Trends in Genetics
Feature ReviewWhere Are the Disease-Associated eQTLs?
Section snippets
Molecular QTL Annotation as a Strategy for Interpreting Disease Genetics
The vast majority of the thousands of genetic loci associated with human disease are located outside coding regions, putatively in genomic regions that participate in gene regulation [1., 2., 3.]. In most cases it remains unclear how disease-associated genetic variants in noncoding regions function to alter disease risk between individuals. Indeed, although the biochemical consequences of mutations in protein-coding sequences can sometimes be predicted from the genetic code and protein
Shortcomings of Standard eQTL Comparisons
In our search to find disease mechanisms and provide functional annotations for disease-associated loci, it is worth considering whether standard regulatory QTL mapping approaches are likely to yield valuable insights. On the one hand, even if all disease-associated loci were also cis eQTLs, one would not expect 100% recall using the colocalization approaches that are applied to current datasets because of incomplete power, allelic heterogeneity when more than one variant affects a gene or the
Dynamic Gene Regulation
The body of work reviewed above suggests that most standard eQTLs are associated with regulatory changes that have minimal phenotypic impact. If most standard eQTLs are generally benign, increasing sample size and adding more tissue types in an effort to identify even more standard eQTLs may not help us to explain many more disease risk mutations. However, this does not mean that regulatory variation does not play a key role in disease. There are other places to look for this variation, given
Concluding Remarks
Standard eQTL studies have generated valuable resources for understanding human gene regulation. Equally importantly, these studies have provided the data necessary to critically consider our expectations regarding the connection between regulatory variation and human disease, and to frame the next important questions (see Outstanding Questions). Despite rigorous efforts, standard eQTLs do not, on the whole, provide the missing mechanistic link to the majority of disease-associated genetic
Acknowledgments
We thank Natalia Gonzales, Jonathan Pritchard, Nicholas Banovich, Gabriella Haddad, and Michelle Ward for useful discussions, comments, and edits to the manuscript. A.B. is supported by National Institutes of Health (NIH) grant R01GM120167; Y.G. is supported by NIH grant R35GM131726.
Glossary
- Dynamic eQTL
- an expression quantitative trait locus (eQTL) ascertained under time-evolving conditions. We use this term to encompass eQTLs revealed by the application of an extrinsic perturbation, sometimes termed ‘response eQTLs’, as well as those that manifest transiently during the course of a developmental process.
- Genome-wide association study (GWAS)
- a method for measuring the correlation between genetic variants and phenotypes, such as disease status.
- Induced pluripotent stem cells (iPSCs)
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