{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T06:29:59Z","timestamp":1770100199760,"version":"3.49.0"},"posted":{"date-parts":[[2026,1,30]]},"group-title":"Genetic and Genomic Medicine","reference-count":66,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T00:00:00Z","timestamp":1769731200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Metabolite genome-wide association studies have identified hundreds of variants, many of which play intermediate roles linking genotype and phenotype with downstream diseases. However, the majority of metabolite GWAS have been published in self-identified Non-Hispanic White (NHW) populations, greatly limiting inference to other populations. Here we report the results of a GWAS of 7,522 untargeted metabolite peaks in 2,183 participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study (714 Black and 1,469 White individuals, mean age = 43.56, women = 56.1%). We performed untargeted metabolomic profiling on plasma samples from these individuals using ultra-high performance liquid chromatography-high resolution mass spectrometry. Using race\/ethnicity-stratified and combined GWAS of 8,534,915 (Black stratum) and 5,886,255 (White stratum) common variants (minor allele frequency \u2265 0.05) from TOPMed Imputation Reference Panel r\n                  <jats:sup>2<\/jats:sup>\n                  , we examined association with the CARDIA 7,522 metabolite peaks. We used MetaboAnalyst 5.0 and publicly available phenome-wide association studies to predict functional pathway activity and characterize unknown peaks. We identified 171 significant (\n                  <jats:italic>P<\/jats:italic>\n                  -value &lt; 6.6\u00d710\n                  <jats:sup>-13<\/jats:sup>\n                  ) sentinel variants across 536 metabolite peaks, of which 39 were annotated with our in-house library in the race-combined CARDIA analysis. PheWAS and pathway enrichment models provided information on unannotated metabolite peaks including the novel\n                  <jats:italic>KHNYN\/SDR39U1<\/jats:italic>\n                  locus which supports vitamin B5\u2019s involvement in the citric acid cycle. We also identified a race-specific variant (rs79530723) near\n                  <jats:italic>SLC28A1<\/jats:italic>\n                  , which plays an important role in cytidine metabolism and was specific to the CARDIA Black participants. Pathway analyses prioritized a role of pyrimidine metabolism for this peak, a finding supported by studies in the Hispanic\/Latino populations. Overall, our study results support a strong shared genetic architecture of the human metabolome across diverse populations and reveal new metabolite GWAS signals, underscoring the value of integrating \u2018omics\u2019 techniques to enhance comprehension of its genetic architecture.\n                <\/jats:p>","DOI":"10.64898\/2026.01.28.26344965","type":"posted-content","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T22:50:13Z","timestamp":1769813413000},"source":"Crossref","is-referenced-by-count":0,"title":["Integration of metabolomic and genetic data reveals novel variants underpinning the human metabolome: the Coronary Artery Risk Development in Young Adults (CARDIA) study"],"prefix":"10.64898","author":[{"given":"Mohanraj","family":"Krishnan","sequence":"first","affiliation":[{"name":"Department of Epidemiology, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, NC, USA"},{"name":"Department of Biobehavioral Health, Health and Human Development, Pennsylvania State University, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Blake R.","family":"Rushing","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"name":"Nutrition Research Institute, The University of North Carolina at Chapel Hill, Kannapolis, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annie Green","family":"Howard","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Carolina Population Center, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather M.","family":"Highland","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoria L.","family":"Buchanan","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samson","family":"Okello","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yao","family":"Tu","sequence":"additional","affiliation":[{"name":"Department of Biobehavioral Health, Health and Human Development, Pennsylvania State University, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuwei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiuxia","family":"Du","sequence":"additional","affiliation":[{"name":"College of Computing and Informatics, University of North Carolina at Charlotte, Kannapolis, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan L.","family":"McRitchie","sequence":"additional","affiliation":[{"name":"Nutrition Research Institute, The University of North Carolina at Chapel Hill, Kannapolis, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Myriam","family":"Fornage","sequence":"additional","affiliation":[{"name":"Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, USA"},{"name":"Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cora E","family":"Lewis","sequence":"additional","affiliation":[{"name":"Division of Preventative Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jared P","family":"Reis","sequence":"additional","affiliation":[{"name":"National Heart, Lung, and Blood Institute, Bethesda, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan J.","family":"Sumner","sequence":"additional","affiliation":[{"name":"Department of Nutrition, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"name":"Nutrition Research Institute, The University of North Carolina at Chapel Hill, Kannapolis, NC, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christy 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