The power of TOPMed imputation for the discovery of Latino-enriched rare variants associated with type 2 diabetes
Por:
Huerta-Chagoya A., Schroeder P., Mandla R., Deutsch A.J., Zhu W., Petty L., Yi X., Cole J.B., Udler M.S., Dornbos P., Porneala B., DiCorpo D., Liu C.-T., Li J.H., Szczerbinski L., Kaur V., Kim J., Lu Y., Martin A., Eizirik D.L., Marchetti P., Marselli L., Chen L., Srinivasan S., Todd J., Flannick J., Gubitosi-Klug R., Levitsky L., Shah R., Kelsey M., Burke B., Dabelea D.M., Divers J., Marcovina S., Stalbow L., Loos R.J.F., Darst B.F., Kooperberg C., Raffield L.M., Haiman C., Sun Q., McCormick J.B., Fisher-Hoch S.P., Ordoñez M.L., Meigs J., Baier L.J., González-Villalpando C., González-Villalpando M.E., Orozco L., García-García L., Moreno-Estrada A., Aguilar-Salinas C.A., Tusié T., Dupuis J., Ng M.C.Y., Manning A., Highland H.M., Cnop M., Hanson R., Below J., Florez J.C., Leong A., Mercader J.M., Mexican Biobank
Publicada:
1 ene 2023
Ahead of Print:
1 may 2023
Resumen:
Aims/hypothesis: The Latino population has been systematically underrepresented in large-scale genetic analyses, and previous studies have relied on the imputation of ungenotyped variants based on the 1000 Genomes (1000G) imputation panel, which results in suboptimal capture of low-frequency or Latino-enriched variants. The National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) released the largest multi-ancestry genotype reference panel representing a unique opportunity to analyse rare genetic variations in the Latino population. We hypothesise that a more comprehensive analysis of low/rare variation using the TOPMed panel would improve our knowledge of the genetics of type 2 diabetes in the Latino population. Methods: We evaluated the TOPMed imputation performance using genotyping array and whole-exome sequence data in six Latino cohorts. To evaluate the ability of TOPMed imputation to increase the number of identified loci, we performed a Latino type 2 diabetes genome-wide association study (GWAS) meta-analysis in 8150 individuals with type 2 diabetes and 10,735 control individuals and replicated the results in six additional cohorts including whole-genome sequence data from the All of Us cohort. Results: Compared with imputation with 1000G, the TOPMed panel improved the identification of rare and low-frequency variants. We identified 26 genome-wide significant signals including a novel variant (minor allele frequency 1.7%; OR 1.37, p=3.4 × 10-9). A Latino-tailored polygenic score constructed from our data and GWAS data from East Asian and European populations improved the prediction accuracy in a Latino target dataset, explaining up to 7.6% of the type 2 diabetes risk variance. Conclusions/interpretation: Our results demonstrate the utility of TOPMed imputation for identifying low-frequency variants in understudied populations, leading to the discovery of novel disease associations and the improvement of polygenic scores. Data availability: Full summary statistics are available through the Common Metabolic Diseases Knowledge Portal (https://t2d.hugeamp.org/downloads.html) and through the GWAS catalog (https://www.ebi.ac.uk/gwas/ , accession ID: GCST90255648). Polygenic score (PS) weights for each ancestry are available via the PGS catalog (https://www.pgscatalog.org , publication ID: PGP000445, scores IDs: PGS003443, PGS003444 and PGS003445). Graphical abstract: [Figure not available: see fulltext.] © 2023, The Author(s).
Filiaciones:
Huerta-Chagoya A.:
Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, United States
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
Unidad de Biología Molecular y Medicina Genómica, Instituto Nacional de Ciencias Médicas y Nutrición, Mexico City, Mexico
Schroeder P.:
Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, United States
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
Diabetes Unit, Massachusetts General Hospital, Boston, MA, United States
Mandla R.:
Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, United States
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
Diabetes Unit, Massachusetts General Hospital, Boston, MA, United States
Deutsch A.J.:
Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, United States
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
Diabetes Unit, Massachusetts General Hospital, Boston, MA, United States
Department of Medicine, Massachusetts General Hospital, Boston, MA, United States
Zhu W.:
Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, United States
Petty L.:
Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, United States
Yi X.:
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
Cole J.B.:
Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, United States
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
Department of Medicine, Harvard Medical School, Boston, MA, United States
Division of Endocrinology, Boston Children’s Hospital, Boston, MA, United States
Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO, United States
Udler M.S.:
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
Dornbos P.:
Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, United States
Porneala B.:
Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, United States
DiCorpo D.:
Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States
Liu C.-T.:
Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States
Li J.H.:
Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, United States
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
Diabetes Unit, Massachusetts General Hospital, Boston, MA, United States
Department of Medicine, Massachusetts General Hospital, Boston, MA, United States
Szczerbinski L.:
Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, United States
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
Diabetes Unit, Massachusetts General Hospital, Boston, MA, United States
Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland
Kaur V.:
Diabetes Unit, Massachusetts General Hospital, Boston, MA, United States
Kim J.:
Vanderbilt Genetics Institute, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
Lu Y.:
Vanderbilt Genetics Institute, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
Martin A.:
Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, United States
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, United States
Eizirik D.L.:
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
WELBIO, Université Libre de Bruxelles, Brussels, Belgium
Marchetti P.:
Department of Clinical and Experimental Medicine, and AOUP Cisanello University Hospital, University of Pisa, Pisa, Italy
Marselli L.:
Department of Clinical and Experimental Medicine, and AOUP Cisanello University Hospital, University of Pisa, Pisa, Italy
Chen L.:
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
Srinivasan S.:
Department of Pediatrics, University of California San Francisco, San Francisco, CA, United States
Todd J.:
Department of Pediatrics, University of Vermont, Burlington, VT, United States
Flannick J.:
Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, United States
Department of Pediatrics, Boston Children’s Hospital, Boston, MA, United States
Gubitosi-Klug R.:
Pediatric Endocrinology, Diabetes, and Metabolism, Case Western Reserve University and Rainbow Babies and Children’s Hospital, Cleveland, OH, United States
Levitsky L.:
Department of Pediatrics, Division of Pediatric Endocrinology and Pediatric Diabetes Center, Massachusetts General Hospital, Boston, MA, United States
Shah R.:
Pediatric Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
Kelsey M.:
Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, CO, United States
Burke B.:
Biostatistics Center, The George Washington University, Rockville, MD, United States
Dabelea D.M.:
Department of Epidemiology, University of Colorado School of Medicine, Aurora, CO, United States
Divers J.:
NYU Langone Health, New York, NY, United States
Marcovina S.:
Medpace Reference Laboratories, Cincinnati, OH, United States
Stalbow L.:
The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
Loos R.J.F.:
The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark
Darst B.F.:
Division of Public Health Science, Fred Hutchinson Cancer Center, Seattle, WA, United States
Kooperberg C.:
Division of Public Health Science, Fred Hutchinson Cancer Center, Seattle, WA, United States
Raffield L.M.:
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
Haiman C.:
Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, United States
Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States
Sun Q.:
Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
McCormick J.B.:
School of Public Health, The University of Texas Health Science Center at Houston, Brownsville, TX, United States
Fisher-Hoch S.P.:
School of Public Health, The University of Texas Health Science Center at Houston, Brownsville, TX, United States
Ordoñez M.L.:
Unidad de Biología Molecular y Medicina Genómica, Instituto Nacional de Ciencias Médicas y Nutrición, Mexico City, Mexico
Meigs J.:
Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, United States
Department of Medicine, Massachusetts General Hospital, Boston, MA, United States
Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, United States
Baier L.J.:
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, United States
González-Villalpando C.:
Centro de Estudios en Diabetes, Unidad de Investigacion en Diabetes y Riesgo Cardiovascular, Centro de Investigacion en Salud Poblacional, Instituto Nacional de Salud Pública, Mexico City, Mexico
González-Villalpando M.E.:
Centro de Estudios en Diabetes, Unidad de Investigacion en Diabetes y Riesgo Cardiovascular, Centro de Investigacion en Salud Poblacional, Instituto Nacional de Salud Pública, Mexico City, Mexico
Orozco L.:
Laboratorio Inmunogénomica y Enfermedades Metabólicas, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
García-García L.:
Instituto Nacional de Salud Pública, Cuernavaca, Mexico
Moreno-Estrada A.:
Laboratorio Nacional de Genómica para la Biodiversidad (LANGEBIO), Unidad de Genómica Avanzada (UGA), CINVESTAV, Irapuato, Mexico
Aguilar-Salinas C.A.:
Unidad de Investigación de Enfermedades Metabólicas y Dirección de Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
Tusié T.:
Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
Unidad de Biología Molecular y Medicina Genómica, Instituto Nacional de Ciencias Médicas y Nutrición, Mexico City, Mexico
Dupuis J.:
Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States
Ng M.C.Y.:
Vanderbilt Genetics Institute, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
Manning A.:
Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, United States
Highland H.M.:
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
Cnop M.:
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium
Hanson R.:
Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, United States
Below J.:
Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, United States
Florez J.C.:
Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, United States
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
Diabetes Unit, Massachusetts General Hospital, Boston, MA, United States
Department of Medicine, Massachusetts General Hospital, Boston, MA, United States
Department of Medicine, Harvard Medical School, Boston, MA, United States
Endocrine Division, Massachusetts General Hospital, Boston, MA, United States
Leong A.:
Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, United States
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
Diabetes Unit, Massachusetts General Hospital, Boston, MA, United States
Department of Medicine, Massachusetts General Hospital, Boston, MA, United States
Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, United States
Endocrine Division, Massachusetts General Hospital, Boston, MA, United States
Mercader J.M.:
Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, United States
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
Diabetes Unit, Massachusetts General Hospital, Boston, MA, United States
Department of Medicine, Harvard Medical School, Boston, MA, United States
Green Submitted, Green Published, hybrid
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