FUNCTIONAL DISSECTION OF REGULATORY GENE NETWORKS GOVERNING COMPLEX TRAIT EXPRESSION

Abstract

Complex traits occur due to polygenic architectures that are highly complex, with the majority of related variants relative to protein sequence occurring in non-coding regions and affecting the regulation of genes, as opposed to protein sequence. Despite the genome-wide association studies (GWAS) discovering thousands of loci of interest associated with a trait, causal mechanisms of these signals are challenging due to linkage disequilibrium, allelic heterogeneity and tissue-specific regulation. In this paper, we have introduced an integrative model of the functional dissection of regulatory gene networks that regulate expression of complex traits. We integrated GWAS summary statistics with functionally informed fine-mapping, integration of expression quantitative trait locus (eQTL), enhancerpromoter linking, transcription factor (TF) footprinting, motif disruption analysis, and topologybased prioritization of networks. High-confidence variants were mapped onto target genes downstream of phenotype-relevant tissues using public datasets of NHGRI-EBI GWAS Catalog, GTEx and epigenomic reference atlases. A pipeline was run pitting a subset of regulatory variants highly enriched with active enhancers and TF footprints, and high functional plausibility. The reconstruction of the networks revealed modular communities of genes and indicated central hub regulators linking various pathways associated with traits. Enrichment analysis revealed that it converged on biological process involving chromatin organization, signal transduction and tissue specific differentiation. Collectively, these results indicate that statistical genetics can be utilized in a systematic fashion to transform signals of association into mechanistic regulatory models by combining statistical genetics with functional genomics and network analysis. This framework offers a reproducible approach of finding candidate causal variants, important regulatory genes and the pathway level mechanisms of expressing complex traits.