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Hum Genet. 2019 Apr;138(4):375-388. doi: 10.1007/s00439-019-01994-x. Epub 2019 Mar 9.

The metabolic network coherence of human transcriptomes is associated with genetic variation at the cadherin 18 locus.

Author information

1
Institute of Medical Informatics and Statistics, Kiel University, University Hospital Schleswig-Holstein, 24105, Kiel, Germany.
2
Department of Life Sciences and Chemistry, Jacobs University, 28759, Bremen, Germany.
3
Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB, Groningen, The Netherlands.
4
Department of Epidemiology, University of Michigan, Ann Arbor, MI, 48109, USA.
5
Research Unit Molecular Epidemiology, Helmholtz-Zentrum München-German Research Center for Environmental Health, 85764, Neuherberg, Germany.
6
Institute of Epidemiology, Helmholtz-Zentrum München-German Research Center for Environmental Health, 85764, Neuherberg, Germany.
7
Institute of Human Genetics, Helmholtz-Zentrum München-German Research Center for Environmental Health, 85764, Neuherberg, Germany.
8
Institute of Genetic Epidemiology, Helmholtz-Zentrum München-German Research Center for Environmental Health, 85764, Neuherberg, Germany.
9
Chair of Genetic Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians University, 81377, Munich, Germany.
10
Department of Dermatology, University Hospital Schleswig-Holstein, 24105, Kiel, Germany.
11
Institute of Epidemiology and Preventive Medicine, University Hospital Regensburg, 93053, Regensburg, Germany.
12
Institute of Clinical Molecular Biology, Kiel University, University Hospital Schleswig-Holstein, 24105, Kiel, Germany.
13
Institute of Medical Informatics and Statistics, Kiel University, University Hospital Schleswig-Holstein, 24105, Kiel, Germany. krawczak@medinfo.uni-kiel.de.

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.

PMID:
30852652
PMCID:
PMC6483969
DOI:
10.1007/s00439-019-01994-x
[Indexed for MEDLINE]
Free PMC Article

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