Gene-gene and gene-environment interactions detected by transcriptome sequence analysis in twins

Abstract

Understanding the genetic architecture of gene expression is an intermediate step in understanding the genetic architecture of complex diseases. RNA sequencing technologies have improved the quantification of gene expression and allow measurement of allele-specific expression (ASE). ASE is hypothesized to result from the direct effect of cis regulatory variants, but a proper estimation of the causes of ASE has not been performed thus far. In this study, we take advantage of a sample of twins to measure the relative contributions of genetic and environmental effects to ASE, and we find substantial effects from gene × gene (G×G) and gene × environment (G×E) interactions. We propose a model where ASE requires genetic variability in cis, a difference in the sequence of both alleles, but where the magnitude of the ASE effect depends on trans genetic and environmental factors that interact with the cis genetic variants.

Figure 1

ASE correlation among twin pairs for different categories of genetic similarity. MZ: monozygotic twins; DZ: dizygotic twins; DZibs05: DZ twins with identical by state (IBS) equal to 0.5 at the eQTL locus. The 95% confidence intervals were calculated by using 1000 bootstrap permutations.

Figure 2

Variance components for ASE for the model with cis × trans interaction: ‘H2’ (equal to eqtl + cis + cis.trans + trans) is the heritability of ASE, ‘eqtl’ is the proportion of variance explained by a common eQTL, ‘cis’ is the proportion of variance explained by other variants in cis, ‘cis.trans’ is the proportion of variance explained by interactions between cis and trans genetic variants, ‘trans’ in the proportion of variance explained by genetic variants in trans, ‘c’ is the proportion of variance explained by the shared environment and ‘e’ is the proportion of variance explained by the individual environment. The 95% confidence intervals where calculated using 1000 bootstrap permutations.

Figure 3

G×E examples discovered using discordant MZ twins analysis. MZ twin pairs show a different ASE effect on some genes depending on the genotype of specific SNPs. The Y axis shows the ASE difference between MZ twins. Since MZ twins are genetically identical, this association reflects the interaction of the SNP with an unknown environment. Boxplots represent the difference in ASE in MZ twin pairs that are heterozygous (in green) and homozygous (in orange) at the SNP of interest. A) ASE in gene ACSL1 shows G×E interaction with SNP r334710824 in Fat; B) ASE in gene ADIPOQ shows G×E interaction with SNP rs4686817 in Fat; C) ASE in gene EBI3 shows G×E interaction with SNP rs67782188 in LCLs.