{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:22:28Z","timestamp":1787026948607,"version":"build-2736575974"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,1,15]],"date-time":"2024-01-15T00:00:00Z","timestamp":1705276800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Nutr."],"abstract":"<jats:p>\n                    Dysregulation of fatty acid metabolites can play a crucial role in the progression of complex diseases, such as cardiovascular disease, digestive diseases, and metabolic diseases. Metabolites can have either protective or risk effects on a disease; however, the details of such associations remain contentious. In this study, we demonstrate an integrative PheWAS approach to establish high confidence, causally suggestive of metabolite\u2013disease associations for three fatty acid metabolites, namely, omega-3 fatty acids, omega-6 fatty acids, and docosahexaenoic acid, for 1,254 disease endpoints. Metabolite\u2013disease associations were established if there was a concordant direction of effect and significance for metabolite level and genetic risk score for the metabolite. There was enrichment for metabolite associations with diseases of the respiratory system for omega-3 fatty acids, diseases of the circulatory system and endocrine system for omega-6 fatty acids, and diseases of the digestive system for docosahexaenoic acid. Upon performing Mendelian randomization on a subset of the outcomes, we identified 3, 6, and 15 significant diseases associated with omega-3 fatty acids, omega-6 fatty acids, and docosahexaenoic acid, respectively. We then demonstrate a class of prevalence-risk relationships indicative of (de)canalization of disease under high and low fatty acid metabolite levels. Finally, we show that the interaction between the metabolites and obesity demonstrates that the degree of protection afforded by fatty acid metabolites is strongly modulated by underlying metabolic health. This study evaluated the disease architectures of three polyunsaturated fatty acids (PUFAs), which were validated by several PheWAS modes of support. Our results not only highlight specific diseases associated with each metabolite but also disease group enrichments. In addition, we demonstrate an integrative PheWAS methodology that can be applied to other components of the human metabolome or other traits of interest. The results of this study can be used as an atlas to cross-compare genetic with non-genetic disease associations for the three PUFAs investigated. The findings can be explored through our R shiny app at\n                    <jats:ext-link>https:\/\/pufa.biosci.gatech.edu<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.3389\/fnut.2023.1308622","type":"journal-article","created":{"date-parts":[[2024,1,14]],"date-time":"2024-01-14T23:37:01Z","timestamp":1705275421000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Integrative polygenic analysis of the protective effects of fatty acid metabolism on disease as modified by obesity"],"prefix":"10.3389","volume":"10","author":[{"given":"Courtney","family":"Astore","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greg","family":"Gibson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,1,15]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"658997","DOI":"10.3389\/fphys.2021.658997","article-title":"Metabolic homeostasis in life as we know it: its origin and thermodynamic basis","volume":"12","author":"Wilson","year":"2021","journal-title":"Front Physiol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1007\/s00204-010-0609-6","article-title":"The role of metabolites and metabolomics in clinically applicable biomarkers of disease","volume":"85","author":"Mamas","year":"2011","journal-title":"Arch Toxicol"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"4788","DOI":"10.1038\/s41467-019-12703-7","article-title":"A comprehensive study of metabolite genetics reveals strong pleiotropy and heterogeneity across time and context","volume":"10","author":"Gallois","year":"2019","journal-title":"Nat Commun"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1080\/07315724.2002.10719248","article-title":"Omega-3 fatty acids in inflammation and autoimmune diseases","volume":"21","author":"Simopoulos","year":"2002","journal-title":"J Am Coll Nutr"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1134","DOI":"10.1093\/advances\/nmaa055","article-title":"Consumption of fish and \u03c9-3 fatty acids and cancer risk: an umbrella review of meta-analyses of observational studies","volume":"11","author":"Lee","year":"2020","journal-title":"Adv Nutr"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"204","DOI":"10.3390\/nu13010204","article-title":"An update on omega-3 polyunsaturated fatty acids and cardiovascular health","volume":"13","author":"Elagizi","year":"2021","journal-title":"Nutrients"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1051\/rnd:2005001","article-title":"Omega-3 fatty acids and neuropsychiatric disorders","volume":"45","author":"Young","year":"2005","journal-title":"Reprod Nutr Dev"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1001\/jamacardio.2017.5205","article-title":"Omega-3 treatment Trialists\u2019 collaboration. 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