Experiment
Metabolites are produced in the cell as a result of various enzymatic reactions and in part reflect the metabolic state of the cell. The authors profiled and analyzed 283 metabolites representing eight major classes of molecules including Lipids, Carbohydrates, Amino Acids, Peptides, Xenobiotics, Vitamins and Cofactors, Energy Metabolism, and Nucleotides in mouse liver from the Hybrid Mouse Diversity Panel (HMDP) comprised of 104 inbred and recombinant inbred strains. Using genome-wide association analysis, the authors mapped 40% of the quantified metabolites to at least one locus in the genome.
To identify the loci regulating the metabolite variation, the authors applied the genome-wide association analysis approach utilizing 107,145 SNPs from the Broad Institute and Wellcome Trust Center database which had a minor allele frequency >5% in the HMDP population of 104 inbred and recombinant inbred mouse strains. With this panel of SNPs, the authors performed genome-wide association for each of the 283 metabolites using Efficient Mixed Modeling Algorithm (EMMA) that corrects for population structure and genetic relatedness among strains.
Using 5% FDR as the genome-wide cutoff (P-value = 7.6 x 10^-6), the authors were able to identify 240 significant associations, from which 12 are expected to be false positives, for 119 of the 283 metabolites (Table 1 lists the top 10 associations and Supplementary Table S3 lists all the significant associations). Based on the peak SNP, the 240 significant associations corresponded to 227 distinct loci across the genome.
The top ten GWAS results listed in Table 1 have been assigned offical QTL nomenclature (all coordinates relative to GRCm38/mm10):
Metl1 (metabolite locus 1, pyridoxate) maps to Chr 1: 58,236,240 with a p-value of 1.66 x 10^-28. C57BL/6J contributes the high allele at Metl1.
Metl2 (metabolite locus 2, glucarate) maps to Chr 4: 118,382,970 with a p-value of 7.84 x 10^-17.
Metl3 (metabolite locus 3, N-acetylglutamate) maps to Chr 9: 106,563,342 with a p-value of 1.09 x 10^-15. C57BL/6J contributes the high allele at Metl3.
Metl4 (metabolite locus 4, malonate) maps to Chr 8: 119,096,872 with a p-value of 2.59 x 10^-15.
Metl5 (metabolite locus 5, glycerate) maps to Chr 12: 43,670,942 with a p-value of 2.11 x 10^-14.
Metl6 (metabolite locus 6, methylmalonate) maps to Chr 8: 119,096,872 with a p-value of 6.50 x 10^-14.
Metl7 (metabolite locus 7, succinylcarnitine) maps to Chr 3: 144,100,853 with a p-value of 1.16 x 10^-13.
Metl8 (metabolite locus 8, methylmalonate) maps to Chr 19: 46,764,525 with a p-value of 4.79 x 10^-13.
Metl9 (metabolite locus 9, methylmalonate) maps to Chr 1: 32,385,974 with a p-value of 8.84 x 10^-13.
Metl10 (metabolite locus 10, kynurenate) maps to Chr 2: 134,733,767 with a p-value of 3.83 x 10^-11.
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