Skip to main content
SpringerLink
Log in

eQTL analysis links inflammatory bowel disease associated 1q21 locus to ECM1 gene

  • Human Genetics • Original Paper
  • Published:
Journal of Applied Genetics Aims and scope Submit manuscript

Abstract

Genome-wide association studies (GWAS) have been highly successful in inflammatory bowel disease (IBD) with 163 confirmed associations so far. We used expression quantitative trait loci (eQTL) mapping to analyze IBD associated regions for which causative gene from the region is still unknown. First, we performed an extensive literature search and in silico analysis of published GWAS in IBD and eQTL studies and extracted 402 IBD associated SNPs assigned to 208 candidate loci, and 9562 eQTL correlations. When crossing GWA and eQTL data we found that for 50 % of loci there is no eQTL gene, while for 31.2 % we can determine one gene, for 11.1 % two genes and for the remaining 7.7 % three or more genes. Based on that we selected loci with one, two, and three or more eQTL genes and analyzed them in peripheral blood lymphocytes and intestine tissue samples of 606 Slovene patients with IBD and in 449 controls. Association analysis of selected SNPs showed statistical significance for three (rs2631372 and rs1050152 on 5q locus and rs13294 on 1q locus) out of six selected SNPs with at least one phenotype. Furthermore, with eQTL analysis of selected chromosomal regions, we confirmed a link between SNP and gene for four (SLC22A5 on 5q, ECM1 on 1q, ORMDL3 on 17q, and PUS10 on 2p locus) out of five selected regions. For 1q21 loci, we confirmed gene ECM1 as the most plausible gene from this region to be involved in pathogenesis of IBD and thereby contributed new eQTL correlation from this genomic region.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Anderson CA et al (2011) Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 43:246–252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Asano K et al (2009) A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population. Nat Genet 41:1325–1329

    Article  CAS  PubMed  Google Scholar 

  • Barrett JC et al (2008) Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet 40:955–962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barrett JC et al (2009) Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat Genet 41:1330–1334

    Article  CAS  PubMed  Google Scholar 

  • Bullaughey K, Chavarria CI, Coop G, Gilad Y (2009) Expression quantitative trait loci detected in cell lines are often present in primary tissues. Hum Mol Genet 18:4296–4303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chan I, Liu L, Hamada T, Sethuraman G, McGrath JA (2007) The molecular basis of lipoid proteinosis: mutations in extracellular matrix protein 1. Exp Dermatol 16:881–890

    Article  CAS  PubMed  Google Scholar 

  • Derveaux S, Vandesompele J, Hellemans J (2010) How to do successful gene expression analysis using real-time PCR. Methods 50:227–230. doi:10.1016/j.ymeth.2009.11.001

    Article  CAS  PubMed  Google Scholar 

  • Deutsch S et al (2005) Gene expression variation and expression quantitative trait mapping of human chromosome 21 genes. Hum Mol Genet 14:3741–3749

    Article  CAS  PubMed  Google Scholar 

  • Dixon AL et al (2007) A genome-wide association study of global gene expression. Nat Genet 39:1202–1207

    Article  CAS  PubMed  Google Scholar 

  • Dubois PC et al (2010) Multiple common variants for celiac disease influencing immune gene expression. Nat Genet 42:295–302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duerr RH et al (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314:1461–1463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Feng T, Zhu X (2010) Genome-wide searching of rare genetic variants in WTCCC data. Hum Genet 128:269–280

    Article  PubMed  PubMed Central  Google Scholar 

  • Festen EA et al (2010) Genetic analysis in a Dutch study sample identifies more ulcerative colitis susceptibility loci and shows their additive role in disease risk. Am J Gastroenterol 105:395–402

    Article  CAS  PubMed  Google Scholar 

  • Fisher SA et al (2008) Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn’s disease. Nat Genet 40:710–712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Franke A et al (2008a) Replication of signals from recent studies of Crohn’s disease identifies previously unknown disease loci for ulcerative colitis. Nat Genet 40:713–715

    Article  CAS  PubMed  Google Scholar 

  • Franke A et al (2008b) Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat Genet 40:1319–1323

    Article  CAS  PubMed  Google Scholar 

  • Franke A et al (2008c) Genome-wide association analysis in sarcoidosis and Crohn’s disease unravels a common susceptibility locus on 10p12.2. Gastroenterology 135:1207–1215

    Article  CAS  PubMed  Google Scholar 

  • Franke A et al (2010a) Genome-wide association study for ulcerative colitis identifies risk loci at 7q22 and 22q13 (IL17REL). Nat Genet 42:292–294

    Article  CAS  PubMed  Google Scholar 

  • Franke A et al (2010b) Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet 42:1118–1125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fransen K et al (2010) Analysis of SNPs with an effect on gene expression identifies UBE2L3 and BCL3 as potential new risk genes for Crohn’s disease. Hum Mol Genet 19:3482–3488

    Article  CAS  PubMed  Google Scholar 

  • Freedman ML et al (2011) Principles for the post-GWAS functional characterization of cancer risk loci. Nat Genet 43:513–518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goring HH et al (2007) Discovery of expression QTLs using large-scale transcriptional profiling in human lymphocytes. Nat Genet 39:1208–1216

    Article  PubMed  Google Scholar 

  • Grundberg E et al (2009) Population genomics in a disease targeted primary cell model. Genome Res 19:1942–1952

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hampe J et al (2007) A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet 39:207–211

    Article  CAS  PubMed  Google Scholar 

  • Heap GA et al (2009) Complex nature of SNP genotype effects on gene expression in primary human leucocytes. BMC Med Genomics 2:1

    Article  PubMed  PubMed Central  Google Scholar 

  • Imielinski M et al (2009) Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat Genet 41:1335–1340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang J, Cui W, Vongsangnak W, Hu G, Shen B (2013) Post genome-wide association studies functional characterization of prostate cancer risk loci. BMC Genomics 14(Suppl 8):S9

    Article  PubMed  PubMed Central  Google Scholar 

  • Jostins L et al (2012) Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491:119–124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • King MC, Wilson AC (1975) Evolution at two levels in humans and chimpanzees. Science 188:107–116

    Article  CAS  PubMed  Google Scholar 

  • Kugathasan S et al (2008) Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease. Nat Genet 40:1211–1215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Libioulle C et al (2007) Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLoS Genet 3:e58

    Article  PubMed  PubMed Central  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 25:402–408

    Article  CAS  PubMed  Google Scholar 

  • Majewski J, Pastinen T (2011) The study of eQTL variations by RNA-seq: from SNPs to phenotypes. Trends Genet 27:72–79. doi:10.1016/j.tig.2010.10.006

    Article  CAS  PubMed  Google Scholar 

  • Matsuda A et al (2003) Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways. Oncogene 22:3307–3318

    Article  CAS  PubMed  Google Scholar 

  • McGovern DP et al (2010a) Genome-wide association identifies multiple ulcerative colitis susceptibility loci. Nat Genet 42:332–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McGovern DP et al (2010b) Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn’s disease. Hum Mol Genet 19:3468–3476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meggyesi N et al (2010) NKX2-3 and IRGM variants are associated with disease susceptibility to IBD in Eastern European patients. World J Gastroenterol 16:5233–5240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Min JL et al (2011) The use of genome-wide eQTL associations in lymphoblastoid cell lines to identify novel genetic pathways involved in complex traits. PLoS One 6, e22070. doi:10.1371/journal.pone.0022070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morley M, Molony CM, Weber TM, Devlin JL, Ewens KG, Spielman RS, Cheung VG (2004) Genetic analysis of genome-wide variation in human gene expression. Nature 430:743–747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nicolae DL, Gamazon E, Zhang W, Duan S, Dolan ME, Cox NJ (2010) Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS. PLoS Genet 6, e1000888

    Article  PubMed  PubMed Central  Google Scholar 

  • Noble CL et al (2005) The contribution of OCTN1/2 variants within the IBD5 locus to disease susceptibility and severity in Crohn's disease. Gastroenterology 129:1854–1864

  • Parkes M et al (2007) Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn’s disease susceptibility. Nat Genet 39:830–832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Petretto E et al (2006) Heritability and tissue specificity of expression quantitative trait loci. PLoS Genet 2, e172

    Article  PubMed  PubMed Central  Google Scholar 

  • Raelson JV et al (2007) Genome-wide association study for Crohn’s disease in the Quebec Founder Population identifies multiple validated disease loci. Proc Natl Acad Sci U S A 104:14747–14752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Repnik K, Potocnik U (2011) Haplotype in the IBD5 region is associated with refractory Crohn’s disease in Slovenian patients and modulates expression of the SLC22A5 gene. J Gastroenterol 46:1081–1091

    Article  PubMed  Google Scholar 

  • Rioux JD et al (2007) Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 39:596–604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schadt EE et al (2003) Genetics of gene expression surveyed in maize, mouse and man. Nature 422:297–302

    Article  CAS  PubMed  Google Scholar 

  • Silverberg MS et al (2009) Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. Nat Genet 41:216–220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stranger BE et al (2005) Genome-wide associations of gene expression variation in humans. PLoS Genet 1, e78

    Article  PubMed  PubMed Central  Google Scholar 

  • Stranger BE et al (2007) Population genomics of human gene expression. Nat Genet 39:1217–1224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • The Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–678

  • Wang K et al (2009) Diverse genome-wide association studies associate the IL12/IL23 pathway with Crohn Disease. Am J Hum Genet 84:399–405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Westra HJ et al (2015) Cell specific eQTL analysis without sorting cells. PLoS Genet 11, e1005223. doi:10.1371/journal.pgen.1005223

    Article  PubMed  PubMed Central  Google Scholar 

  • Yamazaki K et al (2005) Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn’s disease. Hum Mol Genet 14:3499–3506

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Faculty of Medicine, Center for Human Molecular Genetics and Pharmacogenomics, University of Maribor, Taborska ulica 8, 2000, Maribor, Slovenia

    Katja Repnik & Uroš Potočnik

  2. Faculty for Chemistry and Chemical Engineering, University of Maribor, Maribor, Slovenia

    Katja Repnik & Uroš Potočnik

Authors
  1. Katja Repnik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Uroš Potočnik
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Uroš Potočnik.

Additional information

Communicated by: Michal Witt

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Repnik, K., Potočnik, U. eQTL analysis links inflammatory bowel disease associated 1q21 locus to ECM1 gene. J Appl Genetics 57, 363–372 (2016). https://doi.org/10.1007/s13353-015-0334-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13353-015-0334-1

Keywords

Search

Navigation