An atlas of genome-wide gene expression and metabolite associations and possible mediation effects towards body mass index.
Carl BeuchelJulia DittrichSusen BeckerHolger KirstenAnke TönjesPeter KovacsMichael StumvollMarkus LoefflerAndrej TerenJoachim ThieryBerend IsermannUta CeglarekMarkus ScholzPublished in: Journal of molecular medicine (Berlin, Germany) (2023)
Investigating the cross talk of different omics layers is crucial to understand molecular pathomechanisms of metabolic diseases like obesity. Here, we present a large-scale association meta-analysis of genome-wide whole blood and peripheral blood mononuclear cell (PBMC) gene expressions profiled with Illumina HT12v4 microarrays and metabolite measurements from dried blood spots (DBS) characterized by targeted liquid chromatography tandem mass spectrometry (LC-MS/MS) in three large German cohort studies with up to 7706 samples. We found 37,295 associations comprising 72 amino acids (AA) and acylcarnitine (AC) metabolites (including ratios) and 8579 transcripts. We applied this catalogue of associations to investigate the impact of associating transcript-metabolite pairs on body mass index (BMI) as an example metabolic trait. This is achieved by conducting a comprehensive mediation analysis considering metabolites as mediators of gene expression effects and vice versa. We discovered large mediation networks comprising 27,023 potential mediation effects within 20,507 transcript-metabolite pairs. Resulting networks of highly connected (hub) transcripts and metabolites were leveraged to gain mechanistic insights into metabolic signaling pathways. In conclusion, here, we present the largest available multi-omics integration of genome-wide transcriptome data and metabolite data of amino acid and fatty acid metabolism and further leverage these findings to characterize potential mediation effects towards BMI proposing candidate mechanisms of obesity and related metabolic diseases. KEY MESSAGES: Thousands of associations of 72 amino acid and acylcarnitine metabolites and 8579 genes expand the knowledge of metabolome-transcriptome associations. A mediation analysis of effects on body mass index revealed large mediation networks of thousands of obesity-related gene-metabolite pairs. Highly connected, potentially mediating hub genes and metabolites enabled insight into obesity and related metabolic disease pathomechanisms.
Keyphrases
- genome wide
- body mass index
- dna methylation
- weight gain
- gene expression
- amino acid
- single cell
- ms ms
- insulin resistance
- metabolic syndrome
- copy number
- social support
- rna seq
- weight loss
- liquid chromatography tandem mass spectrometry
- type diabetes
- peripheral blood
- fatty acid
- high fat diet induced
- electronic health record
- adipose tissue
- epithelial mesenchymal transition
- signaling pathway
- human health
- artificial intelligence
- bone marrow
- machine learning
- oxidative stress
- deep brain stimulation
- big data
- cell therapy
- risk assessment
- induced apoptosis
- drug induced