The Architecture of Gene Regulatory Variation across Multiple Human Tissues: The MuTHER Study

English version České info

While there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL), skin, and fat. The samples (156 LCL, 160 skin, 166 fat) were derived simultaneously from a subset of well-phenotyped healthy female twins of the MuTHER resource. We discover an abundance of cis-eQTLs in each tissue similar to previous estimates (858 or 4.7% of genes). In addition, we apply factor analysis (FA) to remove effects of latent variables, thus more than doubling the number of our discoveries (1,822 eQTL genes). The unique study design (Matched Co-Twin Analysis—MCTA) permits immediate replication of eQTLs using co-twins (93%–98%) and validation of the considerable gain in eQTL discovery after FA correction. We highlight the challenges of comparing eQTLs between tissues. After verifying previous significance threshold-based estimates of tissue-specificity, we show their limitations given their dependency on statistical power. We propose that continuous estimates of the proportion of tissue-shared signals and direct comparison of the magnitude of effect on the fold change in expression are essential properties that jointly provide a biologically realistic view of tissue-specificity. Under this framework we demonstrate that 30% of eQTLs are shared among the three tissues studied, while another 29% appear exclusively tissue-specific. However, even among the shared eQTLs, a substantial proportion (10%–20%) have significant differences in the magnitude of fold change between genotypic classes across tissues. Our results underline the need to account for the complexity of eQTL tissue-specificity in an effort to assess consequences of such variants for complex traits.

Vyšlo v časopise: The Architecture of Gene Regulatory Variation across Multiple Human Tissues: The MuTHER Study. PLoS Genet 7(2): e32767. doi:10.1371/journal.pgen.1002003
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002003

Souhrn

Zdroje

1. MontgomerySBSammethMGutierrez-ArcelusMLachRPIngleC 2010 Transcriptome genetics using second generation sequencing in a Caucasian population. Nature 464 773 777

2. PickrellJKMarioniJCPaiAADegnerJFEngelhardtBE 2010 Understanding mechanisms underlying human gene expression variation with RNA sequencing. Nature 464 768 772

3. CheungVGSpielmanRSEwensKGWeberTMMorleyM 2005 Mapping determinants of human gene expression by regional and genome-wide association. Nature 437 1365 1369

4. StrangerBEForrestMSClarkAGMinichielloMJDeutschS 2005 Genome-wide associations of gene expression variation in humans. PLoS Genet 1 e78 doi:10.1371/journal.pgen.0010078

5. StrangerBENicaACForrestMSDimasABirdCP 2007 Population genomics of human gene expression. Nat Genet 39 1217 1224

6. StrangerBEForrestMSDunningMIngleCEBeazleyC 2007 Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315 848 853

7. DimasASDeutschSStrangerBEMontgomerySBBorelC 2009 Common regulatory variation impacts gene expression in a cell type-dependent manner. Science 325 1246 1250

8. MyersAJGibbsJRWebsterJARohrerKZhaoA 2007 A survey of genetic human cortical gene expression. Nat Genet 39 1494 1499

9. EmilssonVThorleifssonGZhangBLeonardsonASZinkF 2008 Genetics of gene expression and its effect on disease. Nature 452 423 428

10. SchadtEEMolonyCChudinEHaoKYangX 2008 Mapping the genetic architecture of gene expression in human liver. PLoS Biol 6 e107 doi:10.1371/journal.pbio.0060107

11. GoringHHCurranJEJohnsonMPDyerTDCharlesworthJ 2007 Discovery of expression QTLs using large-scale transcriptional profiling in human lymphocytes. Nat Genet 39 1208 1216

12. 2007 Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447 661 678

13. DermitzakisET 2008 From gene expression to disease risk. Nat Genet 40 492 493

14. ChenYZhuJLumPYYangXPintoS 2008 Variations in DNA elucidate molecular networks that cause disease. Nature 452 429 435

15. MoffattMFKabeschMLiangLDixonALStrachanD 2007 Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 448 470 473

16. McCarrollSAHuettAKuballaPChilewskiSDLandryA 2008 Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease. Nat Genet 40 1107 1112

17. NicaACMontgomerySBDimasASStrangerBEBeazleyC 2010 Candidate causal regulatory effects by integration of expression QTLs with complex trait genetic associations. PLoS Genet 6 e1000895 doi:10.1371/journal.pgen.1000895

18. NicolaeDLGamazonEZhangWDuanSDolanME 2010 Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS. PLoS Genet 6 e1000888 doi:10.1371/journal.pgen.1000888

19. LoosRJLindgrenCMLiSWheelerEZhaoJH 2008 Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet 40 768 775

20. RavasiTSuzukiHCannistraciCVKatayamaSBajicVB 2010 An atlas of combinatorial transcriptional regulation in mouse and man. Cell 140 744 752

21. ZhongHYangXKaplanLMMolonyCSchadtEE 2010 Integrating Pathway Analysis and Genetics of Gene Expression for Genome-wide Association Studies. Am J Hum Genet

22. SpectorTDWilliamsFM 2006 The UK Adult Twin Registry (TwinsUK). Twin Res Hum Genet 9 899 906

23. StoreyJDTibshiraniR 2003 Statistical significance for genomewide studies. Proc Natl Acad Sci U S A 100 9440 9445

24. IdaghdourYCzikaWShiannaKVLeeSHVisscherPM 2010 Geographical genomics of human leukocyte gene expression variation in southern Morocco. Nat Genet 42 62 67

25. StegleOPartsLDurbinRWinnJ 2010 A Bayesian framework to account for complex non-genetic factors in gene expression levels greatly increases power in eQTL studies. PLoS Comput Biol 6 e1000770 doi:10.1371/journal.pcbi.1000770

26. TeoYYInouyeMSmallKSGwilliamRDeloukasP 2007 A genotype calling algorithm for the Illumina BeadArray platform. Bioinformatics 23 2741 2746

27. McVeanGAMyersSRHuntSDeloukasPBentleyDR 2004 The fine-scale structure of recombination rate variation in the human genome. Science 304 581 584