Re-annotation of presumed noncoding disease/trait-associated genetic variants by integrative analyses

Using RefSeq annotations, most disease/trait-associated genetic variants identified by genome-wide association studies (GWAS) appear to be located within intronic or intergenic regions, which makes it difficult to interpret their functions. We reassessed GWAS-Associated single-nucleotide polymorphisms (herein termed as GASs) for their potential functionalities using integrative approaches. 8834 of 9184 RefSeq “noncoding” GASs were reassessed to have potential regulatory functionalities. As examples, 3 variants (rs3130320, rs3806932 and rs6890853) were shown to have regulatory properties in HepG2, A549 and 293T cells. Except rs3130320 as a known expression quantitative trait loci (eQTL), rs3806932 and rs6890853 were not reported as eQTLs in previous reports. 1999 of 9184 “noncoding” GASs were re-annotated to the promoters or intragenic regions using Ensembl, UCSC and AceView gene annotations but they were not annotated into corresponding regions in RefSeq database. Moreover, these GAS-harboring genes were broadly expressed across different tissues and a portion of them was expressed in a tissue-specific manner, suggesting that they could be functional. Collectively, our study demonstrates the benefits of using integrative analyses to interpret genetic variants and may help to predict or explain disease susceptibility more accurately and comprehensively.