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We aimed to reveal early metabolic features characterizing liability to adult disease by examining genetic liability to adult type 2 diabetes in relation to metabolomic traits across early life.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                    <jats:p>Up to 4,761 offspring from the Avon Longitudinal Study of Parents and Children were studied. Linear models were used to examine effects of a genetic risk score (162 variants) for adult type 2 diabetes on 229 metabolomic traits (lipoprotein subclass\u2013specific cholesterol and triglycerides, amino acids, glycoprotein acetyls, and others) measured at age 8 years, 16 years, 18 years, and 25 years. Two-sample Mendelian randomization (MR) was also conducted using genome-wide association study data on metabolomic traits in an independent sample of 24,925 adults.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>At age 8 years, associations were most evident for type 2 diabetes liability (per SD higher) with lower lipids in HDL subtypes (e.g., \u22120.03 SD [95% CI \u22120.06, \u22120.003] for total lipids in very large HDL). At 16 years, associations were stronger with preglycemic traits, including citrate and with glycoprotein acetyls (0.05 SD; 95% CI 0.01, 0.08), and at 18 years, associations were stronger with branched-chain amino acids. At 25 years, associations had strengthened with VLDL lipids and remained consistent with previously altered traits, including HDL lipids. Two-sample MR estimates among adults indicated persistent patterns of effect of disease liability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>Our results support perturbed HDL lipid metabolism as one of the earliest features of type 2 diabetes liability, alongside higher branched-chain amino acid and inflammatory levels. Several features are apparent in childhood as early as age 8 years, decades before the clinical onset of disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/dc19-2348","type":"journal-article","created":{"date-parts":[[2020,4,28]],"date-time":"2020-04-28T23:15:31Z","timestamp":1588115731000},"page":"1537-1545","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":35,"title":["Early Metabolic Features of Genetic Liability to Type 2 Diabetes: Cohort Study With Repeated Metabolomics Across Early Life"],"prefix":"10.2337","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6892-8786","authenticated-orcid":false,"given":"Joshua A.","family":"Bell","sequence":"first","affiliation":[{"name":"Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, U.K."},{"name":"Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, 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