Home LiteratureArticle Details
PMID: 22275870 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Unraveling the regulatory mechanisms underlying tissue-dependent genetic variation of gene expression.

PLoS genetics ·Vol. 8 ·No. 1 ·2012-01-00 ·Pages e1002431

Fu J, Wolfs MG, Deelen P, Westra HJ, Fehrmann RS, Te Meerman GJ, Buurman WA, Rensen SS, Groen HJ, Weersma RK, van den Berg LH, Veldink J, Ophoff RA, Snieder H, van Heel D, Jansen RC, Hofker MH, Wijmenga C, Franke L

Abstract

It is known that genetic variants can affect gene expression, but it is not yet completely clear through what mechanisms genetic variation mediate this expression. We therefore compared the cis-effect of single nucleotide polymorphisms (SNPs) on gene expression between blood samples from 1,240 human subjects and four primary non-blood tissues (liver, subcutaneous, and visceral adipose tissue and skeletal muscle) from 85 subjects. We characterized four different mechanisms for 2,072 probes that show tissue-dependent genetic regulation between blood and non-blood tissues: on average 33.2% only showed cis-regulation in non-blood tissues; 14.5% of the eQTL probes were regulated by different, independent SNPs depending on the tissue of investigation. 47.9% showed a different effect size although they were regulated by the same SNPs. Surprisingly, we observed that 4.4% were regulated by the same SNP but with opposite allelic direction. We show here that SNPs that are located in transcriptional regulatory elements are enriched for tissue-dependent regulation, including SNPs at 3' and 5' untranslated regions (P = 1.84×10(-5) and 4.7×10(-4), respectively) and SNPs that are synonymous-coding (P = 9.9×10(-4)). SNPs that are associated with complex traits more often exert a tissue-dependent effect on gene expression (P = 2.6×10(-10)). Our study yields new insights into the genetic basis of tissue-dependent expression and suggests that complex trait associated genetic variants have even more complex regulatory effects than previously anticipated.

MeSH Terms
Adolescent Adult Aged Alleles Blood Proteins/genetics Female Gene Expression Profiling Gene Expression Regulation Genome, Human Genotype Humans Intra-Abdominal Fat/metabolism Liver/metabolism Male Middle Aged Muscle, Skeletal/metabolism Organ Specificity Polymorphism, Single Nucleotide/genetics Quantitative Trait Loci/genetics Regulatory Sequences, Nucleic Acid/genetics Subcutaneous Tissue/metabolism
Chemicals
Blood Proteins
Authors & Affiliations
19 authors, click to expand affiliations / ORCID
Fu Jingyuan
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. fjingyuan@gmail.com
Wolfs Marcel G M
Deelen Patrick
Westra Harm-Jan
Fehrmann Rudolf S N
Te Meerman Gerard J
Buurman Wim A
Rensen Sander S M
Groen Harry J M
Weersma Rinse K
van den Berg Leonard H
Veldink Jan
Ophoff Roel A
Snieder Harold
van Heel David
Jansen Ritsert C
Hofker Marten H
Wijmenga Cisca
Franke Lude
Conflict of Interest

The authors have declared that no competing interests exist.

References (41)
41 references, click to expand
  1. Genetics of gene expression and its effect on disease.
    Nature. 2008 Mar 27;452(7186):423-8 PMID: 18344981
  2. A genome-wide association study identifies two new lung cancer susceptibility loci at 13q12.12 and 22q12.2 in Han Chinese.
    Nat Genet. 2011 Jul 03;43(8):792-6 PMID: 21725308
  3. The architecture of gene regulatory variation across multiple human tissues: the MuTHER study.
    PLoS Genet. 2011 Feb 03;7(2):e1002003 PMID: 21304890
  4. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits.
    Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9362-7 PMID: 19474294
  5. SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap.
    Bioinformatics. 2008 Dec 15;24(24):2938-9 PMID: 18974171
  6. Genome-wide association study identifies susceptibility loci for IgA nephropathy.
    Nat Genet. 2011 Mar 13;43(4):321-7 PMID: 21399633
  7. Genome-wide survey reveals dynamic widespread tissue-specific changes in DNA methylation during development.
    BMC Genomics. 2011 May 11;12(1):231 PMID: 21569359
  8. Human DNA methylomes at base resolution show widespread epigenomic differences.
    Nature. 2009 Nov 19;462(7271):315-22 PMID: 19829295
  9. Single-tissue and cross-tissue heritability of gene expression via identity-by-descent in related or unrelated individuals.
    PLoS Genet. 2011 Feb;7(2):e1001317 PMID: 21383966
  10. Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease.
    Am J Hum Genet. 2009 Sep;85(3):377-93 PMID: 19732864
  11. Expression quantitative trait loci are highly sensitive to cellular differentiation state.
    PLoS Genet. 2009 Oct;5(10):e1000692 PMID: 19834560
  12. Genetic inheritance of gene expression in human cell lines.
    Am J Hum Genet. 2004 Dec;75(6):1094-105 PMID: 15514893
  13. Cell-type selective chromatin remodeling defines the active subset of FOXA1-bound enhancers.
    Genome Res. 2009 Mar;19(3):372-80 PMID: 19129543
  14. Liver and adipose expression associated SNPs are enriched for association to type 2 diabetes.
    PLoS Genet. 2010 May 06;6(5):e1000932 PMID: 20463879
  15. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes.
    Nat Genet. 2009 Jun;41(6):703-7 PMID: 19430480
  16. Complex nature of SNP genotype effects on gene expression in primary human leucocytes.
    BMC Med Genomics. 2009 Jan 07;2:1 PMID: 19128478
  17. Mapping complex disease traits with global gene expression.
    Nat Rev Genet. 2009 Mar;10(3):184-94 PMID: 19223927
  18. Schizophrenia susceptibility alleles are enriched for alleles that affect gene expression in adult human brain.
    Mol Psychiatry. 2012 Feb;17(2):193-201 PMID: 21339752
  19. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents.
    N Engl J Med. 2000 Nov 9;343(19):1350-4 PMID: 11070098
  20. Common variants at five new loci associated with early-onset inflammatory bowel disease.
    Nat Genet. 2009 Dec;41(12):1335-40 PMID: 19915574
  21. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.
    Nat Genet. 2011 Mar;43(3):246-52 PMID: 21297633
  22. Gene expression in skin and lymphoblastoid cells: Refined statistical method reveals extensive overlap in cis-eQTL signals.
    Am J Hum Genet. 2010 Dec 10;87(6):779-89 PMID: 21129726
  23. Multiple common variants for celiac disease influencing immune gene expression.
    Nat Genet. 2010 Apr;42(4):295-302 PMID: 20190752
  24. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease.
    Nat Genet. 2008 Aug;40(8):955-62 PMID: 18587394
  25. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies.
    PLoS Genet. 2009 Jun;5(6):e1000529 PMID: 19543373
  26. A haplotype map of the human genome.
    Nature. 2005 Oct 27;437(7063):1299-320 PMID: 16255080
  27. Biological, clinical and population relevance of 95 loci for blood lipids.
    Nature. 2010 Aug 5;466(7307):707-13 PMID: 20686565
  28. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease.
    Nat Genet. 2011 Mar 06;43(4):333-8 PMID: 21378990
  29. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma.
    Nature. 2007 Jul 26;448(7152):470-3 PMID: 17611496
  30. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis.
    Nat Genet. 2011 Mar 13;43(4):329-32 PMID: 21399635
  31. Combining probability from independent tests: the weighted Z-method is superior to Fisher's approach.
    J Evol Biol. 2005 Sep;18(5):1368-73 PMID: 16135132
  32. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci.
    Nat Genet. 2010 Dec;42(12):1118-25 PMID: 21102463
  33. Trans-eQTLs reveal that independent genetic variants associated with a complex phenotype converge on intermediate genes, with a major role for the HLA.
    PLoS Genet. 2011 Aug;7(8):e1002197 PMID: 21829388
  34. From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus.
    Nature. 2010 Aug 5;466(7307):714-9 PMID: 20686566
  35. Expression quantitative trait loci detected in cell lines are often present in primary tissues.
    Hum Mol Genet. 2009 Nov 15;18(22):4296-303 PMID: 19671653
  36. Natural variation in human gene expression assessed in lymphoblastoid cells.
    Nat Genet. 2003 Mar;33(3):422-5 PMID: 12567189
  37. Common regulatory variation impacts gene expression in a cell type-dependent manner.
    Science. 2009 Sep 4;325(5945):1246-50 PMID: 19644074
  38. Mapping the genetic architecture of gene expression in human liver.
    PLoS Biol. 2008 May 6;6(5):e107 PMID: 18462017
  39. Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS.
    PLoS Genet. 2010 Apr 01;6(4):e1000888 PMID: 20369019
  40. A survey of genetic human cortical gene expression.
    Nat Genet. 2007 Dec;39(12):1494-9 PMID: 17982457
  41. Large-scale analysis of the human and mouse transcriptomes.
    Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4465-70 PMID: 11904358
Article Info
Journal
PLoS genetics
Abbr.
PLoS Genet
ISSN
1553-7404
DOI
10.1371/journal.pgen.1002431
Email
fjingyuan@gmail.com
Published
2012-01-00
Epub
2012-00-19
Pages
e1002431
Language
English
Region
United States
NLM ID
101239074
PMCID
PMC3261927
Subset
IM
Grants
NINDS NIH HHS · R01 NS058980 · United States
Medical Research Council · G1001158 · United Kingdom
Wellcome Trust · 084743 · United Kingdom
External Links
PubMed source DOI: 10.1371/journal.pgen.1002431 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2