Type 2 diabetes mellitus (T2D), a major cause of worldwide morbidity and mortality, is characterized by dysfunction of insulin-producing pancreatic islet β cells1,2. T2D genome-wide association studies (GWAS) have identified hundreds of signals in non-coding and β cell regulatory genomic regions, but deciphering their biological mechanisms remains challenging3–5. Here, to identify early disease-driving events, we performed traditional and multiplexed pancreatic tissue imaging, sorted-islet cell transcriptomics and islet functional analysis of early-stage T2D and control donors. By integrating diverse modalities, we show that early-stage T2D is characterized by β cell-intrinsic defects that can be proportioned into gene regulatory modules with enrichment in signals of genetic risk. After identifying the β cell hub gene and transcription factor RFX6 within one such module, we demonstrated multiple layers of genetic risk that converge on an RFX6
Cardiometabolic risk factors for COVID-19 susceptibility and severity: A Mendelian randomization analysis
Aaron Leong , Roles Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Writing – original draft
Affiliations Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America, Division of General Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America, Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America, Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America Roles Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation,
Research Article
Genetic associations with temporal shifts in obesity and severe obesity during the obesity epidemic in Norway: A longitudinal population-based cohort (the HUNT Study)
Maria Brandkvist , Roles Conceptualization, Funding acquisition, Methodology, Supervision, Validation, Writing – review & editing
Affiliations Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway, Faculty of Nursing and Health Sciences, Nord University, Levanger, Norway Roles Supervision, Validation, Writing – review & editing
Affiliations Children’s Clinic, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway, Obesity Centre, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway, Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway