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Comprehensive characterization of putative genetic influences on plasma metabolome in a pediatric cohort

ABSTRACT: Background: The human exposome is composed of diverse metabolites and small chemical compounds originated from endogenous and exogenous sources, respectively. Genetic and environmental factors influence metabolite levels while the extent of genetic contributions across metabolic pathways is not yet known. Untargeted profiling of human metabolome using high-resolution mass spectrometry (HRMS) combined with genome-wide genotyping allows comprehensive identification of genetically influenced metabolites. As such previous studies of adults discovered and replicated genotype-metabotype associations. However, these associations have not been characterized in children. Results: We conducted the largest genome by metabolome-wide association study to date of children (N=441) using 619,688 common genetic variants and 14,342 features measured by HRMS. Narrow-sense heritability (h2) estimates of plasma metabolite concentrations using genomic relatedness matrix restricted maximum likelihood (GREML) method showed a bimodal distribution with high h2 (>0.8) for 15.9% of features and low h2 (<0.2) for most of features (62.0%). The features with high h2 were enriched for amino acid and nucleic acid metabolism while carbohydrate and lipid concentrations showed low h2. For each feature, a metabolite quantitative trait locus (mQTL) analysis was performed to identify genetic variants that were potentially associated with plasma levels. Fifty-four associations among 29 features and 43 genetic variants were identified at a genome-wide significance threshold p < 3.5x10-12 (= 5 x 10-8/14,342 features). Previously reported associations such as UGT1A1 and bilirubin; PYROXD2 and methyl lysine; ACADS and butyrylcarnitine were successfully replicated in our pediatric cohort. We found potential candidates for novel associations including CSMD1 and a monostearyl alcohol triglyceride; CALN1 and a triglyceride; RBFOX1 and dimethylarginine. A gene-level enrichment analysis using MAGMA revealed highly interconnected modules for ADP biosynthesis, sterol synthesis, and long-chain fatty acid transport in the gene-feature network. Conclusion: Comprehensive profiling of plasma metabolome across age groups combined with genome-wide genotyping revealed a wide range of genetic influence on diverse chemical species and metabolic pathways. The developmental trajectory of a biological system is shaped by gene-environment interaction especially in early life. Therefore, continuous efforts on generating metabolomics data in diverse human tissue types across age groups are required to understand gene-environment interaction toward healthy aging trajectories.

ORGANISM(S): Human Homo Sapiens

TISSUE(S): Blood

SUBMITTER: Sek Won Kong

PROVIDER: ST002331 | MetabolomicsWorkbench | Thu Oct 13 00:00:00 BST 2022

REPOSITORIES: MetabolomicsWorkbench

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Project description:Background: The mechanisms of how genetic variants (SNPs) identified in genome-wide association studies act to influence body mass remain unknown for most of these SNPs, which continue to puzzle the scientific community. Recent evidence points to epigenetic and chromatin state of the genome to have an important role. Methods: 355 healthy young individuals were genotyped for 52 known obesity-associated SNPs and we obtained DNA methylation levels in their blood using the Illumina 450K BeadChip. Associations between alleles and methylation at proximal cytosine residues were tested using a linear model adjusted for age, sex, weight category and a proxy for blood cell type counts. For replication in other tissues, we used two open-access datasets (skin fibroblasts, n=62; four brain regions, n=121-133) and an additional dataset in subcutaneous and visceral fat (n=149). Results: We found that alleles at 28 of these obesity-associated SNPs associate with methylation levels at 107 proximal CpG sites. Out of 107 CpG sites, 38 are located in gene promoters, including genes strongly implicated in obesity (MIR148A, BDNF, PTPMT1, NR1H3, MGAT1, SCGB3A1, HOXC12, PMAIP1, PSIP1, RPS10-NUDT3, RPS10, SKOR1, MAP2K5, SIX5, AGRN, IMMP1L, ELP4, ITIH4, SEMA3G, POMC, ADCY3, SSPN, LGR4, TUFM, MIR4721, SULT1A1, SULT1A2, APOBR, CLN3, SPNS1,SH2B1, ATXN2L, and IL27). Interestingly, the associated SNPs are in known eQTLs for some of these genes. We also found that the 107 CpGs are enriched in enhancers in peripheral blood mononuclear cells. Finally, our results indicate that some of these associations are not be blood-specific as we successfully replicated four associations in skin fibroblasts. Conclusions: Our results strongly suggest that many obesity-associated SNPs are associated with proximal gene regulation, which was reflected by association of obesity risk allele genotypes with differential DNA methylation. This study highlights the importance of DNA methylation and other chromatin marks as a way to understand the molecular basis of genetic variants associated to human diseases and traits. Bisulphite converted DNA from 355 individuals aged 14-34 were hybridised to the Illumina Infinium 450k Human Methylation Beadchip.

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Comprehensive characterization of putative genetic influences on plasma metabolome in a pediatric cohort

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