Biological constraints on GWAS SNPs at suggestive significance thresholds reveal additional BMI loci
- Children's Hospital of Philadelphia, United States
- Columbia University Vagelos College of Physicians and Surgeons, United States
- University of Michigan Medical School, United States
Abstract
To uncover novel significant association signals (P<5x10-8), GWAS requires increasingly larger sample sizes to overcome statistical correction for multiple testing. As an alternative, we aimed to identify associations among suggestive signals (5x10-8 ≤ P < 5x10-4) in increasingly powered GWAS efforts using chromatin accessibility and direct contact with gene promoters as biological constraints. We conducted retrospective analyses of three GIANT BMI GWAS efforts using ATAC-seq and promoter-focused Capture C data from human adipocytes and ESC-derived hypothalamic-like neurons. This approach, with its extremely low false positive rate, identified 15 loci at P<5x10-5 in the 2010 GWAS, 13 of which achieved genome-wide significance by 2018, including at NAV1, MTIF3 and ADCY3. 80% of constrained 2015 loci achieved genome-wide significance in 2018. We observed similar results in waist-to-hip ratio analyses. In conclusion, biological constraints on sub-significant GWAS signals can reveal potentially true-positive loci for further investigation in existing datasets without increasing sample size.
Data availability
Adipose ATAC-seq and promoter-focused capture C data is available in GEO under accession number GSE164912Hypothalamic Neuron ATAC-eq and promoter-focused capture C data is the subject of another atlas-based manuscript currently under peer review and through that process that dataset will be made available once the paper is published- the corresponding hypothalamus preprint can be found at: https://www.biorxiv.org/content/10.1101/2020.07.06.146951v1.full
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Biological constraints on GWAS SNPs at suggestive significance thresholds reveal true BMI lociNCBI Gene Expression Omnibus, GSE164912.
Article and author information
Author details
Funding
Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01-HD056465)
- Struan FA Grant
National Human Genome Research Institute (R01-HG010067)
- Struan FA Grant
Children's Hospital of Philadelphia (Daniel B. Burke Endowed Chair for Diabetes Research)
- Struan FA Grant
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Hammond 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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Biological constraints on GWAS SNPs at suggestive significance thresholds reveal additional BMI loci
eLife 10:e62206.
https://doi.org/10.7554/eLife.62206
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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.
