Journal Article

The landscape of GWAS validation; systematic review identifying 309 validated non-coding variants across 130 human diseases

Lazar, Jozef, Reeb, Jonas, Ghosh, Sujana, Alsheikh, Ammar J., Wollenhaupt, Sabrina, King, Emily A., Tamim, Saleh, Jacob, Howard J., Stolzenburg, Lindsay R., Davis, J. Wade

2022

Overview

Background The remarkable growth of genome-wide association studies (GWAS) has created a critical need to experimentally validate the disease-associated variants, 90% of which involve non-coding variants. Methods To determine how the field is addressing this urgent need, we performed a comprehensive literature review identifying 36,676 articles. These were reduced to 1454 articles through a set of filters using natural language processing and ontology-based text-mining. This was followed by manual curation and cross-referencing against the GWAS catalog, yielding a final set of 286 articles. Results We identified 309 experimentally validated non-coding GWAS variants, regulating 252 genes across 130 human disease traits. These variants covered a variety of regulatory mechanisms. Interestingly, 70% (215/309) acted through cis-regulatory elements, with the remaining through promoters (22%, 70/309) or non-coding RNAs (8%, 24/309). Several validation approaches were utilized in these studies, including gene expression (n = 272), transcription factor binding (n = 175), reporter assays (n = 171), in vivo models (n = 104), genome editing (n = 96) and chromatin interaction (n = 33). Conclusions This review of the literature is the first to systematically evaluate the status and the landscape of experimentation being used to validate non-coding GWAS-identified variants. Our results clearly underscore the multifaceted approach needed for experimental validation, have practical implications on variant prioritization and considerations of target gene nomination. While the field has a long way to go to validate the thousands of GWAS associations, we show that progress is being made and provide exemplars of validation studies covering a wide variety of mechanisms, target genes, and disease areas.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Biomedical and Life Sciences / Biomedicine / Chromatin / Disease / Diseases / Experimental validation / Functional variant / Gene Expression / Gene loci / Genetic aspects / Genetic transcription / Genome editing / Genome-Wide Association Study / Genomes / Genotype & phenotype / GWAS / Health aspects / Health risk assessment / Human Genetics / Humans / Literature reviews / Microarrays / Non-coding / Ontology / Phenotype / Promoter Regions, Genetic / Regulatory sequences / Regulatory Sequences, Nucleic Acid / Research Article / Risk factors / Systematic review / United States / Validation studies