Limits...
Integration of Genome-Wide SNP Data and Gene-Expression Profiles Reveals Six Novel Loci and Regulatory Mechanisms for Amino Acids and Acylcarnitines in Whole Blood.

Burkhardt R, Kirsten H, Beutner F, Holdt LM, Gross A, Teren A, Tönjes A, Becker S, Krohn K, Kovacs P, Stumvoll M, Teupser D, Thiery J, Ceglarek U, Scholz M - PLoS Genet. (2015)

Bottom Line: In conclusion, our integrative analysis of SNP, gene-expression and metabolite data points to novel genetic factors that may be involved in the regulation of human metabolism.At several loci, we provide evidence for metabolite regulation via gene-expression and observed overlaps with GWAS loci for common diseases.These results form a strong rationale for subsequent functional and disease-related studies.

View Article: PubMed Central - PubMed

Affiliation: LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.

ABSTRACT
Profiling amino acids and acylcarnitines in whole blood spots is a powerful tool in the laboratory diagnosis of several inborn errors of metabolism. Emerging data suggests that altered blood levels of amino acids and acylcarnitines are also associated with common metabolic diseases in adults. Thus, the identification of common genetic determinants for blood metabolites might shed light on pathways contributing to human physiology and common diseases. We applied a targeted mass-spectrometry-based method to analyze whole blood concentrations of 96 amino acids, acylcarnitines and pathway associated metabolite ratios in a Central European cohort of 2,107 adults and performed genome-wide association (GWA) to identify genetic modifiers of metabolite concentrations. We discovered and replicated six novel loci associated with blood levels of total acylcarnitine, arginine (both on chromosome 6; rs12210538, rs17657775), propionylcarnitine (chromosome 10; rs12779637), 2-hydroxyisovalerylcarnitine (chromosome 21; rs1571700), stearoylcarnitine (chromosome 1; rs3811444), and aspartic acid traits (chromosome 8; rs750472). Based on an integrative analysis of expression quantitative trait loci in blood mononuclear cells and correlations between gene expressions and metabolite levels, we provide evidence for putative causative genes: SLC22A16 for total acylcarnitines, ARG1 for arginine, HLCS for 2-hydroxyisovalerylcarnitine, JAM3 for stearoylcarnitine via a trans-effect at chromosome 1, and PPP1R16A for aspartic acid traits. Further, we report replication and provide additional functional evidence for ten loci that have previously been published for metabolites measured in plasma, serum or urine. In conclusion, our integrative analysis of SNP, gene-expression and metabolite data points to novel genetic factors that may be involved in the regulation of human metabolism. At several loci, we provide evidence for metabolite regulation via gene-expression and observed overlaps with GWAS loci for common diseases. These results form a strong rationale for subsequent functional and disease-related studies.

No MeSH data available.


Related in: MedlinePlus

GWAS results for amino acids (a) and acylcarnitines (b) in whole blood.Manhattan plots of the genome-wide association analysis for metabolic phenotypes in 2,107 individuals of the LIFE-Heart cohort. Results are presented separately for 36 acylcarnitines (including free and total carnitine) and 26 amino acids. Results for metabolite ratios are omitted. The horizontal line represents a p-value = 1.0x10-7, which was the cutoff used for inclusion of identified associations in the replication state.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4581711&req=5

pgen.1005510.g001: GWAS results for amino acids (a) and acylcarnitines (b) in whole blood.Manhattan plots of the genome-wide association analysis for metabolic phenotypes in 2,107 individuals of the LIFE-Heart cohort. Results are presented separately for 36 acylcarnitines (including free and total carnitine) and 26 amino acids. Results for metabolite ratios are omitted. The horizontal line represents a p-value = 1.0x10-7, which was the cutoff used for inclusion of identified associations in the replication state.

Mentions: Quantitative concentrations of 26 amino acids, 36 acylcarnitines and 34 metabolite ratios were determined in dried whole blood spots of 2,107 participants of the LIFE Leipzig Heart Study using LC-MS/MS. Metabolites and their ratios reflect metabolic function of various biochemical pathways e.g. urea cycle, branched chain amino acid metabolism or cellular fatty acid oxidation (see S1 Table for complete list of phenotypes and their categories). We performed a genome wide association study (2,619,023 SNPs) for whole blood metabolites and identified 2,261 SNP-metabolite associations (119 after pruning) with p-values <10-7. These associations comprise 42 metabolites (including 19 ratios) and 866 SNPs (54 lead-SNPs after pruning) at 25 unique genomic locations (Fig 1, S2 Table). QQ-plots and regional association plots for all loci demonstrating valid quality control are presented in the supplemental material (S2 and S3 Figs).


Integration of Genome-Wide SNP Data and Gene-Expression Profiles Reveals Six Novel Loci and Regulatory Mechanisms for Amino Acids and Acylcarnitines in Whole Blood.

Burkhardt R, Kirsten H, Beutner F, Holdt LM, Gross A, Teren A, Tönjes A, Becker S, Krohn K, Kovacs P, Stumvoll M, Teupser D, Thiery J, Ceglarek U, Scholz M - PLoS Genet. (2015)

GWAS results for amino acids (a) and acylcarnitines (b) in whole blood.Manhattan plots of the genome-wide association analysis for metabolic phenotypes in 2,107 individuals of the LIFE-Heart cohort. Results are presented separately for 36 acylcarnitines (including free and total carnitine) and 26 amino acids. Results for metabolite ratios are omitted. The horizontal line represents a p-value = 1.0x10-7, which was the cutoff used for inclusion of identified associations in the replication state.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581711&req=5

pgen.1005510.g001: GWAS results for amino acids (a) and acylcarnitines (b) in whole blood.Manhattan plots of the genome-wide association analysis for metabolic phenotypes in 2,107 individuals of the LIFE-Heart cohort. Results are presented separately for 36 acylcarnitines (including free and total carnitine) and 26 amino acids. Results for metabolite ratios are omitted. The horizontal line represents a p-value = 1.0x10-7, which was the cutoff used for inclusion of identified associations in the replication state.
Mentions: Quantitative concentrations of 26 amino acids, 36 acylcarnitines and 34 metabolite ratios were determined in dried whole blood spots of 2,107 participants of the LIFE Leipzig Heart Study using LC-MS/MS. Metabolites and their ratios reflect metabolic function of various biochemical pathways e.g. urea cycle, branched chain amino acid metabolism or cellular fatty acid oxidation (see S1 Table for complete list of phenotypes and their categories). We performed a genome wide association study (2,619,023 SNPs) for whole blood metabolites and identified 2,261 SNP-metabolite associations (119 after pruning) with p-values <10-7. These associations comprise 42 metabolites (including 19 ratios) and 866 SNPs (54 lead-SNPs after pruning) at 25 unique genomic locations (Fig 1, S2 Table). QQ-plots and regional association plots for all loci demonstrating valid quality control are presented in the supplemental material (S2 and S3 Figs).

Bottom Line: In conclusion, our integrative analysis of SNP, gene-expression and metabolite data points to novel genetic factors that may be involved in the regulation of human metabolism.At several loci, we provide evidence for metabolite regulation via gene-expression and observed overlaps with GWAS loci for common diseases.These results form a strong rationale for subsequent functional and disease-related studies.

View Article: PubMed Central - PubMed

Affiliation: LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig Germany; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.

ABSTRACT
Profiling amino acids and acylcarnitines in whole blood spots is a powerful tool in the laboratory diagnosis of several inborn errors of metabolism. Emerging data suggests that altered blood levels of amino acids and acylcarnitines are also associated with common metabolic diseases in adults. Thus, the identification of common genetic determinants for blood metabolites might shed light on pathways contributing to human physiology and common diseases. We applied a targeted mass-spectrometry-based method to analyze whole blood concentrations of 96 amino acids, acylcarnitines and pathway associated metabolite ratios in a Central European cohort of 2,107 adults and performed genome-wide association (GWA) to identify genetic modifiers of metabolite concentrations. We discovered and replicated six novel loci associated with blood levels of total acylcarnitine, arginine (both on chromosome 6; rs12210538, rs17657775), propionylcarnitine (chromosome 10; rs12779637), 2-hydroxyisovalerylcarnitine (chromosome 21; rs1571700), stearoylcarnitine (chromosome 1; rs3811444), and aspartic acid traits (chromosome 8; rs750472). Based on an integrative analysis of expression quantitative trait loci in blood mononuclear cells and correlations between gene expressions and metabolite levels, we provide evidence for putative causative genes: SLC22A16 for total acylcarnitines, ARG1 for arginine, HLCS for 2-hydroxyisovalerylcarnitine, JAM3 for stearoylcarnitine via a trans-effect at chromosome 1, and PPP1R16A for aspartic acid traits. Further, we report replication and provide additional functional evidence for ten loci that have previously been published for metabolites measured in plasma, serum or urine. In conclusion, our integrative analysis of SNP, gene-expression and metabolite data points to novel genetic factors that may be involved in the regulation of human metabolism. At several loci, we provide evidence for metabolite regulation via gene-expression and observed overlaps with GWAS loci for common diseases. These results form a strong rationale for subsequent functional and disease-related studies.

No MeSH data available.


Related in: MedlinePlus