Functional Properties of Genomic Region Associated with Multiple Traits in Genome-Wide Association Studies

Abstract

More than 10,000 associations with over 600 human complex traits have been identified by genome-wide association studies (GWAS) in the past years. An interesting observation is that many genetic loci emerged as associated with multiple distinct traits. Although the pleiotropic phenomena have been examined on certain variants or genes, comprehensive characterization of these loci is still lacking. In this study, we collected a plethora of trait-associated variants from the National Human Genome Research Institute (NHGRI) Catalogue of Published Genome-wide Association Studies, and defined cross-phenotype (CP) loci as a region within which variants are associated with at least two phenotypes. We observed that nearly 25.36% of the GWAS loci are associated with multiple traits, accounting for 7.79% of human genome, suggesting a widespread existence of pleiotropic loci across the human genome. Besides, we showed that the functional markers such as DNase-I hypersensitive sites, transcription factor binding sites and histone modification regions are highly enriched in CP regions, much more so than single trait-associated loci or random genomic controls, suggesting that these loci may contain more functional elements and these elements may play a broader role in genetic regulation. Further study observed the variants within the CP loci are more likely to be eQTLs and are more likely to be located in early DNA replication regions, suggesting that distinct regulatory and functional elements may exist within these loci. Finally, through comparing the genetic overlapping between diseases, we have explored the shared and distinct mechanistic patterns and pathways among different diseases, which may have significant clinical implications and be informative on drug repositioning.