Understanding functional consequences of type 2 diabetes risk loci using the universal data integration and visualization R package CONQUER

Abstract

ABSTRACTBackgroundNumerous large genome-wide association studies (GWASs) have been performed to understand the genetic factors of numerous traits, including type 2 diabetes. Many identified risk loci are located in non-coding and intergenic regions, which complicates the understanding how genes and their downstream pathways are influenced. An integrative data approach is required to understand the mechanism and consequences of identified risk loci.ResultsHere, we developed the R-package CONQUER. Data for SNPs of interest (build GRCh38/hg38) were acquired from static- and dynamic repositories, such as, GTExPortal, Epigenomics Project, 4D genome database and genome browsers such as ENSEMBL. CONQUER modularizes SNPs based on the underlying co-expression data and associates them with biological pathways in specific tissues. CONQUER was used to analyze 403 previously identified type 2 diabetes risk loci. In all tissues, the majority of SNPs (mean = 13.50, SD = 11.70) were linked to metabolism. A tissue-shared effect was found for four type 2 diabetes-associated SNPs (rs601945, rs1061810, rs13737, rs4932265) that were associated with differential expression of HLA-DQA2, HSD17B12, MAN2C1 and AP3S2 respectively. Seven SNPs were identified that influenced the expression of seven ribosomal proteins in multiple tissues. Finally, one SNP (rs601945) was found to influence multiple HLA genes in all twelve tissues investigated.ConclusionWe present an universal R-package that aggregates and visualizes data in order to better understand functional consequences of GWAS loci. Using CONQUER, we showed that type 2 diabetes risk loci have many tissue-shared effects on multiple pathways including metabolism, the ribosome and HLA pathway.