Circulating metabolite levels reflecting the state of human health and disease can be impacted by genetic effects. The NHLBI Trans-Omics for Precision Medicine (TOPMed) Program has sponsored metabolomic measures in ~100,000 samples across multiple studies to promote discovery of causal molecular pathways and therapeutic targets. We initiated a standard operating procedure (SOP) to harmonize metabolite data across TOPMed studies. In Phase 1, we catalogued 1,730 circulating metabolites from two metabolomics cores (25,058 samples; 53% females) and made them accessible through TOPMed portal.
Metabolite levels are heritable. However, their genetic architectures are not fully understood, including the generalizability of findings from European ancestry dominant studies, and the identification of sex-specific metabolic signatures. Whole genome sequencing (WGS) data were available in 16,359 samples (54% females) who had metabolite data from eight studies, including African, Asian, European, and American ancestries. We performed single variant analyses (minor allele frequency &gt 0.5%) on 1,135 circulating metabolites (missing rate &lt 50%), using sex-pooled and sex-stratified approaches by GMMAT pipeline on BioData Catalyst (BDC).
We discovered 147,160 variant-metabolite pairs of associations (1,429 independent loci across 667 metabolites with P &lt 4.4x10-11). Among the associations mapped to well-known genes, four significant loci (CPS1, ALDH1L1, PSPH, GCSH) play critical roles on glycine metabolism. We also identified potential novel loci that require further investigation, e.g., SLC22A24 was associated with 11-beta-hydroxyetiocholanolone glucuronide levels. We observed sex-specific genetic associations in ~10% metabolites. Sex-stratified analysis identified 2,414 variant-metabolite pairs involving 194 independent loci and 74 metabolites (at a Bonferroni-corrected P = 2.5x10-4). We confirmed that CPS1 has a stronger effect on glycine levels in females than males. We also identified potential novel sex-specific loci with genetic effects in only one sex group, e.g., GSPT1 for N-acetylglycine in females, ABCC1 for Glutarylcarnitine (C5-DC) in males. We also detected potential novel association on chromosome X, i.e., ARSD for ascorbic acid 3-sulfate in females. The analytical pipeline is accessible through BDC, while sex-pooled and sex-stratified summary statistics are accessible through dbGaP Exchange Area.
In summary, we created a catalog for TOPMed metabolomics data and identified potential novel sex-pooled and sex-specific genetic associations contributing to our understanding of human circulating metabolites.