The missing link between genetic association and regulatory function
- Harvard Medical School, United States
- Harvard TH Chan School of Public Health, United States
- Altius Institute for Biomedical Sciences, United States
- Boston Children's Hospital, United States
- Broad Institute, United States
- Brigham and Women's Hospital, United States
Abstract
The genetic basis of most traits is highly polygenic and dominated by non-coding alleles. It is widely assumed that such alleles exert small regulatory effects on the expression of cis-linked genes. However, despite the availability of gene expression and epigenomic data sets, few variant-to-gene links have emerged. It is unclear whether these sparse results are due to limitations in available data and methods, or to deficiencies in the underlying assumed model. To better distinguish between these possibilities, we identified 220 gene-trait pairs in which protein-coding variants influence a complex trait or its Mendelian cognate. Despite the presence of expression quantitative trait loci near most GWAS associations, by applying a gene-based approach we found limited evidence that the baseline expression of trait-related genes explains GWAS associations, whether using colocalization methods (8% of genes implicated), transcription-wide association (2% of genes implicated), or a combination of regulatory annotations and distance (4% of genes implicated). These results contradict the hypothesis that most complex trait-associated variants coincide with homeostatic eQTLs, suggesting that better models are needed. The field must confront this deficit, and pursue this 'missing regulation'.
Data availability
Numerical data for results is included in Source Data 1.The dataset generated (GWAS summary statistics conditioned on coding variants) can be found at doi:10.5061/dryad.612jm644q
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GWAS results conditioned on coding variantsDryad Digital Repository, doi:10.5061/dryad.612jm644q.
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NHLBI TOPMedhttps://www.nhlbiwgs.org/topmed-whole-genome-sequencing-project-freeze-5b-phases-1-and-2.
Article and author information
Author details
Noah James Connally
Funding
National Institutes of Health (R35GM127131)
- Shamil R Sunyaev
National Institutes of Health (R01HG010372)
- Shamil R Sunyaev
National Institutes of Health (R01MH101244)
- Shamil R Sunyaev
National Institutes of Health (U01HG012009)
- Chris Cotsapas
National Institutes of Health (T32GM74897)
- Shamil R Sunyaev
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Connally et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The missing link between genetic association and regulatory function
eLife 11:e74970.
https://doi.org/10.7554/eLife.74970
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Enhancers and promoters are classically considered to be bound by a small set of transcription factors (TFs) in a sequence-specific manner. This assumption has come under increasing skepticism as the datasets of ChIP-seq assays of TFs have expanded. In particular, high-occupancy target (HOT) loci attract hundreds of TFs with often no detectable correlation between ChIP-seq peaks and DNA-binding motif presence. Here, we used a set of 1003 TF ChIP-seq datasets (HepG2, K562, H1) to analyze the patterns of ChIP-seq peak co-occurrence in combination with functional genomics datasets. We identified 43,891 HOT loci forming at the promoter (53%) and enhancer (47%) regions. HOT promoters regulate housekeeping genes, whereas HOT enhancers are involved in tissue-specific process regulation. HOT loci form the foundation of human super-enhancers and evolve under strong negative selection, with some of these loci being located in ultraconserved regions. Sequence-based classification analysis of HOT loci suggested that their formation is driven by the sequence features, and the density of mapped ChIP-seq peaks across TF-bound loci correlates with sequence features and the expression level of flanking genes. Based on the affinities to bind to promoters and enhancers we detected five distinct clusters of TFs that form the core of the HOT loci. We report an abundance of HOT loci in the human genome and a commitment of 51% of all TF ChIP-seq binding events to HOT locus formation thus challenging the classical model of enhancer activity and propose a model of HOT locus formation based on the existence of large transcriptional condensates.
