Abstract
Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10−8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 347-357 |
| Number of pages | 11 |
| Journal | Nature |
| Volume | 627 |
| Issue number | 8003 |
| DOIs | |
| State | Published - Mar 14 2024 |
Funding
Central analyses were supported by the Japan Agency for Medical Research and Development (JP21km0405213, JP20km0405202 and JP21tm0424218), NHGRI (HG011723), the American Diabetes Association Innovative and a Clinical Translational Award (1-19-ICTS-068), the European Union\u2019s Horizon 2020 research and innovation programme under grant agreement no. 101017802 (OPTOMICS), American Heart Association Postdoctoral Fellowships (15POST24470131 and 17POST33650016), the American Diabetes Association (11-22-JDFPM-06), Corporal Michael J Crescenz VA Medical Center Research, NIDDK (DK126194 and DK105535), Versus Arthritis (21754), NIHR Manchester Biomedical Research Centre (NIHR203308) and the MRC (MR/W029626/1). A complete list of acknowledgments and funding appears in the\u00A0Supplementary Note. We thank the International Consortium of Blood Pressure (ICBP) and the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) for providing pre-publication access to GWAS summary statistics for blood pressure, proinsulin and post-challenge insulin-resistance measures. The views expressed in this article are those of the authors and do not necessarily represent those of: the UK National Health Service, the UK National Institute for Health Research or the UK Department of Health and Social Care; the US National Heart, Lung, and Blood Institute, the US National Institute of Neurological Disorders and Stroke, the US National Institute on Aging, the US National Institutes of Health, the US Department of Health and Human Services, the US Department of Veterans Affairs, the US Food and Drug Administration or the US Government. Central analyses were supported by the Japan Agency for Medical Research and Development (JP21km0405213, JP20km0405202 and JP21tm0424218), NHGRI (HG011723), the American Diabetes Association Innovative and a Clinical Translational Award (1-19-ICTS-068), the European Union\u2019s Horizon 2020 research and innovation programme under grant agreement no. 101017802 (OPTOMICS), American Heart Association Postdoctoral Fellowships (15POST24470131 and 17POST33650016), the American Diabetes Association (11-22-JDFPM-06), Corporal Michael J Crescenz VA Medical Center Research, NIDDK (DK126194 and DK105535), Versus Arthritis (21754), NIHR Manchester Biomedical Research Centre (NIHR203308) and the MRC (MR/W029626/1). A complete list of acknowledgments and funding appears in the . We thank the International Consortium of Blood Pressure (ICBP) and the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) for providing pre-publication access to GWAS summary statistics for blood pressure, proinsulin and post-challenge insulin-resistance measures. The views expressed in this article are those of the authors and do not necessarily represent those of: the UK National Health Service, the UK National Institute for Health Research or the UK Department of Health and Social Care; the US National Heart, Lung, and Blood Institute, the US National Institute of Neurological Disorders and Stroke, the US National Institute on Aging, the US National Institutes of Health, the US Department of Health and Human Services, the US Department of Veterans Affairs, the US Food and Drug Administration or the US Government.
ASJC Scopus subject areas
- General
