Functional and evolutionary properties of the genomic regions associated with multiple phenotypic traits identified in genome-wide association studies

Abstract

Over the past ten years, thousands of variants have been identified as susceptibility loci for common traits using genome-wide association studies (GWAS). An interesting observation is that many genetic loci emerged as associated with multiple distinct traits, such associations are known as cross-phenotype (CP) associations. Although this phenomenon has been examined on individual variants or genes, a comprehensive characterization of these loci is still lacking. In this study, GWAS findings were collected from the GWAS Catalog. To evaluate whether the loci associated with different traits co-localized due to chance, I performed simulations assuming those associations were randomly mapped. The results showed that the fraction of CP loci in the GWAS Catalog was nearly 3-5 times greater than that found by random chance (empirical p-value < 0.001). The non-random distribution of CP loci suggests important evolutionary and functional properties in these regions. In CP loci, sequences were found to be more conserved, and functional elements were also highly enriched, suggesting elements in CP loci were more likely to have functional consequences. Consistent with the importance of CP loci, the variants located in CP loci were shown to exert larger effects on their associated phenotypes. In addition, compared with other genes, transcription factors (TFs) were more likely to affect multiple traits. To further understand the regulatory mechanisms, TF binding sites were downloaded from the Encyclopedia of DNA Elements (ENCODE) project. A list of TFs was then identified to be highly enriched in the regulatory regions of different disease susceptibility genes, highlighting that they played a major role in CP associations through initiating and regulating those genes. More importantly, I showed that the independent association signals in CP loci might regulate gene expression in a cell-specific manner. Systemic lupus erythematosus (SLE) and ulcerative colitis (UC) shared variant (rs4728142) was found to be implicated in both myeloid and lymphoid cells, in regulating IRF5 expression. However, in the same CP locus, the SLE-specific variant (rs729302) was only involved in lymphoid cell lines in IRF5 regulation, suggesting distinct regulatory mechanisms at play in a CP locus. Moreover, I showed that psychiatric disease-associated loci tended to be located in the later DNA replicating timing regions, suggesting these regions might be under weaker purifying selection or occur more recently. Finally, through analysing GWAS data from both SLE and other autoimmune diseases, a novel SLE-associated locus was identified. Its genetic effect is underestimated in the initial GWASs, highlighting CP meta-analysis may overcome the “winner's curse” in mapping novel disease-associated loci. In summary, the findings from this study may help us better understand the value of CP loci in disease mechanism and novel trait-associated loci mapping.