Complex Traits Heritability is Highly Clustered in the eQTL Bipartite Network

Single Nucleotide Polymorphisms (SNPs) associated with traits typically explain a small part of the trait genetic heritability— with the remainder thought to be distributed throughout the genome. Such SNPs are likely to alter expression levels of biologically relevant genes. Expression Quantitative Trait Locus (eQTL) networks analysis has helped to functionally characterize such variants. We systematically analyze the distribution of SNP heritability for ten traits across 29 tissue-specific eQTL networks. We find that heritability is clustered in a small number or tissue-specific, functionally relevant SNP-gene modules and that the greatest occurs in local “hubs” that are both the cornerstone of the network’s modules and tissue-specific regulatory elements. The network structure could thus both amplify the genotype-phenotype connection and buffer the deleterious effect of the genetic variations on other traits. Together, these results define a conceptual framework for understanding complex trait architecture and identifying key mutations carrying most of the heritability.