Challenges and progress in interpretation of non-coding genetic variants associated with human disease

Abstract

Genome-wide association studies have shown that the far majority of disease-associated variants reside in the non-coding regions of the genome, suggesting that gene regulatory changes contribute to disease risk. To identify truly causal non-coding variants and their affected target genes remains challenging but is a critical step to translate the genetic associations to molecular mechanisms and ultimately clinical applications. Here we review genomic/epigenomic resources and in silico tools that can be used to identify causal non-coding variants and experimental strategies to validate their functionalities. Impact statement Most signals from genome-wide association studies (GWASs) map to the non-coding genome, and functional interpretation of these associations remained challenging. We reviewed recent progress in methodologies of studying the non-coding genome and argued that no single approach allows one to effectively identify the causal regulatory variants from GWAS results. By illustrating the advantages and limitations of each method, our review potentially provided a guideline for taking a combinatorial approach to accurately predict, prioritize, and eventually experimentally validate the causal variants.

Keywords: Causal variants; enhancers; functional genomics; genome-wide association studies; non-coding variants; variant annotation.

Figure 1

The activity of enhancers and super-enhancers is cell- and tissue-specific. (a) Landscapes of GWAS associations in the neighboring genomic regions of MYC locus in Chr. 8q24. PrCa: prostate cancer, CRC: colorectal cancer, BlCa: bladder cancer, LymCa: and lymphoma. (b) A hypothetical model that may explain the genetic association patterns: different types of cancer cells may gain tissue-specific oncogenic enhancers/super-enhancers, resulting in misregulation of the MYC oncogene in a tissue-specific manner. (c) However, in actual case, the gained super-enhancers in tumors were found outside the corresponding LD regions in colorectal cancer (HCT116) and leukemia K562) cell lines. This may suggest a complex mechanism underlying the GWAS association, such as the presence of functional variants that alter the enhancer–target gene interaction network rather than directly affecting enhancer’s capability to facilitate promoter activity. GWAS: genome-wide association studies. (A color version of this figure is available in the online journal.)