Abstract
Metabolic coherence (MC) is a network-based approach to dimensionality reduction that can be used, for example, to interpret the joint expression of genes linked to human metabolism. Computationally, the derivation of ‘transcriptomic’ MC involves mapping of an individual gene expression profile onto a gene-centric network derived beforehand from a metabolic network (currently Recon2), followed by the determination of the connectivity of a particular, profile-specific subnetwork. The biological significance of MC has been exemplified previously in the context of human inflammatory bowel disease, among others, but the genetic architecture of this quantitative cellular trait is still unclear. Therefore, we performed a genome-wide association study (GWAS) of MC in the 1000 Genomes/ GEUVADIS data (n = 457) and identified a solitary genome-wide significant association with single nucleotide polymorphisms (SNPs) in the intronic region of the cadherin 18 (CDH18) gene on chromosome 5 (lead SNP: rs11744487, p = 1.2 × 10− 8). Cadherin 18 is a transmembrane protein involved in human neural development and cell-to-cell signaling. Notably, genetic variation at the CDH18 locus has been associated with metabolic syndrome-related traits before. Replication of our genome-wide significant GWAS result was successful in another population study from the Netherlands (BIOS, n = 2661; lead SNP), but failed in two additional studies (KORA, Germany, n = 711; GENOA, USA, n = 411). Besides sample size issues, we surmise that these discrepant findings may be attributable to technical differences. While 1000 Genomes/GEUVADIS and BIOS gene expression profiles were generated by RNA sequencing, the KORA and GENOA data were microarray-based. In addition to providing first evidence for a link between regional genetic variation and a metabolism-related characteristic of human transcriptomes, our findings highlight the benefit of adopting a systems biology-oriented approach to molecular data analysis.
Highlights
Over the last 15 years, the development of high-throughput molecular technologies has greatly improved the scope and prospects of biological and biomedical research
Genome-wide significant association between sequence variation at a particular gene locus and the metabolic coherence (MC) of human transcriptomes
NADH to ubiquinone GO:0044822 ~ poly(A) RNA binding Transit peptide Transit peptide: mitochondrion GO:0043209 ~ myelin sheath Ubiquinone Transport GO:0070062 ~ extracellular exosome aNumber of Recon2 genes associated with the term in an enrichment analysis with DAVID 6.8 (Huang et al 2009) b p values were Bonferroni corrected for the number of functional terms tested
Summary
Over the last 15 years, the development of high-throughput molecular technologies has greatly improved the scope and prospects of biological and biomedical research. Extended author information available on the last page of the article time, this newly acquired ability to characterize biological entities in their entirety and in great detail has led to an increased need for more efficient and more powerful approaches to data analysis. Omics technologies such as generation DNA sequencing, in particular, generate large amounts of high-dimensional data per study subject that need to be processed and contextualized further to facilitate their biological interpretation. Classical dimensionality reduction techniques such as principal component analysis and multi-dimensional scaling are ‘agnostic’ in the
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