title: Unraveling the regulatory mechanisms underlying tissue-dependent genetic variation of gene expression.
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.
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. fjingyuan@gmail.com
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Fu
authors.forename: Marcel G M
authors.initials: MG
authors.lastname: Wolfs
authors.forename: Patrick
authors.initials: P
authors.lastname: Deelen
authors.forename: Harm-Jan
authors.initials: HJ
authors.lastname: Westra
authors.forename: Rudolf S N
authors.initials: RS
authors.lastname: Fehrmann
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Te Meerman
authors.forename: Wim A
authors.initials: WA
authors.lastname: Buurman
authors.forename: Sander S M
authors.initials: SS
authors.lastname: Rensen
authors.forename: Harry J M
authors.initials: HJ
authors.lastname: Groen
authors.forename: Rinse K
authors.initials: RK
authors.lastname: Weersma
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
authors.forename: Jan
authors.initials: J
authors.lastname: Veldink
authors.forename: Roel A
authors.initials: RA
authors.lastname: Ophoff
authors.forename: Harold
authors.initials: H
authors.lastname: Snieder
authors.forename: David
authors.initials: D
authors.lastname: van Heel
authors.forename: Ritsert C
authors.initials: RC
authors.lastname: Jansen
authors.forename: Marten H
authors.initials: MH
authors.lastname: Hofker
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001798:Blood Proteins / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D050152:Intra-Abdominal Fat / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D009928:Organ Specificity; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D040521:Subcutaneous Tissue / Q000378:metabolism*
chemical_list: D001798:Blood Proteins