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

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 39 and 59 untranslated regions (P = 1.84610 and 4.7610, respectively) and SNPs that are synonymous-coding (P = 9.9610). SNPs that are associated with complex traits more often exert a tissue-dependent effect on gene expression (P = 2.6610). 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. Citation: Fu J, Wolfs MGM, Deelen P, Westra H-J, Fehrmann RSN, et al. (2012) Unraveling the Regulatory Mechanisms Underlying Tissue-Dependent Genetic Variation of Gene Expression. PLoS Genet 8(1): e1002431. doi:10.1371/journal.pgen. 1002431 Editor: Greg Gibson, Georgia Institute of Technology, United States of America Received July 19, 2011; Accepted November 8, 2011; Published January 19, 2012 Copyright: 2012 Fu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by IOP Genomics grant IGE05012A, the Netherlands Organisation for Scientific Research (NWO) VICI grant 918.66. 620 (CW), a European Union FP7 COPACETIC grant 201379 (CW), the Dutch Diabetes Foundation (2006.00.007), the Wellcome Trust (084743 to DvH), the Medical Research Council UK (G1001158 to DvH), Juvenile Diabetes Research Foundation (33-2008-402 to DvH), a NWO VENI grant 863.09. 007 (JF), a NWO VENI grant 916.10. 135, a Horizon Breakthrough grant 92519031 from the Netherlands Genomics Initiative (LF), a NWO clinical fellowship grant 90.700. 281 (RKW), the Netherlands ALS foundation and the Adessium Foundation (LHvdB), the Thierry Latran Foundation (JV), and a Transnational University Limburg (TUL) grant (SSMR). The research leading to these results has received funding from the European Community’s Health Seventh Framework Programme (FP7/2007–2013) under grant agreement nu 259867. This study was financed in part by the SIA-raakPRO subsidy for project BioCOMP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: fjingyuan@gmail.com (JF); lude@ludesign.nl (LF)