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High-coverage RNA-sequencing Reveals Substantial Variation Associated with Geography, Environment and Endophenotypic Variation Awadalla, Philip


Phenotypic variation is the result of the combined effect of genetic variation with environmental influences. Gene-by-environment interactions are thought to be pervasive and may be responsible for a large fraction of the unexplained variance in heritability and disease risk. However, it has been particularly difficult to reliably identify robust gene-by-environment effects in humans. Studies mapping gene expression variation in humans have established that there is an abundant amount of inter-individual regulatory variation and that a significant fraction of this variation is heritable. Yet, a general understanding of the extent of variation of gene expression and how genetic regulatory variation is modulated by environmental factors is lacking. To systematically survey genetic, environmental and interaction effects on whole blood transcriptome, we combined whole transcriptome RNASeq profiling with whole genome genotyping on deeply endophenotyped individuals selected from over 40,000 participants in the CARTaGENE resource. We document substantial geographical variation in whole blood gene expression in this founder population that follows a south-north cline in the province of Quebec. Using haplotype-based methods on genome-wide genotyping, we detected fine-scale genetic structure within the province, and we were able to identify individuals that have migrated within the province from their ancestral region. In addition to the strong signature of geographic regional effects on gene expression, we reveal a substantial impact of environmental factors on global gene expression profiles overpowering that of genotype. Expression profiles of migrants are more similar to those of individuals presently living in the same region than to those of individuals with the same ancestry, but living in a different region. Genes involved in oxygen transport and inflammation are enriched among the differentially expressed genes between regions, suggesting an impact the highly urbanized environments on expression profiles. We also report several instances of genome-wide significant transcriptional gene-environment interactions (environmental eQTLs) that may have a clinical impact for individuals carrying specific genotypes in a given environment. These findings suggest that environmental variation can significantly alter disease genetic risk in both direct and indirect fashion and call for placing regulatory variants in the context of their geographical distribution and associated environmental exposures.

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