Trends in Genetics
Volume 37, Issue 2, February 2021, Pages 109-124
Journal home page for Trends in Genetics

Feature Review
Where Are the Disease-Associated eQTLs?

https://doi.org/10.1016/j.tig.2020.08.009Get rights and content

Highlights

  • Mapping of regulatory quantitative trait loci (QTLs) has emerged as a powerful tool to functionally annotate noncoding DNA variants that are associated with disease risk.

  • Large surveys of gene expression variation in healthy, adult, steady-state tissues have discovered at least one cis expression QTL (eQTL) for nearly every human gene.

  • The properties of standard eQTLs may be inconsistent with mutations that are associated with a fitness cost, in contrast to what might be expected for mutations associated with disease.

  • Regulatory QTL mapping during dynamic cellular processes such as differentiation and perturbation response can reveal otherwise hidden regulatory variation that may be especially relevant for disease.

  • New platform technologies, including in vitro differentiated cell types and single-cell profiling, extend the scope of dynamic eQTL studies.

Most disease-associated variants, although located in putatively regulatory regions, do not have detectable effects on gene expression. One explanation could be that we have not examined gene expression in the cell types or conditions that are most relevant for disease. Even large-scale efforts to study gene expression across tissues are limited to human samples obtained opportunistically or postmortem, mostly from adults. In this review we evaluate recent findings and suggest an alternative strategy, drawing on the dynamic and highly context-specific nature of gene regulation. We discuss new technologies that can extend the standard regulatory mapping framework to more diverse, disease-relevant cell types and states.

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)

References (124)

  • K.K-H. Farh

    Genetic and epigenetic fine mapping of causal autoimmune disease variants

    Nature

    (2015)
  • T.A. Manolio

    Finding the missing heritability of complex diseases

    Nature

    (2009)
  • M.T. Maurano

    Systematic localization of common disease-associated variation in regulatory DNA

    Science

    (2012)
  • E.R. Gamazon

    Using an atlas of gene regulation across 44 human tissues to inform complex disease- and trait-associated variation

    Nat. Genet.

    (2018)
  • S. Smemo

    Obesity-associated variants within FTO form long-range functional connections with IRX3

    Nature

    (2014)
  • M. Claussnitzer

    FTO obesity variant circuitry and adipocyte browning in humans

    N. Engl. J. Med.

    (2015)
  • Cross-Disorder Group of the Psychiatric Genomics Consortium

    Genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders

    Cell

    (2019)
  • T. Fadason

    Chromatin interactions and expression quantitative trait loci reveal genetic drivers of multimorbidities

    Nat. Commun.

    (2018)
  • J. Yang

    Common SNPs explain a large proportion of the heritability for human height

    Nat. Genet.

    (2010)
  • D.A. Cusanovich

    The combination of a genome-wide association study of lymphocyte count and analysis of gene expression data reveals novel asthma candidate genes

    Hum. Mol. Genet.

    (2012)
  • F. Hormozdiari

    Identifying causal variants at loci with multiple signals of association

    Genetics

    (2014)
  • C. Giambartolomei

    Bayesian test for colocalisation between pairs of genetic association studies using summary statistics

    PLoS Genet.

    (2014)
  • B. Zeng

    Comprehensive multiple eQTL detection and its application to GWAS interpretation

    Genetics

    (2019)
  • A.N. Barbeira

    Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics

    Nat. Commun.

    (2018)
  • A. Gusev

    Integrative approaches for large-scale transcriptome-wide association studies

    Nat. Genet.

    (2016)
  • E.R. Gamazon

    A gene-based association method for mapping traits using reference transcriptome data

    Nat. Genet.

    (2015)
  • Z. Zhu

    Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets

    Nat. Genet.

    (2016)
  • E.R. Gamazon

    Multi-tissue transcriptome analyses identify genetic mechanisms underlying neuropsychiatric traits

    Nat. Genet.

    (2019)
  • D. Marbach

    Tissue-specific regulatory circuits reveal variable modular perturbations across complex diseases

    Nat. Methods

    (2016)
  • M.G.P. van der Wijst

    Single-cell RNA sequencing identifies celltype-specific cis-eQTLs and co-expression QTLs

    Nat. Genet.

    (2018)
  • A. Saha

    Co-expression networks reveal the tissue-specific regulation of transcription and splicing

    Genome Res.

    (2017)
  • U.M. Marigorta

    Transcriptional risk scores link GWAS to eQTLs and predict complications in Crohn's disease

    Nat. Genet.

    (2017)
  • D.L. Nicolae

    Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS

    PLoS Genet.

    (2010)
  • A. Battle

    Characterizing the genetic basis of transcriptome diversity through RNA-sequencing of 922 individuals

    Genome Res.

    (2014)
  • D.V. Zhernakova

    Identification of context-dependent expression quantitative trait loci in whole blood

    Nat. Genet.

    (2017)
  • F. Aguet

    The GTEx Consortium atlas of genetic regulatory effects across human tissues

    BioRxiv

    (2019)
  • S. Chun

    Limited statistical evidence for shared genetic effects of eQTLs and autoimmune-disease-associated loci in three major immune-cell types

    Nat. Genet.

    (2017)
  • GTEx Consortium

    Genetic effects on gene expression across human tissues

    Nature

    (2017)
  • D.W. Yao

    Quantifying genetic effects on disease mediated by assayed gene expression levels

    Nat. Genet.

    (2020)
  • E. Grundberg

    Mapping cis- and trans-regulatory effects across multiple tissues in twins

    Nat. Genet.

    (2012)
  • X. Liu

    Trans effects on gene expression can drive omnigenic inheritance

    Cell

    (2019)
  • H-J. Westra

    Systematic identification of trans eQTLs as putative drivers of known disease associations

    Nat. Genet.

    (2013)
  • S. Mortlock

    Tissue specific regulation of transcription in endometrium and association with disease

    Hum. Reprod.

    (2020)
  • U. Vosa

    Unraveling the polygenic architecture of complex traits using blood eQTL metaanalysis

    BioRxiv

    (2018)
  • F. Yang

    Identifying cis-mediators for trans-eQTLs across many human tissues using genomic mediation analysis

    Genome Res.

    (2017)
  • G.A. Wray

    The evolutionary significance of cis-regulatory mutations

    Nat. Rev. Genet.

    (2007)
  • M. Halachev

    Increased ultra-rare variant load in an isolated Scottish population impacts exonic and regulatory regions

    PLoS Genet.

    (2019)
  • M. Lek

    Analysis of protein-coding genetic variation in 60,706 humans

    Nature

    (2016)
  • J. Fu

    Unraveling the regulatory mechanisms underlying tissue-dependent genetic variation of gene expression

    PLoS Genet.

    (2012)
  • Y. He

    Mechanisms of tissue-specific genetic regulation revealed by latent factors across eQTLs

    BioRxiv

    (2019)
  • Cited by (119)

    View all citing articles on Scopus
    View full text