Editors' ChoiceGenomics

Diverse diseases, diverse variants

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Science Translational Medicine  22 Jul 2015:
Vol. 7, Issue 297, pp. 297ec126
DOI: 10.1126/scitranslmed.aac8569

Recent studies using high-throughput sequencing technologies have identified millions of genetic variations in the human genome. Of these, ~97% of identified variants are noncoding variants, and many of them exist in intragenic regions. When the genetic variants are located outside of genes, it is not easy to interpret the function of the noncoding genetic variants by traditional genetic approaches. Ma et al. tested the relationship between disease-associated genetic variants and regulatory elements by comparing existing datasets.

They curated ~100,000 disease-associated genetic variants and compared them against different types of regulatory elements from the FANTOM5 and ENCODE projects. The genetic variants were categorized into four different disease categories: Mendelian diseases, complex diseases, cancer-predisposing germline variants, and recurrent cancer somatic mutations. They found that although Mendelian disease variants and recurrent cancer somatic mutations were enriched in missense variants, the majority of complex disease variants were noncoding variants, and this enrichment did not change even when they tested only the causal variants. They also found that functionality and evolutionary constraints were higher in Mendelian disease variants and cancer (germline or somatic) variants compared with complex disease variants. Last, they showed distinct localization of disease-associated genetic variants between different disease categories. Mendelian disease variants and cancer variants were enriched within the transcriptional promoter regions; however, complex disease variants did not show this enrichment. This suggests that genomic variants within transcriptional promoters may represent a regulatory mechanism for Mendelian disease and cancer pathogenesis but not for complex disease pathogenesis.

This striking difference could be partially due to the fact that most complex disease-associated variants were discovered in genome-wide association studies (GWAS), and therefore may not be the causal variants. The authors also tested for these associations among the potential complex disease causal variants and observed similar enrichment, which suggests that different types of regulatory regions should be investigated for different categories of disease. In addition, this study supports the importance of performing functional genome-wide association studies (functional GWAS) that comprehensively investigate both regulatory elements and genetic variations to test for the association between outcome (disease) and variants.

M. Ma et al., Disease-associated variants in different categories of disease located in distinct regulatory elements. BMC Genomics 10.1186/1471-2164-16-S8-S3 (2015). [Full Text]

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