Multi-ancestry Polygenic Mechanisms of Type 2 Diabetes Elucidate Disease Processes and Clinical Heterogeneity.

Autor: Smith K; Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Deutsch AJ; Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA., McGrail C; Department of Pediatrics, University of California San Diego, San Diego, CA, USA., Kim H; Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Committee on Genetics, Genomics and Systems Biology, University of Chicago, Chicago, IL, USA.; Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA., Hsu S; Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA., Mandla R; Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Schroeder PH; Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Westerman KE; Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA., Szczerbinski L; Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland.; Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland., Majarian TD; Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA., Kaur V; Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Williamson A; Precision Healthcare University Research Institute, Queen Mary University of London, London, UK.; MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK., Claussnitzer M; Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA., Florez JC; Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA., Manning AK; Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA., Mercader JM; Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA., Gaulton KJ; Department of Pediatrics, University of California San Diego, San Diego, CA, USA., Udler MS; Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Programs in Metabolism and Medical & Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.
Jazyk: angličtina
Zdroj: Research square [Res Sq] 2023 Oct 09. Date of Electronic Publication: 2023 Oct 09.
DOI: 10.21203/rs.3.rs-3399145/v1
Abstrakt: We identified genetic subtypes of type 2 diabetes (T2D) by analyzing genetic data from diverse groups, including non-European populations. We implemented soft clustering with 650 T2D-associated genetic variants, capturing known and novel T2D subtypes with distinct cardiometabolic trait associations. The twelve genetic clusters were distinctively enriched for single-cell regulatory regions. Polygenic scores derived from the clusters differed in distribution between ancestry groups, including a significantly higher proportion of lipodystrophy-related polygenic risk in East Asian ancestry. T2D risk was equivalent at a BMI of 30 kg/m 2 in the European subpopulation and 24.2 (22.9-25.5) kg/m 2 in the East Asian subpopulation; after adjusting for cluster-specific genetic risk, the equivalent BMI threshold increased to 28.5 (27.1-30.0) kg/m 2 in the East Asian group, explaining about 75% of the difference in BMI thresholds. Thus, these multi-ancestry T2D genetic subtypes encompass a broader range of biological mechanisms and help explain ancestry-associated differences in T2D risk profiles.
Databáze: MEDLINE