Disease-associated variants in different categories of disease located in distinct regulatory elements

Abstract

BackgroundThe invention of high throughput sequencing technologies has led to the discoveries of hundreds of thousands of genetic variants associated with thousands of human diseases. Many of these genetic variants are located outside the protein coding regions, and as such, it is challenging to interpret the function of these genetic variants by traditional genetic approaches. Recent genome-wide functional genomics studies, such as FANTOM5 and ENCODE have uncovered a large number of regulatory elements across hundreds of different tissues or cell lines in the human genome. These findings provide an opportunity to study the interaction between regulatory elements and disease-associated genetic variants. Identifying these diseased-related regulatory elements will shed light on understanding the mechanisms of how these variants regulate gene expression and ultimately result in disease formation and progression.ResultsIn this study, we curated and categorized 27,558 Mendelian disease variants, 20,964 complex disease variants, 5,809 cancer predisposing germline variants, and 43,364 recurrent cancer somatic mutations. Compared against nine different types of regulatory regions from FANTOM5 and ENCODE projects, we found that different types of disease variants show distinctive propensity for particular regulatory elements. Mendelian disease variants and recurrent cancer somatic mutations are 22-fold and 10- fold significantly enriched in promoter regions respectively (q<0.001), compared with allele-frequency-matched genomic background. Separate from these two categories, cancer predisposing germline variants are 27-fold enriched in histone modification regions (q<0.001), 10-fold enriched in chromatin physical interaction regions (q<0.001), and 6-fold enriched in transcription promoters (q<0.001). Furthermore, Mendelian disease variants and recurrent cancer somatic mutations share very similar distribution across types of functional effects.We further found that regulatory regions are located within over 50% coding exon regions. Transcription promoters, methylation regions, and transcription insulators have the highest density of disease variants, with 472, 239, and 72 disease variants per one million base pairs, respectively.ConclusionsDisease-associated variants in different disease categories are preferentially located in particular regulatory elements. These results will be useful for an overall understanding about the differences among the pathogenic mechanisms of various disease-associated variants.

Non-Coding Loss-of-Function Variation in Human Genomes

“…Previous reviews have described a handful of examples of large-effect non-coding alleles underlying Mendelian disorders including beta-thalassemia and polydactyly [21,22]. A systematic analysis of disease variants curated within the Online Mendelian Inheritance in Man (OMIM) and ClinVar databases reported over 27,000 variants connected to Mendelian diseases [23]. While these variants are certain to be of varying quality [24], the authors reported that 29% were either upstream or downstream of their target gene, highlighting the fact that a significant fraction of variation associated to Mendelian disease resides in the non-coding genome.…”

iRegNet3D: three-dimensional integrated regulatory network for the genomic analysis of coding and non-coding disease mutations

“…Genome-wide association studies (GWASs) and quantitative trait loci (QTL) studies have been widely applied to the identification and annotation of non-coding mutations [47]. Previous studies have found that Mendelian disease mutations and recurrent cancer somatic mutations are enriched within promoter regions [48]. Enhancers in the human genome are also prone to deactivating mutations that disrupt the binding of transcription factors [49].…”

Cellular network perturbations by disease-associated variants

“…Indeed, for noncoding variants identifying the target gene and the regulatory function affected is often much more difficult. For example, multiple regulatory functions can be affected by noncoding variants including the binding of TFs [7,8,29], chromatin structure or accessibility [28], DNA methylation [30,31], and 5′ and 3′UTR function [9,32] (Figure 1). …”