From GWAS variant to function: A study of ∼148,000 variants for blood cell traits

HGG Adv. 2021 Oct 7;3(1):100063. doi: 10.1016/j.xhgg.2021.100063. eCollection 2022 Jan 13.


Genome-wide association studies (GWASs) have identified hundreds of thousands of genetic variants associated with complex diseases and traits. However, most variants are noncoding and not clearly linked to genes, making it challenging to interpret these GWAS signals. We present a systematic variant-to-function study, prioritizing the most likely functional elements of the genome for experimental follow-up, for >148,000 variants identified for hematological traits. Specifically, we developed VAMPIRE: Variant Annotation Method Pointing to Interesting Regulatory Effects, an interactive web application implemented in R Shiny. This tool efficiently integrates and displays information from multiple complementary sources, including epigenomic signatures from blood-cell-relevant tissues or cells, functional and conservation summary scores, variant impact on protein and gene expression, chromatin conformation information, as well as publicly available GWAS and phenome-wide association study (PheWAS) results. Leveraging data generated from independently performed functional validation experiments, we demonstrate that our prioritized variants, genes, or variant-gene links are significantly more likely to be experimentally validated. This study not only has important implications for systematic and efficient revelation of functional mechanisms underlying GWAS variants for hematological traits but also provides a prototype that can be adapted to many other complex traits, paving the path for efficient variant-to-function (V2F) analyses.

Keywords: blood cell traits; experimental validations; functional annotations; genome-wide association studies; variant to function.