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

Jingyuan Fu*, Marcel G M Wolfs, Patrick Deelen, Harm Jan Westra, Rudolf S N Fehrmann, Gerhardus te Meerman, Wim A Buurman, Sander S M Rensen, Hendricus Groen, Rinse K Weersma, Leonard H van den Berg, Jan Veldink, Roel A Ophoff, Harold Snieder, David van Heel, Ritsert C Jansen, Marten H Hofker, Cisca Wijmenga, Lude Franke

*Corresponding author for this work

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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.

Original languageEnglish
Article numbere1002431
Number of pages14
JournalPLoS genetics
Issue number1
Publication statusPublished - 19-Jan-2012


  • Adolescent
  • Adult
  • Aged
  • Alleles
  • Blood Proteins
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Genome, Human
  • Genotype
  • Humans
  • Intra-Abdominal Fat
  • Liver
  • Male
  • Middle Aged
  • Muscle, Skeletal
  • Organ Specificity
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci
  • Regulatory Sequences, Nucleic Acid
  • Subcutaneous Tissue

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