Table 4 |.

Biological relevance of the novel replicated genomic loci-metabolite associations

Chromosomal location; mapped genesa	Associated metabolite	Metabolite superpathway	Metabolite subpathway	Biological or pathological relevance of metabolites	Function of the most likely causal genes and disease associations
1:118887090-119887090; HAO2	2-Hydroxy-3-methylvalerate	Amino acid	Leucine, isoleucine, and valine metabolism	Higher levels seen in maple syrup urine disease	HAO2 encodes 2-hydroxyacid oxidase, which catalyzes the oxidation of l-alpha-hydroxy acids as well as l-alpha amino acids.
2:73105659-74173773; ALMS1, ALMS1P, NAT8, TPRKB	N2-Acetyllysine	Amino acid	Lysine metabolism	N-Acetylated compounds that are derivatives or degradation products of amino acids	NAT8 encodes for N-acetyltransferases, which acetylate cysteine S-conjugates to form mercapturic acids, the final step in the detoxification of various reactive electrophiles.
	N-Acetylleucine	Amino acid	Leucine, isoleucine, and valine metabolism
	N-Acetylarginine	Amino acid	Urea cycle; arginine and proline metabolism
3:51489004-52620872; POC1A, ACY1, ABHD14A-ACY1	N-Acetylmethionine	Amino acid	Methionine, cysteine, SAM, and taurine metabolism	N-Acetylated compounds that are derivatives or degradation products of amino acids	ACY1 encodes an enzyme that catalyzes hydrolysis of acylated l-amino acids and is postulated to participate in the catabolism and salvage of acylated amino acids. Its expression has been shown to be reduced in small cell lung cancer cell lines. Aminoacylase 1 deficiency is characterized by central nervous system defects and increased urinary excretion of N-acetylated amino acids. Read-through transcription exists between ACY1 and the upstream ABHD14A (abhydrolase domain containing 14A). Diseases associated with ACY1 include aminoacylase 1 deficiency and syringomyelia.
8:143564265-144564265; OPLAH, CTD-3065J16.9, EXOSC4, GPAA1, KIAA1875, MAF1	6-Oxopiperidine-2-carboxylate	Amino acid	Lysine metabolism	Monocarboxylic acid anion that is the conjugate base of 6-ketopiperidine-2 carboxylic acid	EXOSC4 encodes a protein that is component of an RNA exosome complex which has 3′→5′ exoribonuclease activity. GPAA1 encodes a protein that presumably functions in posttranslational GPI anchoring.
9:128422557-129422736; LRRC8A, PHYHD1, SH3GLB2	2′-O-Methylcytidine	Nucleotide	Pyrimidine metabolism, cytodine-containing	A methylcytidine that consists of cytidine bearing a single methyl substituent located at position O-2′ on the ribose ring	PHYHD1 encodes a protein with dioxygenase activity.
11:48528971-49528971; PTPRJ, FOLH1	N-Acetyl-aspartyl-glutamate	Amino acid	Glutamate metabolism	Peptide neurotransmitter in the mammalian nervous system
11:67144985-68144985; ACY3, AP003385.2	N-Acetyltryptophan	Amino acid	Tryptophan metabolism	N-Acetylated compounds that are derivatives or degradation products of amino acids	ACY3 encodes aminoacylase 3, which has a role in deacetylating mercapturic acids in kidney proximal tubules. Diseases associated with ACY3 include hepatitis C virus.
	N-Acetyltyrosine	Amino acid	Tyrosine metabolism
17:77706736-78706736; AFMID	N-Formylanthranilic acid	Amino acid	Tryptophan metabolism	An amidobenzoic acid derived from anthranilic acid, occasionally found in human urine	AFMID encodes arylformamidase, which catalyzes the hydrolysis of N-formyl-l-kynurenine to l-kynurenine, the second step in the kynurenine pathway of tryptophan degradation. Kynurenine may further be oxidized to nicotinic acid, NAD(H), and NADP(H) required for the elimination of toxic metabolites.

GPI, glycosylphosphatidylinositol; NADP(H), nicotinamide adenine dinucleotide phosphate (reduced); NAD(H), nicotinamide adenine dinucleotide (reduced); SAM, S-adenosyl methionine.

Bold text indicates most likely causal genes.