Dual Linkage of a Locus to Left Ventricular Mass and a Cardiac Gene Co-Expression Network Driven by a Chromosome Domain

We have previously reported Lvm1 as a quantitative trait locus (QTL) on chromosome 13 that links to cardiac left ventricular mass (LVM) in a panel of AxB/BxA mouse recombinant inbred strains (RIS). When performing a gene expression QTL (eQTL) analysis, we detected 33 cis-eQTLs that correlated with LVM. Among the latter, a group of eight cis-eQTLs clustered in a genomic region smaller than 6 Mb and surrounding the Lvm1 peak on chr13. Co-variant analysis indicated that all eight genes correlated with the phenotype in a causal rather than a reactive fashion, a finding that (despite its functional interest) did not provide grounds to prioritize any of these candidate genes. As a complementary approach, we performed weighted gene co-expression network analysis, which allowed us to detect 49 modules of highly connected genes. The module that correlated best with LVM: (1) showed linkage to a module QTL whose boundaries matched closely those of the phenotypic Lvm1 QTL on chr13; (2) harbored a disproportionately high proportion of genes originating from a small genomic region on chromosome 13 (including the 8 previously detected cis-eQTL genes); (3) contained genes that, beyond their individual level of expression, correlated with LVM as a function of their inter-connectivity; and (4) showed increased abundance of polymorphic insertion-deletion elements in the same region. Taken together, these data suggest that a domain on chromosome 13 constitutes the biologic principle responsible for the organization and linkage of the gene co-expression module, and indicate a mechanism whereby genetic variants within chromosome domains may associate to phenotypic changes via coordinate changes in the expression of several genes. One other possible implication of these findings is that candidate genes to consider as contributors to a particular phenotype should extend further than those that are closest to the QTL peak.