pemetrexed susceptibility markers[J].Hum Mol Genet,2012,21:1470-1480.
65 Glubb,D.M.,Dholakia,N.&Innocenti,F.Liver expression quantitative trait loci:a foundation for pharmacogenomic research[J].Front Genet,2012,3:153.