Loss-of-function variants influence the human serum metabolome · 2016-08-29 · This includes:...

advances.sciencemag.org/cgi/content/full/2/8/e1600800/DC1

Supplementary Materials for

Loss-of-function variants influence the human serum metabolome

Bing Yu, Alexander H. Li, Ginger A. Metcalf, Donna M. Muzny, Alanna C. Morrison, Simon White,

Thomas H. Mosley, Richard A. Gibbs, Eric Boerwinkle

Published 31 August 2016, Sci. Adv. 2, e1600800 (2016)

DOI: 10.1126/sciadv.1600800

This PDF file includes:

table S1. Baseline characteristics of African-Americans in ARIC having

metabolomic and exome sequence data.

table S2. List of 308 named metabolites measured in ARIC.

table S3. Eighteen significant LoF sites with metabolite associations identified

among African-Americans in ARIC.

table S4. Relationship between hexadecanedioate and blood pressure levels

among European-Americans and African-Americans in ARIC.

fig. S1. Distribution of the number of LoF sites per individual among ARIC

African-Americans.

fig. S2. QQ plots of the expected and observed −log P values for 10 identified

metabolites.

fig. S3. Pathways among genes, metabolites, and diseases identified among ARIC

African-Americans.

table S1. Baseline Characteristics of African-Americans in ARIC having metabolomic and

exome sequence data.

Characteristic N = 1,361

Age, years 52.5 ± 5.6

Male, n (%) 464 (34.1)

Body mass index, kg/m2 29.8 ± 6.2

Hypertension, n (%) 705 (51.8)

Diabetes, n (%) 190 (14.0)

Prevalent coronary heart disease, n (%) 49 (3.6)

Current smoker, n (%) 377 (27.7)

Systolic blood pressure, mm Hg 126.9 ± 19.0

Diastolic blood pressure, mm Hg 80.2 ± 11.4

HDL cholesterol, mg/dL 56.1 ± 17.4

LDL cholesterol, mg/dL 135.2 ± 38.0

Triglycerides, mg/dL 106.2 ± 55.9

Total cholesterol, mg/dL 212.5 ± 40.0

For continuous variables, mean values ± standard deviations are shown.

table S2. List of 308 named metabolites measured in ARIC. For each metabolite, the super‐

pathway, sub-pathway, measurement platform, and percent of imputed low values are provided.

Metabolite Super-

Pathway Sub-Pathway Platform

Imputated

(%)

2-aminobutyrate Amino acid Butanoate metabolism LC/MS pos 0

2-hydroxybutyrate (AHB) Amino acid Cysteine, methionine, SAM,

taurine metabolism GC/MS 0

2-hydroxyisobutyrate Amino acid Valine, leucine and

isoleucine metabolism GC/MS 11.94

2-methylbutyroylcarnitine Amino acid Valine, leucine and

isoleucine metabolism LC/MS pos 9.17

3-(4-hydroxyphenyl)lactate Amino acid Phenylalanine & tyrosine

metabolism LC/MS neg 0

3-hydroxy-2-ethylpropionate Amino acid Valine, leucine and

isoleucine metabolism LC/MS neg 30.35

3-hydroxyisobutyrate Amino acid Valine, leucine and

isoleucine metabolism GC/MS 4.29

3-indoxyl sulfate Amino acid Tryptophan metabolism LC/MS neg 0

3-methoxytyrosine Amino acid Phenylalanine & tyrosine

metabolism LC/MS pos 7.35

3-methyl-2-oxovalerate Amino acid Valine, leucine and


3-methylhistidine Amino acid Histidine metabolism LC/MS neg 11.86

3-phenylpropionate (hydrocinnamate) Amino acid Phenylalanine & tyrosine

metabolism LC/MS neg 21.03

4-acetamidobutanoate Amino acid Guanidino and acetamido


4-guanidinobutanoate Amino acid Guanidino and acetamido


4-methyl-2-oxopentanoate Amino acid Valine, leucine and


5-oxoproline Amino acid Glutathione metabolism LC/MS neg 0

alanine Amino acid Alanine and aspartate

metabolism GC/MS 0

alpha-hydroxyisocaproate Amino acid Valine, leucine and


alpha-hydroxyisovalerate Amino acid Valine, leucine and

isoleucine metabolism LC/MS neg 0

anthranilate Amino acid Tryptophan metabolism LC/MS pos 15.94

arginine Amino acid Urea cycle; arginine-,

proline-, metabolism LC/MS neg 3.49

asparagine Amino acid Alanine and aspartate

metabolism GC/MS 16.89

aspartate Amino acid Alanine and aspartate


beta-hydroxyisovalerate Amino acid Valine, leucine and


betaine Amino acid Glycine, serine and threonine

metabolism LC/MS pos 0

C-glycosyltryptophan Amino acid Tryptophan metabolism LC/MS pos 0.07

citrulline Amino acid Urea cycle; arginine-,

proline-, metabolism LC/MS pos 2.47

creatine Amino acid Creatine metabolism LC/MS pos 0

creatinine Amino acid Creatine metabolism LC/MS pos 0

cysteine Amino acid Cysteine, methionine, SAM,

taurine metabolism GC/MS 31.22

dimethylarginine (SDMA + ADMA) Amino acid Urea cycle; arginine-,


dimethylglycine Amino acid Glycine, serine and threonine


glutamate Amino acid Glutamate metabolism LC/MS neg 0

glutarate (pentanedioate) Amino acid Lysine metabolism GC/MS 18.56

glutaroyl carnitine Amino acid Lysine metabolism LC/MS pos 0.66

glycine Amino acid Glycine, serine and threonine

metabolism GC/MS 0

histidine Amino acid Histidine metabolism LC/MS neg 0

homocitrulline Amino acid Urea cycle; arginine-,


homostachydrine Amino acid Urea cycle; arginine-,


hydroxyisovaleroyl carnitine Amino acid Valine, leucine and


indoleacetate Amino acid Tryptophan metabolism LC/MS pos 0.22

indolelactate Amino acid Tryptophan metabolism LC/MS pos 13.61

indolepropionate Amino acid Tryptophan metabolism LC/MS neg 7.13

isobutyrylcarnitine Amino acid Valine, leucine and


isoleucine Amino acid Valine, leucine and

isoleucine metabolism LC/MS pos 0

isovalerylcarnitine Amino acid Valine, leucine and


kynurenine Amino acid Tryptophan metabolism LC/MS pos 0

leucine Amino acid Valine, leucine and


lysine Amino acid Lysine metabolism LC/MS pos 0

methionine Amino acid Cysteine, methionine, SAM,

taurine metabolism LC/MS neg 0.15

methionine sulfoxide Amino acid Cysteine, methionine, SAM,

taurine metabolism LC/MS pos 0.36

N6-acetyllysine Amino acid Lysine metabolism LC/MS pos 0.07

N-acetylalanine Amino acid Alanine and aspartate


N-acetyl-beta-alanine Amino acid Alanine and aspartate


N-acetylglycine Amino acid Glycine, serine and threonine


N-acetylornithine Amino acid Urea cycle; arginine-,


N-acetylphenylalanine Amino acid Phenylalanine & tyrosine


N-acetylserine Amino acid Glycine, serine and threonine


N-acetylthreonine Amino acid Glycine, serine and threonine


N-methyl proline Amino acid Urea cycle; arginine-,


o-cresol sulfate Amino acid Phenylalanine & tyrosine


ornithine Amino acid Urea cycle; arginine-,

proline-, metabolism GC/MS 2.69

p-cresol sulfate Amino acid Phenylalanine & tyrosine


phenol sulfate Amino acid Phenylalanine & tyrosine


phenylacetate Amino acid Phenylalanine & tyrosine


phenylacetylglutamine Amino acid Phenylalanine & tyrosine


phenylalanine Amino acid Phenylalanine & tyrosine


phenyllactate (PLA) Amino acid Phenylalanine & tyrosine


pipecolate Amino acid Lysine metabolism LC/MS pos 0.87

proline Amino acid Urea cycle; arginine-,

proline-, metabolism LC/MS pos 0

pyroglutamine Amino acid Glutamate metabolism LC/MS pos 0.58

serine Amino acid Glycine, serine and threonine

metabolism GC/MS 0

serotonin (5HT) Amino acid Tryptophan metabolism LC/MS pos 1.6

stachydrine Amino acid Urea cycle; arginine-,


threonine Amino acid Glycine, serine and threonine


tiglyl carnitine Amino acid Valine, leucine and


trans-4-hydroxyproline Amino acid Urea cycle; arginine-,


tryptophan Amino acid Tryptophan metabolism LC/MS pos 0

tryptophan betaine Amino acid Tryptophan metabolism LC/MS pos 1.02

tyrosine Amino acid Phenylalanine & tyrosine


urea Amino acid Urea cycle; arginine-,

proline-, metabolism GC/MS 0

urocanate Amino acid Histidine metabolism LC/MS pos 3.28

valine Amino acid Valine, leucine and


1,5-anhydroglucitol (1,5-AG) Carbohydrate Glycolysis, gluconeogenesis,

pyruvate metabolism GC/MS 2.04

1,6-anhydroglucose Carbohydrate Glycolysis, gluconeogenesis,


arabinose Carbohydrate Nucleotide sugars, pentose


erythronate Carbohydrate Aminosugars metabolism GC/MS 1.38

erythrose Carbohydrate

Fructose, mannose,

galactose, starch, and sucrose

metabolism

GC/MS 10.41

fructose Carbohydrate

Fructose, mannose,


metabolism

GC/MS 0

gluconate Carbohydrate Nucleotide sugars, pentose


glucose Carbohydrate Glycolysis, gluconeogenesis,

pyruvate metabolism GC/MS 0

glucuronate Carbohydrate Glycolysis, gluconeogenesis,


glycerate Carbohydrate Glycolysis, gluconeogenesis,


lactate Carbohydrate Glycolysis, gluconeogenesis,


mannitol Carbohydrate

Fructose, mannose,


metabolism

GC/MS 38.28

mannose Carbohydrate

Fructose, mannose,


metabolism

GC/MS 0.07

pyruvate Carbohydrate Glycolysis, gluconeogenesis,


threitol Carbohydrate Nucleotide sugars, pentose


trehalose Carbohydrate

Fructose, mannose,


metabolism

GC/MS 20.31

alpha-tocopherol Cofactors and

vitamins Tocopherol metabolism GC/MS 23.36

arabonate Cofactors and

vitamins

Ascorbate and aldarate


bilirubin (E,E) Cofactors and

vitamins

Hemoglobin and porphyrin


bilirubin (Z,Z) Cofactors and

vitamins



biliverdin Cofactors and

vitamins



gamma-tocopherol Cofactors and

vitamins Tocopherol metabolism GC/MS 32.75

pantothenate Cofactors and

vitamins

Pantothenate and CoA


pyridoxate Cofactors and

vitamins Vitamin B6 metabolism LC/MS neg 0.07

threonate Cofactors and

vitamins

Ascorbate and aldarate

metabolism GC/MS 4

acetylphosphate Energy Oxidative phosphorylation GC/MS 0

cis-aconitate Energy Krebs cycle LC/MS neg 0

citrate Energy Krebs cycle GC/MS 0

malate Energy Krebs cycle GC/MS 15.65

phosphate Energy Oxidative phosphorylation GC/MS 0

succinate Energy Krebs cycle LC/MS neg 0

succinylcarnitine Energy Krebs cycle LC/MS pos 4.44

1,2 propanediol Lipid Ketone bodies GC/MS 0.51

10-heptadecenoate (17:1n7) Lipid Long chain fatty acid LC/MS neg 0

10-nonadecenoate (19:1n9) Lipid Long chain fatty acid LC/MS neg 0

13-HODE + 9-HODE Lipid Fatty acid, monohydroxy LC/MS neg 0

1-arachidonoylglycerophosphocholine Lipid Lysolipid LC/MS pos 8.95

1-arachidonoylglycero

phosphoethanolamine Lipid Lysolipid LC/MS neg 0

1-arachidonoylglycerophosphoinositol Lipid Lysolipid LC/MS neg 0

1-docosahexaenoylglycero

phosphocholine Lipid Lysolipid LC/MS pos 0

1-docosapentaenoylglycerophosphocholine Lipid Lysolipid LC/MS pos 6.4

1-eicosadienoylglycerophosphocholine Lipid Lysolipid LC/MS pos 2.62

1-eicosatrienoylglycerophosphocholine Lipid Lysolipid LC/MS pos 0

1-heptadecanoylglycerophosphocholine Lipid Lysolipid LC/MS pos 0.87

1-linoleoylglycerophosphocholine Lipid Lysolipid LC/MS pos 0.29

1-linoleoylglycerophosphoethanolamine Lipid Lysolipid LC/MS neg 0

1-myristoylglycerophosphocholine Lipid Lysolipid LC/MS pos 0

1-O-hexadecylglycerophosphocholine Lipid Lysolipid LC/MS pos 0

1-oleoylglycerol (1-monoolein) Lipid Monoacylglycerol LC/MS pos 0.07

1-oleoylglycerophosphocholine Lipid Lysolipid LC/MS pos 0

1-oleoylglycerophosphoethanolamine Lipid Lysolipid LC/MS neg 0.36

1-palmitoleoylglycerophosphocholine Lipid Lysolipid LC/MS pos 0

1-palmitoylglycerol (1-monopalmitin) Lipid Monoacylglycerol GC/MS 6.55

1-palmitoylglycerophosphocholine Lipid Lysolipid LC/MS pos 0

1-palmitoylglycerophosphoethanolamine Lipid Lysolipid LC/MS neg 0

1-palmitoylglycerophosphoinositol Lipid Lysolipid LC/MS neg 0.36

1-pentadecanoylglycerophosphocholine Lipid Lysolipid LC/MS pos 2.11

1-stearoylglycerol (1-monostearin) Lipid Monoacylglycerol GC/MS 8.52

1-stearoylglycerophosphocholine Lipid Lysolipid LC/MS pos 0

1-stearoylglycerophosphoethanolamine Lipid Lysolipid LC/MS neg 1.75

1-stearoylglycerophosphoinositol Lipid Lysolipid LC/MS neg 0

21-hydroxypregnenolone disulfate Lipid Sterol/Steroid LC/MS neg 14.85

2-arachidonoylglycerophosphocholine Lipid Lysolipid LC/MS pos 30.42

2-arachidonoylglycero

phosphoethanolamine Lipid Lysolipid LC/MS neg 9.1

2-hydroxyglutarate Lipid Fatty acid, dicarboxylate GC/MS 13.68

2-hydroxyoctanoate Lipid Fatty acid, monohydroxy LC/MS neg 44.61

2-hydroxypalmitate Lipid Fatty acid, monohydroxy LC/MS neg 0

2-hydroxystearate Lipid Fatty acid, monohydroxy LC/MS neg 0

2-linoleoylglycerophosphocholine Lipid Lysolipid LC/MS pos 4.73

2-linoleoylglycerophosphoethanolamine Lipid Lysolipid LC/MS neg 24.82

2-oleoylglycerophosphocholine Lipid Lysolipid LC/MS pos 0.15

2-oleoylglycerophosphoethanolamine Lipid Lysolipid LC/MS neg 42.72

2-palmitoylglycerophosphocholine Lipid Lysolipid LC/MS pos 0

2-palmitoylglycero

phosphoethanolamine Lipid Lysolipid LC/MS neg 10.41

2-stearoylglycerophosphocholine Lipid Lysolipid LC/MS pos 0

3-carboxy-4-methyl-5-propyl-2-

furanpropanoate (CMPF) Lipid Fatty acid, dicarboxylate LC/MS neg 0.07

3-dehydrocarnitine Lipid Carnitine metabolism LC/MS pos 0

3-hydroxybutyrate (BHBA) Lipid Ketone bodies GC/MS 0.07

3-hydroxydecanoate Lipid Fatty acid, monohydroxy LC/MS neg 0.36

4-androsten-3beta,

17beta-diol disulfate 1 Lipid Sterol/Steroid LC/MS neg 0.15

4-androsten-3beta,

17beta-diol disulfate 2 Lipid Sterol/Steroid LC/MS neg 0.58

5alpha-androstan-3beta,

17beta-diol disulfate Lipid Sterol/Steroid LC/MS neg 10.33

5alpha-pregnan-3beta,

20alpha-diol disulfate Lipid Sterol/Steroid LC/MS neg 12.81

5-dodecenoate (12:1n7) Lipid Medium chain fatty acid LC/MS neg 1.16

5-HETE Lipid Fatty acid, monohydroxy LC/MS neg 0.07

7-alpha-hydroxy-3-oxo-4-cholestenoate (7-

Hoca) Lipid Sterol/Steroid LC/MS neg 7.42

7-beta-hydroxycholesterol Lipid Sterol/Steroid GC/MS 4.44

acetylcarnitine Lipid Carnitine metabolism LC/MS pos 1.24

adipate Lipid Fatty acid, dicarboxylate GC/MS 2.98

adrenate (22:4n6) Lipid Long chain fatty acid LC/MS neg 0

andro steroid monosulfate 2 Lipid Sterol/Steroid LC/MS neg 36.83

androsterone sulfate Lipid Sterol/Steroid LC/MS neg 6.11

arachidonate (20:4n6) Lipid Long chain fatty acid LC/MS neg 0

azelate (nonanedioate) Lipid Fatty acid, dicarboxylate LC/MS neg 0

caprate (10:0) Lipid Medium chain fatty acid LC/MS neg 0.07

caproate (6:0) Lipid Medium chain fatty acid LC/MS neg 0

caprylate (8:0) Lipid Medium chain fatty acid LC/MS neg 0

carnitine Lipid Carnitine metabolism LC/MS pos 0

cholate Lipid Bile acid metabolism LC/MS neg 42.5

cholesterol Lipid Sterol/Steroid GC/MS 0

choline Lipid Glycerolipid metabolism LC/MS pos 0

cis-vaccenate (18:1n7) Lipid Long chain fatty acid GC/MS 2.91

cortisol Lipid Sterol/Steroid LC/MS pos 0.29

cortisone Lipid Sterol/Steroid LC/MS pos 1.46

decanoylcarnitine Lipid Carnitine metabolism LC/MS pos 0

dehydroisoandrosterone sulfate

(DHEA-S) Lipid Sterol/Steroid LC/MS neg 0.44

deoxycarnitine Lipid Carnitine metabolism LC/MS pos 0

deoxycholate Lipid Bile acid metabolism LC/MS neg 23.07

dihomo-linoleate (20:2n6) Lipid Long chain fatty acid LC/MS neg 0

dihomo-linolenate (20:3n3 or n6) Lipid Essential fatty acid LC/MS neg 0

docosahexaenoate (DHA; 22:6n3) Lipid Essential fatty acid LC/MS neg 0

docosapentaenoate (n3 DPA; 22:5n3) Lipid Essential fatty acid LC/MS neg 0

docosapentaenoate (n6 DPA; 22:5n6) Lipid Essential fatty acid LC/MS neg 2.98

dodecanedioate Lipid Fatty acid, dicarboxylate LC/MS neg 1.89

eicosapentaenoate (EPA; 20:5n3) Lipid Essential fatty acid LC/MS neg 0

eicosenoate (20:1n9 or 11) Lipid Long chain fatty acid LC/MS neg 0

epiandrosterone sulfate Lipid Sterol/Steroid LC/MS neg 2.98

glycerol Lipid Glycerolipid metabolism GC/MS 0

glycerol 3-phosphate (G3P) Lipid Glycerolipid metabolism GC/MS 0.15

glycerophosphorylcholine (GPC) Lipid Glycerolipid metabolism LC/MS pos 0

glycochenodeoxycholate Lipid Bile acid metabolism LC/MS neg 3.78

glycocholate Lipid Bile acid metabolism LC/MS neg 12.66

glycocholenate sulfate Lipid Bile acid metabolism LC/MS neg 0.15

glycodeoxycholate Lipid Bile acid metabolism LC/MS neg 17.47

glycolithocholate sulfate Lipid Bile acid metabolism LC/MS neg 2.18

heptanoate (7:0) Lipid Medium chain fatty acid LC/MS neg 0

hexadecanedioate Lipid Fatty acid, dicarboxylate LC/MS neg 1.67

hexanoylcarnitine Lipid Carnitine metabolism LC/MS pos 2.69

hyodeoxycholate Lipid Bile acid metabolism LC/MS neg 32.75

inositol 1-phosphate (I1P) Lipid Inositol metabolism GC/MS 19.94

isovalerate Lipid Fatty acid metabolism LC/MS neg 0

laurate (12:0) Lipid Medium chain fatty acid LC/MS neg 0

laurylcarnitine Lipid Carnitine metabolism LC/MS pos 21.83

linoleate (18:2n6) Lipid Long chain fatty acid LC/MS neg 0

linolenate

[alpha or gamma; (18:3n3 or 6)] Lipid Essential fatty acid LC/MS neg 0

margarate (17:0) Lipid Long chain fatty acid LC/MS neg 0.44

methyl palmitate Lipid Fatty acid, methyl ester GC/MS 17.47

myo-inositol Lipid Inositol metabolism GC/MS 0

myristate (14:0) Lipid Long chain fatty acid LC/MS neg 0

myristoleate (14:1n5) Lipid Long chain fatty acid LC/MS neg 0

nonadecanoate (19:0) Lipid Long chain fatty acid LC/MS neg 0.07

octadecanedioate Lipid Fatty acid, dicarboxylate LC/MS neg 3.35

octanoylcarnitine Lipid Carnitine metabolism LC/MS pos 0

oleate (18:1n9) Lipid Long chain fatty acid GC/MS 0

oleoylcarnitine Lipid Carnitine metabolism LC/MS pos 0.29

palmitate (16:0) Lipid Long chain fatty acid LC/MS neg 0

palmitoleate (16:1n7) Lipid Long chain fatty acid LC/MS neg 0

palmitoyl sphingomyelin Lipid Sphingolipid GC/MS 0.36

palmitoylcarnitine Lipid Carnitine metabolism LC/MS pos 8.08

pelargonate (9:0) Lipid Medium chain fatty acid LC/MS neg 0

pregn steroid monosulfate Lipid Sterol/Steroid LC/MS neg 0.15

pregnen-diol disulfate Lipid Sterol/Steroid LC/MS neg 0.07

propionylcarnitine Lipid Fatty acid metabolism (also

BCAA metabolism) LC/MS pos 0.07

scyllo-inositol Lipid Inositol metabolism GC/MS 26.93

sebacate (decanedioate) Lipid Fatty acid, dicarboxylate LC/MS neg 3.86

stearate (18:0) Lipid Long chain fatty acid LC/MS neg 0

stearidonate (18:4n3) Lipid Long chain fatty acid LC/MS neg 1.16

stearoyl sphingomyelin Lipid Sphingolipid GC/MS 6.04

stearoylcarnitine Lipid Carnitine metabolism LC/MS pos 25.91

suberate (octanedioate) Lipid Fatty acid, dicarboxylate LC/MS neg 3.35

taurochenodeoxycholate Lipid Bile acid metabolism LC/MS neg 28.75

taurocholate Lipid Bile acid metabolism LC/MS neg 48.47

taurocholenate sulfate Lipid Bile acid metabolism LC/MS neg 7.13

taurolithocholate 3-sulfate Lipid Bile acid metabolism LC/MS neg 16.01

tetradecanedioate Lipid Fatty acid, dicarboxylate LC/MS neg 19.14

undecanedioate Lipid Fatty acid, dicarboxylate LC/MS neg 3.49

undecanoate (11:0) Lipid Medium chain fatty acid LC/MS neg 0.15

valerate Lipid Short chain fatty acid LC/MS neg 2.33

5-methyluridine (ribothymidine) Nucleotide Pyrimidine metabolism,

uracil containing LC/MS neg 13.03

7-methylguanine Nucleotide Purine metabolism, guanine

containing LC/MS pos 5.75

adenosine Nucleotide Purine metabolism, adenine


allantoin Nucleotide Purine metabolism, urate


guanosine Nucleotide Purine metabolism, guanine


hypoxanthine Nucleotide

Purine metabolism,

(hypo)xanthine/inosine

containing

LC/MS neg 0.73

inosine Nucleotide

Purine metabolism,


containing

LC/MS neg 2.18

N1-methyladenosine Nucleotide Purine metabolism, adenine


pseudouridine Nucleotide Pyrimidine metabolism,

uracil containing LC/MS pos 0

urate Nucleotide Purine metabolism, urate


uridine Nucleotide Pyrimidine metabolism,

uracil containing LC/MS neg 0

xanthine Nucleotide

Purine metabolism,


containing

LC/MS pos 0.07

[H]HWESASLLR[OH] Peptide Polypeptide LC/MS pos 7.42

alanylleucine Peptide Dipeptide LC/MS pos 22.71

alpha-glutamylglutamate Peptide Dipeptide LC/MS pos 41.48

aspartylphenylalanine Peptide Dipeptide LC/MS pos 0

bradykinin, des-arg(9) Peptide Polypeptide LC/MS pos 9.32

DSGEGDFXAEGGGVR Peptide Fibrinogen cleavage peptide LC/MS pos 3.06

gamma-glutamylalanine Peptide gamma-glutamyl LC/MS pos 4.37

gamma-glutamylglutamate Peptide gamma-glutamyl LC/MS pos 1.02

gamma-glutamylisoleucine Peptide gamma-glutamyl LC/MS pos 0

gamma-glutamylleucine Peptide gamma-glutamyl LC/MS pos 0

gamma-glutamylphenylalanine Peptide gamma-glutamyl LC/MS pos 0

gamma-glutamylthreonine Peptide gamma-glutamyl LC/MS pos 0.22

gamma-glutamyltyrosine Peptide gamma-glutamyl LC/MS pos 0.15

gamma-glutamylvaline Peptide gamma-glutamyl LC/MS pos 0

glycylleucine Peptide Dipeptide LC/MS pos 1.16

glycylphenylalanine Peptide Dipeptide LC/MS neg 7.13

glycyltyrosine Peptide Dipeptide LC/MS pos 27.95

glycylvaline Peptide Dipeptide LC/MS pos 0

HWESASXX Peptide Polypeptide LC/MS pos 0

HXGXA Peptide Polypeptide LC/MS pos 1.75

leucylleucine Peptide Dipeptide LC/MS pos 0.07

leucylphenylalanine Peptide Dipeptide LC/MS neg 0.22

pro-hydroxy-pro Peptide Dipeptide LC/MS pos 0.22

pyroglutamylglycine Peptide Dipeptide LC/MS neg 11.06

threonylphenylalanine Peptide Dipeptide LC/MS pos 0.66

1,7-dimethylurate Xenobiotics Xanthine metabolism LC/MS neg 38.72

1-methylurate Xenobiotics Xanthine metabolism LC/MS neg 31.59

2-hydroxyhippurate (salicylurate) Xenobiotics Benzoate metabolism LC/MS neg 35.88

3-ethylphenylsulfate Xenobiotics Benzoate metabolism LC/MS neg 24.53

4-ethylphenylsulfate Xenobiotics Benzoate metabolism LC/MS neg 44.98

4-hydroxyhippurate Xenobiotics Benzoate metabolism LC/MS neg 17.54

4-vinylphenol sulfate Xenobiotics Benzoate metabolism LC/MS neg 4.51

5-acetylamino-6-amino-3-methyluracil Xenobiotics Xanthine metabolism LC/MS neg 39.67

benzoate Xenobiotics Benzoate metabolism GC/MS 0

caffeine Xenobiotics Xanthine metabolism LC/MS pos 11.43

catechol sulfate Xenobiotics Benzoate metabolism LC/MS neg 0

erythritol Xenobiotics Sugar, sugar substitute,

starch GC/MS 0.51

glycerol 2-phosphate Xenobiotics Chemical GC/MS 23.14

hippurate Xenobiotics Benzoate metabolism LC/MS neg 0

paraxanthine Xenobiotics Xanthine metabolism LC/MS pos 9.17

piperine Xenobiotics Food component/Plant LC/MS pos 0.87

salicylate Xenobiotics Drug LC/MS neg 12.88

theobromine Xenobiotics Xanthine metabolism LC/MS pos 11.64

theophylline Xenobiotics Xanthine metabolism LC/MS neg 22.93

thymol sulfate Xenobiotics Food component/Plant LC/MS neg 27.44

table S3. Eighteen significant LoF sites with metabolite associations identified among African-Americans in ARIC.

metabolite gene variant site function p beta SE MAC LoF prediction in

ExAC

cholesterol PCSK9 1:55529215:C:A stopgain 6.78E-07 -0.22 0.04 20 low-confidence

PCSK9 1:55512222:C:G stopgain 0.02 -0.16 0.07 9 high-confidence

PCSK9 1:55524293:TG:T frameshift 0.02 -0.46 0.20 1 high-confidence

deoxycarnitine LRRC69 8:92213022:T:A splicing 4.98E-11 -0.37 0.06 14 high-confidence

LRRC69 8:92212839:A:G splicing 4.46E-07 -0.65 0.13 3 not found in ExAC

hexadecanedioate SLCO1B1 12:21329832:D:T splicing 2.18E-09 0.38 0.06 67 high-confidence

histidine HAL 12:96380932:G:A stopgain 2.31E-13 0.25 0.03 26 high-confidence

mannose TEX15 8:30702839:CTTTCA:C frameshift 7.28E-23 -4.28 0.43 1 high-confidence

TEX15 8:30705099:CTCTA:C frameshift 1.15E-08 -1.44 0.25 3 high-confidence

TEX15 8:30701535:C:A stopgain 0.38 -0.38 0.44 1 high-confidence

TEX15 8:30694729:C:CA frameshift 0.86 0.06 0.31 2 high-confidence

TEX15 8:30700833:TTC:T frameshift 0.96 0.01 0.25 3 high-confidence

methionine sulfoxide C6orf25 6:31692558:C:T stopgain 1.32E-08 -0.48 0.08 9 high-confidence

5-HETE FAM198B 4:159091864:G:A stopgain 2.68E-24 -1.37 0.13 4 high-confidence

FAM198B 4:159091422:T:A stopgain 0.25 -0.10 0.09 10 high-confidence

urate LRRC46 17:45913719:TG:T frameshift 1.04E-23 -1.84 0.18 2 not found in ExAC

LRRC46 17:45911791:GT:G frameshift 0.36 -0.08 0.09 8 high-confidence

decanoylcarnitine

octanoylcarnitine

CD36 7:80300449:T:G stopgain 2.7E-7

3.9E-8

-0.19

-0.20

0.04

0.04

221 high-confidence

Variant indicates chromosome: position: reference allele: alternative allele; SE, standard error; MAC, minor allele counts.

ExAC: Exome Aggregation Consortium (http://exac.broadinstitute.org/, accessed Apr 5th, 2016)

http://exac.broadinstitute.org/

table S4. Relationship between hexadecanedioate and blood pressure levels among European-Americans and African-

Americans in ARIC.

European-Americans

(n = 1,551)

African-Americans

(n = 2,448)

Beta (SE) p-value Beta (SE) p-value

Systolic blood pressure 1.30 (0.43) 0.002 3.38 (0.61) 4E-8

Diastolic blood pressure 0.74 (0.26) 0.004 1.33 (0.36) 2E-4

Systolic and diastolic blood pressure was treated as continuous variables. Linear models were applied adjusting for age, age square, gender and

body mass index (BMI).

fig. S1. Distribution of the number of LoF sites per individual among ARIC African-Americans.

0

20

40

60

80

100

120

140

160

Heterozygotes Homozygotes

fig. S2. QQ plots of the expected and observed –log P values for 10 identified metabolites.

fig. S3. Pathways among genes, metabolites, and diseases identified among ARIC African-Americans. Arrows between genes

and metabolites indicate significant effects of LoF variants (p < 1.310-7). Arrows between metabolites and incident diseases indicate

significant associations after adjusting for age, gender and other risk factors using Cox proportional hazards modeling (p < 4.510-5).

Loss-of-function variants influence the human serum metabolome · 2016-08-29 · This includes:...

Documents

Transcript of Loss-of-function variants influence the human serum metabolome · 2016-08-29 · This includes:...