title: Polygenic type 2 diabetes prediction at the limit of common variant detection.
abstract: Genome-wide association studies (GWAS) may have reached their limit of detecting common type 2 diabetes (T2D)-associated genetic variation. We evaluated the performance of current polygenic T2D prediction. Using data from the Framingham Offspring (FOS) and the Coronary Artery Risk Development in Young Adults (CARDIA) studies, we tested three hypotheses: 1) a 62-locus genotype risk score (GRSt) improves T2D prediction compared with previous less inclusive GRSt; 2) separate GRS for β-cell (GRSβ) and insulin resistance (GRSIR) independently predict T2D; and 3) the relationships between T2D and GRSt, GRSβ, or GRSIR do not differ between blacks and whites. Among 1,650 young white adults in CARDIA, 820 young black adults in CARDIA, and 3,471 white middle-aged adults in FOS, cumulative T2D incidence was 5.9%, 14.4%, and 12.9%, respectively, over 25 years. The 62-locus GRSt was significantly associated with incident T2D in all three groups. In FOS but not CARDIA, the 62-locus GRSt improved the model C statistic (0.698 and 0.726 for models without and with GRSt, respectively; P < 0.001) but did not materially improve risk reclassification in either study. Results were similar among blacks compared with whites. The GRSβ but not GRSIR predicted incident T2D among FOS and CARDIA whites. At the end of the era of common variant discovery for T2D, polygenic scores can predict T2D in whites and blacks but do not outperform clinical models. Further optimization of polygenic prediction may require novel analytic methods, including less common as well as functional variants.
authors: Harvard Medical School, Boston, MASection of General Internal Medicine, VA Boston Healthcare System, Boston, MADivision of General Internal Medicine and Primary Care, Brigham and Women's Hospital, Boston, MA.
authors: Jason L
authors: JL
authors: Vassy
authors: Harvard Medical School, Boston, MADepartment of Population Medicine, Harvard Pilgrim Health Care Institute, Boston, MADivision of Endocrinology, Department of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors: Marie-France
authors: MF
authors: Hivert
authors: General Medicine Division, Massachusetts General Hospital, Boston, MA.
authors: Bianca
authors: B
authors: Porneala
authors: Harvard Medical School, Boston, MAGeneral Medicine Division, Massachusetts General Hospital, Boston, MADivision of Endocrinology and Metabolic Diseases, Department of Medicine, University of Verona Medical School and Hospital Trust of Verona, Verona, Italy.
authors: Marco
authors: M
authors: Dauriz
authors: Harvard Medical School, Boston, MADiabetes Research Center (Diabetes Unit), and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MAProgram in Medical and Population Genetics, Broad Institute, Cambridge, MA.
authors: Jose C
authors: JC
authors: Florez
authors: Department of Biostatistics, Boston University School of Public Health, Boston, MANational Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA.
authors: Josée
authors: J
authors: Dupuis
authors: Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA.
authors: David S
authors: DS
authors: Siscovick
authors: Center for Human Genetics, University of Texas Health Science Center at Houston, Houston, TX.
authors: Myriam
authors: M
authors: Fornage
authors: Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.
authors: Laura J
authors: LJ
authors: Rasmussen-Torvik
authors: Human Genomics Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA.
authors: Claude
authors: C
authors: Bouchard
authors: Harvard Medical School, Boston, MAGeneral Medicine Division, Massachusetts General Hospital, Boston, MA jmeigs@partners.org.
authors: James B
authors: JB
authors: Meigs
mesh_terms: D000293:Adolescent; D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D002648:Child; D002675:Child, Preschool; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D004781:Environmental Exposure; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D057185:Sedentary Behavior; D044465:White People / Q000235:genetics*