The Trans-Ancestral Genomic Architecture of Glycaemic Traits

Glycaemic traits are used to diagnose and monitor type 2 diabetes, and cardiometabolic health. To date, most genetic studies of glycaemic traits have focused on individuals of European ancestry. Here, we aggregated genome-wide association studies in up to 281,416 individuals without diabetes (30% non-European ancestry) with fasting glucose, 2h-glucose post-challenge, glycated haemoglobin, and fasting insulin data. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P <5×10-8), 80% with no significant evidence of between-ancestry heterogeneity. Analyses restricted to European ancestry individuals with equivalent sample size would have led to 24 fewer new loci. Compared to single-ancestry, equivalent sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase understanding of diabetes pathophysiology by use of trans-ancestry studies for improved power and resolution. ### Competing Interest Statement Dr. Arne Astrup is recipient of honoraria as speaker for a wide range of Danish and international concerns and receives royalties from textbooks, and from popular diet and cookery books. Dr. Astrup is also co-inventor of a number of patents, including Methods of inducing weight loss, treating obesity and preventing weight gain (licensee Gelesis, USA) and Biomarkers for predicting degree of weight loss (licensee Nestec SA, CH), owned by the University of Copenhagen, in accordance with Danish law. Ines Barroso and spouse own stock in GlaxoSmithKline and Incyte Corporation. Mark Caulfield is an NIHR Senior Investigator. MC is also seconded to Genomics England as Chief Scientist, but there is no conflict to declare. Brian H. Chen is current Employee of Life Epigenetics, Inc. All work was completed prior to employment at Life Epigenetics. Audrey Y. Chu is current Employee of Merck & Co. All work was completed prior to employment by Merck & Co. Jose C Florez consults honorarium from Janssen Javier Gayan is currently an employee of F. Hoffmann-La Roche Ltd, and owns stock of Roche and GSK. Anna L Gloyn consults honorarium from Merck, speaker honorarium from Novo Nordisk Christian Herder has received honoraria from Sanofi and Lilly and research support from Sanofi unrelated to this manuscript. Winfried Marz has Grants from Siemens Healthineers, grants and personal fees from Aegerion Pharmaceuticals, grants and personal fees from AMGEN, grants from Astrazeneca, grants and personal fees from Sanofi, grants and personal fees from Alexion Pharmaceuticals, grants and personal fees from BASF, grants and personal fees from Abbott Diagnostics, grants and personal fees from Numares AG, grants and personal fees from Berlin-Chemie, grants and personal fees from Akzea Therapeutics, grants from Bayer Vital GmbH, grants from bestbion dx GmbH, grants from Boehringer Ingelheim Pharma GmbH Co KG, grants from Immundiagnostik GmbH, grants from Merck Chemicals GmbH, grants from MSD Sharp and Dohme GmbH, grants from Novartis Pharma GmbH, grants from Olink Proteomics, other from Synlab Holding Deutschland GmbH, all outside the submitted work. Mark I McCarthy has served on advisory panels for Pfizer, NovoNordisk, Zoe Global and received honoraria from Merck, Pfizer, NovoNordisk and Eli Lilly. He holds stock options in Zoe Global and has received research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier, Takeda. As of June 2019, he is an employee of Roche-Genentech, and a holder of Roche stock. James B Meigs consultants for Quest Diagnostics, Inc. They make an HbA1c assay. May E Montasser reports grant from Regeneron Pharmaceuticals.MEM is an inventor on a patent that was published by the United States Patent and Trademark Office on December 6, 2018 under Publication Number US 2018-0346888, and international patent application that was published on December 13, 2018 under Publication Number WO-2018/226560. All work was completed before these COI arise, and all work in unrelated to these COI Dennis O. Mook-Kanamori is Part-time clinical research consultant for Metabolon, Inc. Colin N.A. Palmer has received research support from GSK and AZ not related to this manuscript. Bruce M Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Naveed Sattar has consulted for Astrazeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Napp and Sanofi and received grant support from Boehringer Ingelheim Tim Spector is founder of Zoe Global Ltd.