From DNA to RNA to disease and back: the 'central dogma' of regulatory disease variation

Abstract

Much of the focus of human disease genetics is directed towards identifying nucleotide variants that contribute to disease phenotypes. This is a complex problem, often involving contributions from multiple loci and their interactions, as well as effects due to environmental factors. Although some diseases with a genetic basis are caused by nucleotide changes that alter an amino acid sequence, in other cases, disease risk is associated with altered gene regulation. This paper focuses on how studies of gene expression variation might complement disease studies and provide crucial links between genotype and phenotype.

Figure 1

Flow charts demonstrating the use of genome-wide gene expression studies in relation to disease studies. (A) Generating hypotheses for disease studies. Expression quantitative trait loci (eQTL) mapping studies identify variable regions of the genome with functional effects on gene expression. Single nucleotide polymorphisms within these functional regions can be candidates for involvement in disease. (B) Supporting disease association studies. Disease mapping studies often identify non-coding regions of the genome exhibiting significant association with disease. eQTL studies can provide a link to an associated gene by providing annotation of the function of that non-coding region.

Figure 2

The three panels show the signal of association (as - log p-value of individual single nucleotide polymorphism (SNP) - phenotype associations) of genomic regions with disease, gene expression of gene A and gene expression of gene B. From this plot, it is suggested that genetic variation that increases disease risk is also associated with gene expression variation of gene A (assuming that the associated SNPs and haplotypes are the same). This probably indicates that the disease risk is a regulatory effect and that the amount of transcript (or protein) of gene A is critical for the development of the disease.