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. Gene expression can be affected by genetic variation, e.g. single nucleotide polymorphisms (SNPs). These are called expression-affecting SNPs or eSNPs. Gene expression levels are known to vary across different tissues in the same individual, despite the fact that genetic variation is the same in these tissues. We explored the different mechanisms by which genetic variants can mediate tissue-dependent gene expression. We observed that the genetic variants that associated with complex traits are more likely to affect gene expression in a tissue-dependent manner. Our results suggest that complex traits are even more complex than we had anticipated, and they underline the great importance of using expression data from tissues relevant to the disease being studied in order to further the understanding of the biology underlying the disease association.