Circ Res

Abstract

Rationale and ObjectiveIn this Emerging Science Review, we discuss a systems genetics strategy, which we call Gene Module Association Study (GMAS), as a novel approach complementing Genome Wide Association Studies (GWAS), to understand complex diseases by focusing on how genes work together in groups rather than singly.MethodsThe first step is to characterize phenotypic differences among a genetically diverse population. The second step is to use gene expression microarray (or other high throughput) data from the population to construct gene co-expression networks. Co-expression analysis typically groups 20,000 genes into 20\u201330 modules containing 10\u2019s to 100\u2019s of genes, whose aggregate behavior can be represented by the module\u2019s \u201ceigengene.\u201d The third step is to correlate expression patterns with phenotype, as in GWAS, only applied to eigengenes instead of SNPs.Results and ConclusionsThe goal of the GMAS approach is to identify groups of co-regulated genes that explain complex traits from a systems perspective. From an evolutionary standpoint, we hypothesize that variability in eigengene patterns reflects the \u201cgood enough solution\u201d concept, that biological systems are sufficiently complex so that many possible combinations of the same elements (in this case eigengenes) can produce an equivalent output, i.e. a \u201cgood enough solution\u201d to accomplish normal biological functions. However, when faced with environmental stresses, some \u201cgood enough solutions\u201d adapt better than others, explaining individual variability to disease and drug susceptibility. If validated, GMAS may imply that common polygenic diseases are related as much to group interactions between normal genes, as to multiple gene mutations.R01 HL094322/HL/NHLBI NIH HHSUnited States/P01 HL080111/HL/NHLBI NIH HHSUnited States/HHSN268201000035C/HL/NHLBI NIH HHSUnited States/1DP3 D094311/DP/NCCDPHP CDC HHSUnited States/R01 HL101228/HL/NHLBI NIH HHSUnited States/P01 HL30568/HL/NHLBI NIH HHSUnited States/R21 HL110667-01/HL/NHLBI NIH HHSUnited States/P01 HL030568/HL/NHLBI NIH HHSUnited States/T32 HL069766/HL/NHLBI NIH HHSUnited States/R01 GM095656/GM/NIGMS NIH HHSUnited States/R21 HL110667/HL/NHLBI NIH HHSUnited States/P01 HL28481/HL/NHLBI NIH HHSUnited States/K25 HL080079/HL/NHLBI NIH HHSUnited States/P01 HL078931/HL/NHLBI NIH HHSUnited States/P01 HL028481/HL/NHLBI NIH HHSUnited States/UL1 TR000124/TR/NCATS NIH HHSUnited States/T32HL69766/HL/NHLBI NIH HHSUnited States/R01 HL070748/HL/NHLBI NIH HHSUnited States