Table 1.

GWAS studies of metabolites

Cohort	Platform	N	Results	Significance	Adjustment for: 1) Multiple comparisons 2) Clinical variables
KORA population-based cohort38	Targeted tandem MS, 163 metabolites	2231	9 replicating loci (FADS1, ELOVL2, ACADS ACADM, ACADL, SPTLC3, ETFDH SLC16A9, PLEKHH1)	p=3×10−24 – 6.5×10−179	1) Bonferroni for SNPs and metabolic combinations (p<3.64×10−12) 2) None
InCHIANTI study on aging37	GC, 6 polyunsaturated unsaturated fatty acids	1075	FADS1-3, ELOVL2	p=1.1×10−6 – 6.0×10−46	1) Bonferroni at level of SNPs (p<1×10−7) 2) Sex, age, age2
Prostate cancer, Swedish men39	Nontargeted UPLC-MS, 6138 molecular features	893	7 replicating loci (PYROXD2, FADS1, PON1 CYP4F2, UGT1A8, ACADL, LIPC); pathway analysis reflected enrichment of genes with acyl-coA dehydrogenase activity	p=8.8×10−13 – 3.4×10−60	1) Bonferroni (p<2.44×10−11) 2) None
Finnish individuals40	Nontargeted NMR, 117 metabolites	8330	31 loci (including SLC1A4, PPM1K, F12 SLC25A1, GCKR, G6PC2, CPT1A, PCSK9 ANGPTL3, LPL, ABCA1, FADS1-3, LIPC CETP, LIPG, LDLR, APOE, PLTP). Metabolites showed heritability.	p=8.7×10−11 – 2.5×10−58	1) Bonferroni (p<2.31×10−10) 2) Age, sex, 10 genetic principal components
Two European cohorts41	Nontargeted NMR in urine and plasma, 526 metabolite peaks	211	3 replicating loci (PYROXD2, NAT8, AGXT2)	p=8.6×10−11 – 2.8×10−23	1) Permutation based procedure constraining genome-wide false discovery probability to be <0.001 for each metabolite GWAS 2) Age, gender
KORA population-based cohort36	Targeted tandem MS, 363 metabolites	284	No individual metabolite genomewide significant; 4 loci genomewide significant for metabolite ratios (FADS1, LIPC, SCAD MCAD)	p=2.0×10−9 for best single metabolite; p=10−21 – 10−16 for metabolite ratios	1) Bonferroni (p<1.33×10−9) 2) None
European cohorts42	Targeted electrospray ionization tandem MS, 33 sphingolipids	4400	5 loci with strongest associations in/near 7 genes involved in ceramide biosynthesis and trafficking (SPTLC3, LASS4, SGPP1, ATP10D FADS1-3); SNPs in 3 loci, but not necessarily the same SNPs (ATP10D, FADS3 and SPTLC3) were also associated with myocardial infarction in different cohorts	Lowest p=9.1×10−66	1) Bonferroni at level of SNPs (p<7.2×10−8) 2) Age, sex
German cohort43	Nontargeted LC/GC tandem MS, 517 metabolic traits	1768	34 loci with strongest results for 7 loci (SLC22A2, COMT, CYP3A5, CYP2C18, GBA3 UGT3A1, rs12413935); also overlaid metabolic networks to generate hypotheses for unknown compounds and performed experimental validation of those compounds.	p=1.5×10−10 – 2.2×10−281	1) Bonferroni (p<1.6×10−10) 2) Age, gender
SHIP and KORA population-based studies44	Nontargeted NMR in urine, 59 metabolites	2893	5 loci validated (SLC7A9, NAT2, SLC6A20 AGXT2, WDR66)	p=2.3×10−13 – 3.2×10−75	1) Bonferroni (p<4.5×10−11) 2) Age
KORA population-based and Twins UK studies45	Nontargeted UPLC and GC tandem MS, >250 metabolites	2820	37 loci (including NAT8, GCKR, ABO, ACADS ACADM, UGT1A, CPS1, ELOVL2); 30 of these mapped to protein biochemically linked to associated metabolites; 15 associated with disease endpoints from previous studies in other cohorts	p=1.4×10−12 – 4.4×10−305	1) Bonferroni (p<2.0×10−12) 2) Age, gender, family structure
Meta-analysis of 5 European family-based studies46	Targeted tandem MS, 153 phospho- and sphingolipids	4034	35 loci (including FADS1-2-3, PAQR9 AGPAT1, PKD2L1, PDXDC1, PLD2, APOE PNLIPRP2, ABDH3, APOA1, ELOVL2, LIPC APOE); 3 associated with disease phenotypes in other cohorts (FADS1-2-3, AGPAT1 APOA1)	p=4.9×10−8 – 9.9×10−204	1) Bonferroni (p<2.2×10−9) 2) Familial relatedness
Cardiovascular Risk in Young Finns Study (YFS) and Northern Finland Birth Cohort 1966 (NFBC66)47	Nontargeted NMR in serum, 130 metabolite measures	6608	34 loci (including PCSK9, APOB, GCKR ELOVL2, LPL, ABCA1, FADS1-2-3, CETP); SERPINA1 and AQP9 showed eQTL, upregulated in atherosclerotic plaques	p=3.9×10−9 – 3.9×10−264	1) Metabolic networks used as traits; significance set at p<4.5×10−9 2) None
KORA population-based and Twins UK studies48	LC- and GC-tandem MS in plasma/serum, 529 metabolites	7824	145 loci (including NAT8, LIPC, ANGPTL3, FMO3, ELOVL2 FADS1, CETP, CPS1, APOE, PPM1K and 84 new loci); integrated with gene expression; created web-based resources for data mining and results visualization	p=5.2×10−9 – 6.2×10−860	1) Bonferroni (p<1.03×10−10 for individual metabolites; p<5.08×10−13 for metabolite ratios) 2) Age, sex

MS: mass spectrometry; GC: gas chromatography; NMR: nuclear magnetic resonance; UPLC: ultra-high performance liquid chromatography; LC: liquid chromatography.