title: Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes.
abstract: Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)<P<5 × 10(-8), odds ratio (OR)  = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America; Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
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authors.affiliation: The GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
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authors.forename: James G
authors.initials: JG
authors.lastname: Wilson
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America.
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authors.initials: JI
authors.lastname: Rotter
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America; Department of Medicine, University of Virginia, Charlottesville, Virginia, United States of America; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Michèle M
authors.initials: MM
authors.lastname: Sale
authors.affiliation: Program on Genomics and Nutrition, School of Public Health, University of California Los Angeles, Los Angeles, California, United States of America; Department of Epidemiology, University of California Los Angeles, Los Angeles, California, United States of America; Departments of Epidemiology and Medicine, Brown University, Providence, Rhode Island, United States of America.
authors.forename: Simin
authors.initials: S
authors.lastname: Liu
authors.affiliation: Center for Research on Genomics and Global Health, National Human Genome Research Institute, Bethesda, Maryland, United States of America.
authors.forename: Charles N
authors.initials: CN
authors.lastname: Rotimi
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America; Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America; Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
mesh_terms: D001741:Black or African American / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000473:pathology; D055106:Genome-Wide Association Study; D015796:HLA-B27 Antigen / Q000235:genetics*; D025743:HMGA2 Protein / Q000235:genetics*; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D050506:Mutant Chimeric Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics*
chemical_list: C090660:HLA-B protein, human; D015796:HLA-B27 Antigen; D025743:HMGA2 Protein; C584675:INS-IGF2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D050506:Mutant Chimeric Proteins; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein
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