Annotation of functional variation in personal genomes using RegulomeDB
Open accessAbstract
As the sequencing of healthy and disease genomes becomes more commonplace, detailed annotation provides interpretation for individual variation responsible for normal and disease phenotypes. Current approaches focus on direct changes in protein coding genes, particularly nonsynonymous mutations that directly affect the gene product. However, most individual variation occurs outside of genes and, indeed, most markers generated from genome-wide association studies (GWAS) identify variants outside of coding segments. Identification of potential regulatory changes that perturb these sites will lead to a better localization of truly functional variants and interpretation of their effects. We have developed a novel approach and database, RegulomeDB, which guides interpretation of regulatory variants in the human genome. RegulomeDB includes high-throughput, experimental data sets from ENCODE and other sources, as well as computational predictions and manual annotations to identify putative regulatory potential and identify functional variants. These data sources are combined into a powerful tool that scores variants to help separate functional variants from a large pool and provides a small set of putative sites with testable hypotheses as to their function. We demonstrate the applicability of this tool to the annotation of noncoding variants from 69 full sequenced genomes as well as that of a personal genome, where thousands of functionally associated variants were identified. Moreover, we demonstrate a GWAS where the database is able to quickly identify the known associated functional variant and provide a hypothesis as to its function. Overall, we expect this approach and resource to be valuable for the annotation of human genome sequences.
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Of 1,873 prioritized variants, 71-99% have regulatory potential when considering all tissues according to RegulomeDB and HaploReg.
“Of these variants, 71–99% have regulatory potential when considering all tissues according to RegulomeDB56 and HaploReg57”
From Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing (2019) · cites this paper as [56]
Bioinformatic annotation suggested that the 19p13.3 risk locus contains regulatory elements and that the risk variant(s) might confer disease susceptibility by modulating expression of target genes.
“Notably, these data suggested the presence of regulatory elements at the identified loci, and therefore the risk variant(s) might confer disease susceptibility by modulating the expression of target genes.”
From A regulatory variant at 19p13.3 is associated with primary biliary cholangitis risk and ARID3A expression (2023) · cites this paper as [17]
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Histone Acetylome-wide Association Study of Autism Spectrum Disorder
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The <i>MS4A</i> gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk
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“1 ( 83 ).”
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Transcriptome-wide Discovery of microRNA Binding Sites in Human Brain
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Integrative Genomics Reveals Novel Molecular Pathways and Gene Networks for Coronary Artery Disease
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Novel loci and pathways significantly associated with longevity
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3DSNP: a database for linking human noncoding SNPs to their three-dimensional interacting genes
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Alzheimer’s disease risk polymorphisms regulate gene expression in the ZCWPW1 and the CELF1 loci
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Association of Gamma-Aminobutyric Acid A Receptor α2 Gene (GABRA2) with Alcohol Use Disorder
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Shared genetic etiology underlying Alzheimer’s disease and type 2 diabetes
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Multiple sclerosis-associated CLEC16A controls HLA class II expression via late endosome biogenesis
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Gene-environment interactions of circadian-related genes for cardiometabolic traits
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Sensitive detection of chromatin-altering polymorphisms reveals autoimmune disease mechanisms
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“Regulome scores were obtained from the Regulome database, which annotates variants with regulatory information from 962 different data sets and a variety of sources, including ENCODE [16].”
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Functional evaluation of genetic variants associated with endometriosis near GREB1
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Endometrial vezatin and its association with endometriosis risk
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Genome-Wide Association Study of Autistic-Like Traits in a General Population Study of Young Adults
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Genetic studies of plasma analytes identify novel potential biomarkers for several complex traits
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A signature of Neanderthal introgression on molecular mechanisms of environmental responses
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- Authors
- Boyle, A. P., Hong, E. L., Hariharan, M., Cheng, Y., Schaub, M. A., Kasowski, M., Karczewski, K. J., Park, J., Hitz, B. C., Weng, S., Cherry, J. M., & Snyder, M.
- Affiliations
- Stanford Medicine (US)
- Stanford University (US)
- Corresponding author
- Snyder, Michael
- ORCID
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2012-09
- Volume
- 22
- Issue
- 9
- Pages
- 1790-1797
- ISSN
- 1088-9051 (ISSN-L)
- PMC
- PMC3431494
- OpenAlex
- W2141820415
- Cited by
- 2,722
- References
- 50
- Citations by year
- 2026: 123 · 2025: 169 · 2024: 173 · 2023: 195 · 2022: 213 · 2021: 245 · 2020: 225 · 2019: 213 · 2018: 226 · 2017: 218 · 2016: 232 · 2015: 204 · 2014: 173 · 2013: 102 · 2012: 11
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- Genome Research (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Vanderbilt University Medical Center
- National Institutes of Health
- National Human Genome Research Institute (U54HG004558)
- National Institute of General Medical Sciences (T32GM007205)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- RegulomeDB, regulatory variants, non-coding variants, genome-wide association study, ENCODE, human genome
- MeSH terms
- Tumor Necrosis Factor alpha-Induced Protein 3, DNA-Binding Proteins, Genotype, Humans, Lupus Erythematosus, Systemic, Nuclear Proteins, Regulatory Sequences, Nucleic Acid, Genetic Variation, Genome, Human, Open Reading Frames, Internet, Polymorphism, Single Nucleotide, Databases, Genetic, Intracellular Signaling Peptides and Proteins, Genome-Wide Association Study, Molecular Sequence Annotation
About these checks
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