Tissue-Specific Genetic Control of Splicing: Implications for the Study of Complex Traits

Abstract

Numerous genome-wide screens for polymorphisms that influence gene expression have provided key insights into the genetic control of transcription. Despite this work, the relevance of specific polymorphisms to in vivo expression and splicing remains unclear. We carried out the first genome-wide screen, to our knowledge, for SNPs that associate with alternative splicing and gene expression in human primary cells, evaluating 93 autopsy-collected cortical brain tissue samples with no defined neuropsychiatric condition and 80 peripheral blood mononucleated cell samples collected from living healthy donors. We identified 23 high confidence associations with total expression and 80 with alternative splicing as reflected by expression levels of specific exons. Fewer than 50% of the implicated SNPs however show effects in both tissue types, reflecting strong evidence for distinct genetic control of splicing and expression in the two tissue types. The data generated here also suggest the possibility that splicing effects may be responsible for up to 13 out of 84 reported genome-wide significant associations with human traits. These results emphasize the importance of establishing a database of polymorphisms affecting splicing and expression in primary tissue types and suggest that splicing effects may be of more phenotypic significance than overall gene expression changes.

Author Summary

Although humans have a relatively small complement of genes, the proteins encoded by those genes and their biologic function are far more complex. The increased complexity is achieved in part through processes that create different messages from the same gene sequence (alternative splicing) and that regulate the expression of those messages in a tissue-specific fashion. These processes expand the functional capacity of the human genome, but also can create predisposition to disease when these processes go awry. In this study, we investigated how single nucleotide polymorphisms influence both overall gene expression and alternative splicing in two important cell types (brain and blood) highly relevant to human disease. Extensive and tissue-specific regulation of gene expression and alternative splicing were observed in the two tissue types, and some of these polymorphisms were shown to be connected to other polymorphsims that have been recently implicated in human diseases through genome-wide association studies. Most of these connections appeared to relate to alternative splicing as opposed to overall expression changes, suggesting that changes in splicing patterns may be more consequential for disease than those affecting only expression. These data emphasize the importance of comprehensive studies into genetic regulation of gene expression in all human tissue types in order to help understand how genetic variation influences risk of common diseases.

Abstract

We investigated tissue-specific genetic control of gene expression and alternative splicing in primary human cells, and we describe here the implications for understanding how genetic variation influences human disease.