Transcriptional risk scores link GWAS to eQTLs and predict complications in Crohn's disease

Nature Genetics

Volumn 49, Issue 10, 2017, Pages 1517-1521

  Marigorta, Urko M ^a   Denson, Lee A ^b   Hyams, Jeffrey S ^c   Mondal, Kajari ^d   Prince, Jarod ^d   Walters, Thomas D ^e   Griffiths, Anne ^e   Noe, Joshua D ^f   Crandall, Wallace V ^g   Rosh, Joel R ^h   Mack, David R ⁱ   Kellermayer, Richard ^j   Heyman, Melvin B ^k   Baker, Susan S ^l   Stephens, Michael C ^m   Baldassano, Robert N ⁿ   Markowitz, James F ^o   Kim, Mi Ok ^b   Dubinsky, Marla C ^p   Cho, Judy ^p   Aronow, Bruce J ^b   Kugathasan, Subra ^d   Gibson, Greg ^a   more..

^a GEORGIA INSTITUTE OF TECHNOLOGY   (United States)

^b CINCINNATI CHILDREN'S HOSPITAL MEDICAL CENTER   (United States)

^c Division of Pediatric Infectious Diseases   (United States)

^d EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

^e HOSPITAL FOR SICK CHILDREN   (Canada)

^f MEDICAL COLLEGE OF WISCONSIN   (United States)

^g THE OHIO STATE UNIVERSITY COLLEGE OF MEDICINE   (United States)

^h Goryeb Children's Hospital   (United States)

ⁱ CHILDREN S HOSPITAL OF EASTERN ONTARIO   (Canada)

^j TEXAS CHILDREN S HOSPITAL   (United States)

^k UNIVERSITY OF CALIFORNIA   (United States)

^l UNIVERSITY AT BUFFALO   (United States)

^m MAYO CLINIC   (United States)

ⁿ UNIVERSITY OF PENNSYLVANIA   (United States)

^o Northwell Health   (United States)

^p MOUNT SINAI HOSPITAL   (United States)

more..

Author keywords

[No Author keywords available]

Indexed keywords

TUMOR NECROSIS FACTOR; MESSENGER RNA;

ALLELE; ARTICLE; CD4+ T LYMPHOCYTE; COHORT ANALYSIS; COMPARATIVE STUDY; CONTROLLED STUDY; CROHN DISEASE; DISEASE COURSE; GENE EXPRESSION; GENE LINKAGE DISEQUILIBRIUM; GENETIC ASSOCIATION; GENETIC RISK; GENETIC SUSCEPTIBILITY; GENETIC TRANSCRIPTION; GENOME-WIDE ASSOCIATION STUDY; HUMAN; IMMUNOSTIMULATION; MAJOR CLINICAL STUDY; MENDELIAN RANDOMIZATION ANALYSIS; OBSERVATIONAL STUDY; PHENOTYPE; PRIORITY JOURNAL; PROSPECTIVE STUDY; RNA SEQUENCE; SINGLE NUCLEOTIDE POLYMORPHISM; ULCERATIVE COLITIS; BIOLOGICAL MODEL; BIOSYNTHESIS; CHILD; COMPLICATION; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION; GENETIC PREDISPOSITION; GENETICS; ILEUM; INFLAMMATORY BOWEL DISEASE; INFORMATION PROCESSING; METABOLISM; ONSET AGE; PROGNOSIS; QUANTITATIVE TRAIT LOCUS; RISK ASSESSMENT;

AGE OF ONSET; ALLELES; CHILD; CROHN DISEASE; DATASETS AS TOPIC; DISEASE PROGRESSION; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION; GENETIC PREDISPOSITION TO DISEASE; GENOME-WIDE ASSOCIATION STUDY; HUMANS; ILEUM; INFLAMMATORY BOWEL DISEASES; MODELS, GENETIC; OBSERVATIONAL STUDIES AS TOPIC; POLYMORPHISM, SINGLE NUCLEOTIDE; PROGNOSIS; QUANTITATIVE TRAIT LOCI; RISK ASSESSMENT; RNA, MESSENGER; TRANSCRIPTION, GENETIC;

EID: 85030184192     PISSN: 10614036     EISSN: 15461718     Source Type: Journal    
DOI: 10.1038/ng.3936     Document Type: Article

References (45)

1. Fairfax, B.P. & Knight, J.C. Genetics of gene expression in immunity to infection. Curr. Opin. Immunol. 30, 63-71 (2014).
2. Gibson, G., Powell, J.E. & Marigorta, U.M. Expression quantitative trait locus analysis for translational medicine. Genome Med. 7, 60 (2015).
3. Haberman, Y. et al. Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature. J. Clin. Invest. 124, 3617-3633 (2014).
4. Kugathasan, S. et al. Prediction of complicated disease course for children newly diagnosed with Crohn's disease: A multicentre inception cohort study. Lancet 389, 1710-1718 (2017).
5. Witte, J.S., Visscher, P.M. & Wray, N.R. The contribution of genetic variants to disease depends on the ruler. Nat. Rev. Genet. 15, 765-776 (2014).
6. Wray, N.R., Yang, J., Goddard, M.E. & Visscher, P.M. The genetic interpretation of area under the ROC curve in genomic profiling. PLoS Genet. 6, e1000864 (2010).
7. Wray, N.R., Goddard, M.E. & Visscher, P.M. Prediction of individual genetic risk to disease from genome-wide association studies. Genome Res. 17, 1520-1528 (2007).
8. Chatterjee, N., Shi, J. & García-Closas, M. Developing and evaluating polygenic risk prediction models for stratified disease prevention. Nat. Rev. Genet. 17, 392-406 (2016).
9. Walters, T.D. et al. Increased effectiveness of early therapy with anti-tumor necrosis factor-vs an immunomodulator in children with Crohn's disease. Gastroenterology 146, 383-391 (2014).
10. Liu, J.Z. et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat. Genet. 47, 979-986 (2015).
11. Westra, H.J. et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat. Genet. 45, 1238-1243 (2013).
12. Kabakchiev, B. & Silverberg, M.S. Expression quantitative trait loci analysis identifies associations between genotype and gene expression in human intestine. Gastroenterology 144, 1488-1496 (2013).
13. GTEx Consortium. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348, 648-660 (2015).
14. Di Narzo, A.F. et al. Blood and intestine eQTLs from an anti-TNF-resistant Crohn's disease cohort inform IBD genetic association loci. Clin. Transl. Gastroenterol. 7, e177 (2016).
15. Giambartolomei, C. et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 10, e1004383 (2014).
16. Hormozdiari, F. et al. Colocalization of GWAS and eQTL signals detects target genes. Am. J. Hum. Genet. 99, 1245-1260 (2016).
17. Zhu, Z. et al. Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nat. Genet. 48, 481-487 (2016).
18. Lee, J.C. et al. Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn's disease. Nat. Genet. 49, 262-268 (2017).
19. Ning, K. et al. Improved integrative framework combining association data with gene expression features to prioritize Crohn's disease genes. Hum. Mol. Genet. 24, 4147-4157 (2015).
20. Singh, T. et al. Characterization of expression quantitative trait loci in the human colon. Inflamm. Bowel Dis. 21, 251-256 (2015).
21. Albert, F.W. & Kruglyak, L. The role of regulatory variation in complex traits and disease. Nat. Rev. Genet. 16, 197-212 (2015).
22. Gibson, G. & Weir, B. The quantitative genetics of transcription. Trends Genet. 21, 616-623 (2005).
23. de Souza, H.S. & Fiocchi, C. Immunopathogenesis of IBD: current state of the art. Nat. Rev. Gastroenterol. Hepatol. 13, 13-27 (2016).
24. McGovern, D.P., Kugathasan, S. & Cho, J.H. Genetics of inflammatory bowel diseases. Gastroenterology 149, 1163-1176 (2015).
25. Nabekura, T. et al. Costimulatory molecule DNAM-1 is essential for optimal differentiation of memory natural killer cells during mouse cytomegalovirus infection. Immunity 40, 225-234 (2014).
26. Martinet, L. & Smyth, M.J. Balancing natural killer cell activation through paired receptors. Nat. Rev. Immunol. 15, 243-254 (2015).
27. Petrillo, M.G. et al. GITR+ regulatory T cells in the treatment of autoimmune diseases. Autoimmun. Rev. 14, 117-126 (2015).
28. Reikvam, D.H. et al. Increase of regulatory T cells in ileal mucosa of untreated pediatric Crohn's disease patients. Scand. J. Gastroenterol. 46, 550-560 (2011).
29. Ye, C.J. et al. Intersection of population variation and autoimmunity genetics in human T cell activation. Science 345, 1254665 (2014).
30. Wiley, S.E. et al. The outer mitochondrial membrane protein mitoNEET contains A novel redox-active 2Fe-2S cluster. J. Biol. Chem. 282, 23745-23749 (2007).
31. Novak, E.A. & Mollen, K.P. Mitochondrial dysfunction in inflammatory bowel disease. Front. Cell Dev. Biol. 3, 62 (2015).
32. Levine, A. et al. Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification. Inflamm. Bowel Dis. 17, 1314-1321 (2011).
33. Satsangi, J., Silverberg, M.S., Vermeire, S. & Colombel, J.F. The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications. Gut 55, 749-753 (2006).
34. Cleynen, I. et al. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: A genetic association study. Lancet 387, 156-167 (2016).
35. Kim, D. et al. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 14, R36 (2013).
36. Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078-2079 (2009).
37. Anders, S., Pyl, P.T. & Huber, W. HTSeq-a Python framework to work with highthroughput sequencing data. Bioinformatics 31, 166-169 (2015).
38. Robinson, M.D., McCarthy, D.J. & Smyth, G.K. edgeR: A Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139-140 (2010).
39. Mortazavi, A., Williams, B.A., McCue, K., Schaeffer, L. & Wold, B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat. Methods 5, 621-628 (2008).
40. Onengut-Gumuscu, S. et al. Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Nat. Genet. 47, 381-386 (2015).
41. Leek, J.T., Johnson, W.E., Parker, H.S., Jaffe, A.E. & Storey, J.D. The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics 28, 882-883 (2012).
42. Mecham, B.H., Nelson, P.S. & Storey, J.D. Supervised normalization of microarrays. Bioinformatics 26, 1308-1315 (2010).
43. Zhou, X. & Stephens, M. Genome-wide efficient mixed-model analysis for association studies. Nat. Genet. 44, 821-824 (2012).
44. Chun, S. et al. Limited statistical evidence for shared genetic effects of eQTLs and autoimmune-disease-associated loci in three major immune-cell types. Nat. Genet. 49, 600-605 (2017).
45. Lee, M.N. et al. Common genetic variants modulate pathogen-sensing responses in human dendritic cells. Science 343, 1246980 (2014).