The power of TOPMed imputation for the discovery of Latino-enriched rare variants associated with type 2 diabetes
Year: 2023
Type: article
Study design: Observational Study
Abstract: 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: ). 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).
Source: Diabetologia
Authors: Alicia Huerta-Chagoya, Philip Schroeder, Ravi Mandla, Aaron J. Deutsch, Wanying Zhu, Lauren Petty, Xiaoyan Yi, Joanne B. Cole, Miriam S. Udler, Peter Dornbos, Bianca Porneala, Daniel DiCorpo, Ching-Ti Liu, Josephine H. Li, Lukasz Szczerbiński, Varinderpal Kaur, Joohyun Kim, Yingchang Lu, Alicia Martin, Decio L. Eizirik, Piero Marchetti, Lorella Marselli, Ling Chen, Shylaja Srinivasan, Jennifer Todd, Jason Flannick, Rose Gubitosi-Klug, Lynne Levitsky, Rachana Shah, Megan Kelsey, Brian Burke, Dana M. Dabelea, Jasmin Divers, Santica Marcovina, Lauren Stalbow, Ruth J. F. Loos, Burcu F. Darst, Charles Kooperberg, Laura M. Raffield, Christopher Haiman, Quan Sun, Joseph B. McCormick, Susan P. Fisher-Hoch, Maria L. Ordoñez, James Meigs, Leslie J. Baier, Clicerio González-Villalpando, Maria Elena González-Villalpando, Lorena Orozco, Lourdes García-García, Andrés Moreno-Estrada, Mexican Biobank, Carlos A. Aguilar-Salinas, Teresa Tusié, Josée Dupuis, Maggie C. Y. Ng, Alisa Manning, Heather M. Highland, Miriam Cnop, Robert Hanson, Jennifer Below, Jose C. Florez, Aaron Leong, Josep M. Mercader
Institutions: Broad Institute, Harvard University, Massachusetts General Hospital, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Universidad Nacional Autónoma de México, Vanderbilt University Medical Center, Université Libre de Bruxelles, Boston Children's Hospital, University of Colorado Anschutz, Boston University, Medical University of Białystok, Vanderbilt University, Walloon Excellence in Lifesciences and Biotechnology, University of Pisa, Ospedale Cisanello, University of California, San Francisco, University of Vermont, Rainbow Babies & Children's Hospital, Case Western Reserve University, Children's Hospital of Philadelphia, University of Colorado Denver, George Washington University, NYU Langone Health, Medpace (United States), Icahn School of Medicine at Mount Sinai, University of Copenhagen, Novo Nordisk Foundation Center for Basic Metabolic Research, Fred Hutch Cancer Center, University of North Carolina at Chapel Hill, University of Southern California, USC Norris Comprehensive Cancer Center, The University of Texas Health Science Center at Houston, National Institute of Diabetes and Digestive and Kidney Diseases, Instituto Nacional de Salud Pública, National Institute of Genomic Medicine, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Erasmus Hospital
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,990
Funders: U.S. Department of Health and Human Services, American Diabetes Association, Office of Dietary Supplements, Doris Duke Charitable Foundation, Ellison Medical Foundation, Robert Wood Johnson Foundation, Wayne and Gladys Valley Foundation, Andrea and Charles Bronfman Philanthropies, Kaiser Permanente, University of Miami, Leona M. and Harry B. Helmsley Charitable Trust, Northwestern University, San Diego State University, Icahn School of Medicine at Mount Sinai, Newton Fund, European Federation of Pharmaceutical Industries and Associations, Waalse Gewest, European Commission, Fonds De La Recherche Scientifique - FNRS, Fonds Wetenschappelijk Onderzoek, Consejo Nacional de Ciencia y Tecnología, Ministerio de Economía y Competitividad, China Scholarship Council, Fondo de Cooperación Internacional en Ciencia y Tecnología, Instituto Carlos Slim de la Salud, Innovative Medicines Initiative, Fundación Gonzalo Río Arronte, Walloon excellence in life sciences and biotechnology, National Institutes of Health, University of California, San Francisco, Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México, National Institute on Aging, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Cancer Institute, National Institute on Deafness and Other Communication Disorders, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Minority Health and Health Disparities
Awards: G1004541261, G1042216835, G1057152193, G1081972346, G1165142596, G1301356587, G1312369436, G1367698656, G1455175283, G153510172, G1548097448, G1587824183, G1751341341, G1784978456, Healthy Americas: All of Us Research Program, G1917633662, G1947136479, G1969433312, G2008135766, G2059762424, G2135211244, G2135293100, G2140338431, G2175624253, G2187930703, G2278520250, G2297961971, G2399315060, G243962516, GENOMIC, PHYSIOLOGICAL AND PHARMACOLOGICAL CHARACTERIZATION OF GENETIC VARIATION ASSOCIATED WITH TYPE 2 DIABETES IN LATIN AMERICANS, G2466919156, G247402385, G2501967490, G2548880556, G2575730562, G2576267651, G2636451769, G2644289446, G2739657492, G2782006793, G287178428, G2929134159, G2973842679, Translational approaches to disease modifying therapy of type 1 diabetes - HARVESTing the fruits of INNODIA, G3062787641, G3174308905, G3230220297, G3255761503, Development of a systems biomedicine approach for risk identification, prevention and treatment of type 2 diabetes, G3276551827, G331103514, G3429522092, G3488149570, Bridging the gap between type 2 diabetes GWAS and therapeutic targets, G3545534745, G362301402, G3639549833, G3677686024, G3706143287, Polygenic Risk Scores for Diverse Populations - Bridging Research and Clinical Care, G3786555737, G3796112702, G3838006641, Harnessing the power of genetic relatedness for disease gene discovery, G3952816605, G4021838900, G4050667541, G4121762840, PAGE III: Population Architecture using Genomics and Epidemiology, Diverse ancestry biobank to map biomedical traits and elucidate health disparitie, G4240450635, G4240498284, G4312823968, G433713863, G434337789, G4430667546, G4450071017, G4552920371, G4614542344, Genome-wide association study of coronary artery diseases in individuals of African ancestry, G4860668542, G4919155732, G4940192625, G4989378220, G5130508838, G5243773420, G528357465, G543802643, University of Arizona-Banner Health All of Us Research Program , G5547620395, G555858244, G560916241, G5622894757, G5624510383, G5654258805, G5739677117, G5878028785, G589878898, G5906656038, G5929339958, G6072109818, G608039257, G614814196, G6156511736, G619791618, G642675487, Translational approaches to disease modifying therapy of type 1 diabetes: an innovative approach towards understanding and arresting type 1 diabetes – Sofia ref.: 115797, G6585687856, G6633336419, G6710151292, G6744188800, G6757907, G6817911067, G693077865, G6967911674, G6992538300, G7057037114, G7160167013, G7203655167, G7239480477, G7272721675, G7278742613, G7373349122, SouthEast Enrollment Center (SEEC) , G7408420985, G7513901258, G7520410954, G7678550560, G7696965656, Molecular Epidemiology of Nutrition and Cancer in the Multiethnic Cohort Study, G7990718016, G805890577, G8075407775, G8083151929, G8102260223, G820454163, G8312218698, G8355735039, G8386326007, G8536616440, HISPANIC COMMUNITY HEALTH STUDY-268065233, G8840902395, G8904081916, G9000000024, G9000004253, G9000006085, G9000011423, G9000011771, G9000013175, G9000016544, G9000021463, G9000021538, G9000032397, G9000035207, G9000041091, G9000041420, G9000042288, G9000046817, G9000051044, G9000053822, G9000055272, G9000058670, G9000063695, G9000063797, G9000071344, G9000072038, G9000076846, G9000077829, G9000079831, G9000085573, G9000092963, G9000110083, G9000128449, G9000145785, G9000147789, G9000169788, G9000200762, G9000206094, G9000219966, G9000226307, G9000248565, G9000269129, G9000276921, G9000279044, G9000290334, G9000300478, G9000303384, G9000312855, G9000318789, The next iteration of the AMP-T2D Knowledge Portal, Mentoring Investigators on the Clinical Translation of Cardiometabolic Genetic Discoveries, Pharmacogenetics of the Response to GLP-1 in Mexican-Americans with Prediabetes
OpenAlex ID: W4372354995