Loss-of-function variants influence the human serum metabolome.
The metabolome is a collection of small molecules resulting from multiple cellular and biological processes that can act as biomarkers of disease, and African-Americans exhibit high levels of genetic diversity. Exome sequencing of a sample of deeply phenotyped African-Americans allowed us to analyze the effects of annotated loss-of-function (LoF) mutations on 308 serum metabolites measured by untargeted liquid and gas chromatography coupled with mass spectrometry. In an independent sample, we identified and replicated four genes harboring six LoF mutations that significantly affected five metabolites. These sites were related to a 19 to 45% difference in geometric mean metabolite levels, with an average effect size of 25%. We show that some of the affected metabolites are risk predictors or diagnostic biomarkers of disease and, using the principle of Mendelian randomization, are in the causal pathway of disease. For example, LoF mutations in SLCO1B1 elevate the levels of hexadecanedioate, a fatty acid significantly associated with increased blood pressure levels and risk of incident heart failure in both African-Americans and an independent sample of European-Americans. We show that SLCO1B1 LoF mutations significantly increase the risk of incident heart failure, thus implicating the metabolite in the causal pathway of disease. These results reveal new avenues into gene function and the understanding of disease etiology by integrating -omic technologies into a deeply phenotyped population study.
Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Bing
B
Yu
Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Alexander H
0000-0003-0057-7515
AH
Li
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Ginger A
0000-0002-8316-0071
GA
Metcalf
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Donna M
DM
Muzny
Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Alanna C
AC
Morrison
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Simon
S
White
Department of Medicine (Geriatrics), University of Mississippi Medical Center, Jackson, MS 39216, USA.
Thomas H
TH
Mosley
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Richard A
RA
Gibbs
Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Eric
E
Boerwinkle
D001741:Black or African American / Q000235:genetics; D000368:Aged; D015415:Biomarkers / Q000097:blood*; D059472:Exome / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006333:Heart Failure / Q000097:blood / Q000235:genetics* / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000235:genetics* / Q000473:pathology; D027381:Liver-Specific Organic Anion Transporter 1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D055442:Metabolome / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D012307:Risk Factors; D044465:White People / Q000235:genetics
D015415:Biomarkers; D027381:Liver-Specific Organic Anion Transporter 1; C503999:SLCO1B1 protein, human
Metabolomics; loss-of-function; metabolite; rare genetic variant