Unraveling the Regulatory Mechanisms Underlying Tissue-Dependent Genetic Variation of Gene Expression

被引：162

作者：

Fu, Jingyuan ^{[1
,2
]}

Wolfs, Marcel G. M. ^{[3
]}

Deelen, Patrick ^{[4
]}

Westra, Harm-Jan ^{[1
]}

Fehrmann, Rudolf S. N. ^{[1
,5
]}

Meerman, Gerard J. Te ^{[1
]}

Buurman, Wim A. ^{[6
,7
]}

Rensen, Sander S. M. ^{[6
,7
]}

Groen, Harry J. M. ^{[8
]}

Weersma, Rinse K. ^{[9
]}

van den Berg, Leonard H. ^{[10
]}

Veldink, Jan ^{[10
]}

Ophoff, Roel A. ^{[11
]}

Snieder, Harold ^{[2
]}

van Heel, David ^{[12
]}

Jansen, Ritsert C. ^{[13
]}

Hofker, Marten H. ^{[3
]}

Wijmenga, Cisca ^{[1
]}

Franke, Lude ^{[1
]}

机构：

[1] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands

[2] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands

[3] Univ Groningen, Univ Med Ctr Groningen, Dept Pathol & Med Biol, Groningen, Netherlands

[4] Hanze Univ Groningen, Groningen, Netherlands

[5] Univ Groningen, Univ Med Ctr Groningen, Dept Med Oncol, Groningen, Netherlands

[6] Maastricht Univ, Nutr & Toxicol Res Inst NUTRIM, Maastricht, Netherlands

[7] Univ Hosp Maastricht, Dept Surg, Maastricht, Netherlands

[8] Univ Groningen, Univ Med Ctr Groningen, Dept Pulmonol, Groningen, Netherlands

[9] Univ Groningen, Dept Gastroenterol & Hepatol, Univ Med Ctr Groningen, Groningen, Netherlands

[10] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Neurol, Utrecht, Netherlands

[11] Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands

[12] Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst Cell & Mol Sci, London, England

[13] Univ Groningen, Groningen Bioinformat Ctr, Groningen Biomol Sci & Biotechnol Inst, Haren, Netherlands

来源：

PLOS GENETICS | 2012年 / 8卷 / 01期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; COMMON VARIANTS; RISK; NUMBER;

D O I：

10.1371/journal.pgen.1002431

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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=1.84x10(-5) and 4.7x10(-4), respectively) and SNPs that are synonymous-coding (P = 9.9x10(-4)). SNPs that are associated with complex traits more often exert a tissue-dependent effect on gene expression (P = 2.6x10(-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.

引用

页数：14

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