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Here we performed the largest genome-wide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose\u2013raising alleles were associated with a measure of first-phase insulin secretion at P &amp;lt; 0.05 and provided new evidence, or the strongest evidence yet, that insulin secretion, intrinsic to the islet cells, is a key mechanism underlying the associations at the HNF1A, IGF2BP2, KCNQ1, HNF1B, VPS13C\/C2CD4A, FAF1, PTPRD, AP3S2, KCNK16, MAEA, LPP, WFS1, and TMPRSS6 loci. The fasting glucose\u2013raising allele near PDX1, a known key insulin transcription factor, was strongly associated with lower first-phase insulin secretion but has no evidence for an effect on type 2 diabetes risk. The diabetes risk allele at TCF7L2 was associated with a stronger effect on peak insulin response than on C-peptide\u2013based insulin secretion rate, suggesting a possible additional role in hepatic insulin clearance or insulin processing. In summary, our study provides further insight into the mechanisms by which common genetic variation influences type 2 diabetes risk and glycemic traits.<\/jats:p>","DOI":"10.2337\/db16-1452","type":"journal-article","created":{"date-parts":[[2017,5,11]],"date-time":"2017-05-11T12:40:49Z","timestamp":1494506449000},"page":"2296-2309","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":113,"title":["A Genome-Wide Association Study of IVGTT-Based Measures of First-Phase Insulin Secretion Refines the Underlying Physiology of Type 2 Diabetes Variants"],"prefix":"10.2337","volume":"66","author":[{"given":"Andrew R.","family":"Wood","sequence":"first","affiliation":[{"name":"Genetics of Complex Traits, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, U.K."}]},{"given":"Anna","family":"Jonsson","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"}]},{"given":"Anne U.","family":"Jackson","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI"}]},{"given":"Nan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA"},{"name":"Diabetes & Obesity Research Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA"}]},{"given":"Nienke","family":"van Leewen","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands"}]},{"given":"Nicholette D.","family":"Palmer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Wake Forest 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