Abstract
Aims/hypothesis: Type 2 diabetes is a growing global public health challenge. Investigating quantitative traits, including fasting glucose, fasting insulin and HbA1c, that serve as early markers of type 2 diabetes progression may lead to a deeper understanding of the genetic aetiology of type 2 diabetes development. Previous genome-wide association studies (GWAS) have identified over 500 loci associated with type 2 diabetes, glycaemic traits and insulin-related traits. However, most of these findings were based only on populations of European ancestry. To address this research gap, we examined the genetic basis of fasting glucose, fasting insulin and HbA1c in participants of the diverse Population Architecture using Genomics and Epidemiology (PAGE) Study. Methods: We conducted a GWAS of fasting glucose (n = 52,267), fasting insulin (n = 48,395) and HbA1c (n = 23,357) in participants without diabetes from the diverse PAGE Study (23% self-reported African American, 46% Hispanic/Latino, 40% European, 4% Asian, 3% Native Hawaiian, 0.8% Native American), performing transethnic and population-specific GWAS meta-analyses, followed by fine-mapping to identify and characterise novel loci and independent secondary signals in known loci. Results: Four novel associations were identified (p < 5 × 10−9), including three loci associated with fasting insulin, and a novel, low-frequency African American-specific locus associated with fasting glucose. Additionally, seven secondary signals were identified, including novel independent secondary signals for fasting glucose at the known GCK locus and for fasting insulin at the known PPP1R3B locus in transethnic meta-analysis. Conclusions/interpretation: Our findings provide new insights into the genetic architecture of glycaemic traits and highlight the continued importance of conducting genetic studies in diverse populations. Data availability: Full summary statistics from each of the population-specific and transethnic results are available at NHGRI-EBI GWAS catalog (https://www.ebi.ac.uk/gwas/downloads/summary-statistics). Graphical abstract: [Figure not available: see fulltext.]
| Original language | English (US) |
|---|---|
| Pages (from-to) | 477-489 |
| Number of pages | 13 |
| Journal | Diabetologia |
| Volume | 65 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2022 |
Funding
(6) The HCHS/SOL is a collaborative study supported by contracts from the National Heart, Lung and Blood Institute (NHLBI) to the University of North Carolina (HHSN268201300001I / N01-HC-65233), University of Miami (HHSN268201300004I / N01-HC-65234), Albert Einstein College of Medicine (HHSN268201300002I / N01-HC 65235), University of Illinois at Chicago (HHSN268201300003I / N01-HC-65236 Northwestern University), and San Diego State University (HHSN268201300005I / N01-HC-65237). The following Institutes/Centres/Offices have contributed to the HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities; National Institute on Deafness and Other Communication Disorders; National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Neurological Disorders and Stroke; and NIH Institution-Office of Dietary Supplements. The Genetic Analysis Center at the University of Washington was supported by NHLBI and NIDCR contracts (HHSN268201300005C AM03 and MOD03). (4) The MEC characterisation of epidemiological architecture is funded through the NHGRI PAGE programme (U01HG004802 and its NHGRI ARRA supplement). The MEC study is funded by the National Cancer Institute (R37CA54281, R01CA63, P01CA33619, U01CA136792 and U01CA98758). (1) The ARIC study is funded in whole or in part by federal funds from the National Heart, Lung and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract nos HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I), R01HL087641, R01HL059367 and R01HL086694, National Human Genome Research Institute contract U01HG004402, and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by grant no. UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The PAGE consortium thanks the staff and participants of all PAGE studies for their important contributions. The complete list of PAGE members can be found at http://www.pagestudy.org/page-investigators/. We thank the staff and participants of the ARIC study for their important contributions. More detail about the ARIC study may be found at: https://sites.cscc.unc.edu/aric/. We thank the WHI investigators and staff for their dedication and the study participants for making the programme possible. Full listing of WHI investigators can be found at https://www.whi.org/researchers/DocumentsWriteaPaper/WHIInvestigatorShortList.pdf. We also thank the investigators, the staff and the participants of MESA for their valuable contributions. A full list of participating MESA institutions and investigators can be found at http://www.mesa-nhlbi.org and https://www.mesa-nhlbi.org/aboutMESAPersonnel.aspx , respectively. We also thank the staff and participants of CARDIA for their important contributions. More details about CARDIA may be found at: https://www.cardia.dopm.uab.edu/. Representatives of the National Institute of Neurological Disorders and Stroke were involved in the review of the manuscript but were not directly involved in the collection, management, analysis or interpretation of data. The authors thank the other investigators, the staff, and the participants of the REGARDS study for their valuable contributions. A full list of participating REGARDS investigators and institutions can be found at: https://www.uab.edu/soph/regardsstudy/. The authors wish to thank the staff and participants of the JHS. We also thank the National Institute for Nutrition and Health, China Center for Disease Control and Prevention, Beijing Municipal Center for Disease Control and Prevention, and the Chinese National Human Genome Center at Shanghai. HMH receives a stipend from the American Heart Association for serving as a statistical editor for the journal Circulation Research. SAB has a financial interest in Adaptive Biotechnologies. LSP has served on Scientific Advisory Boards for Janssen, and has or had research support from Merck, Pfizer, Eli Lilly, Novo Nordisk, Sanofi, PhaseBio, Roche, AbbVie, Vascular Pharmaceuticals, Janssen, Glaxo SmithKline and the Cystic Fibrosis Foundation. LSP is also a cofounder and Officer and Board member and stockholder for a company, Diasyst, Inc., which markets software aimed to help improve diabetes management. The remaining authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. The PAGE Study is funded by the National Human Genome Research Institute with co-funding from the National Institute on Minority Health and Health Disparities. Assistance with data management, data integration, data dissemination, genotype imputation, ancestry deconvolution, population genetics, analysis pipelines and general study coordination was provided by the PAGE Coordinating Center (NI-HU01HG007419). Genotyping services were provided by the Center for Inherited Disease Research, which is fully funded through a federal contract from the National Institutes of Health (NIH) to The Johns Hopkins University, contract number HHSN268201200008I. Genotype data quality control and quality assurance services were provided by the Genetic Analysis Center in the Biostatistics Department of the University of Washington, through support provided by the Center for Inherited Disease Research contract. PAGE data and materials included in this report were funded through the following studies and organisations: (3) The CARDIA Study is supported by contracts HHSN268201800003I, HHSN268201800004I, HHSN268201800005I, HHSN268201800006I and HHSN268201800007I from the National Heart, Lung and Blood Institute (NHLBI). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging (NIA) and an intra-agency agreement between NIA and NHLBI (AG0005). GWAS genotyping and data analyses were funded in part by grants U01-HG004729 and R01-HL093029 from the National Institutes of Health to M. Fornage. (8) The REGARDS project is supported by cooperative agreement U01 NS041588 co-funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA), National Institutes of Health, Department of Health and Human Services. (11) The CHNS receives research grant funding from the National Institute for Health (NIH), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) for R01 HD30880, National Institute on Aging (NIA) for R01 AG065357, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) for R01DK104371 and R01HL108427, the NIH Fogarty grant D43 TW009077 since 1989, and the China-Japan Friendship Hospital, Ministry of Health for support for CHNS 2009, Chinese National Human Genome Center at Shanghai since 2009, and Beijing Municipal Center for Disease Prevention and Control since 2011. (9) MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079 and UL1-TR-001420. Funding for SHARe genotyping was provided by NHLBI contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, CA, USA) and the Broad Institute of Harvard and MIT (Boston, MA, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. CLA, HMH, CGD, SFD, MG and KEN are supported by R01HL142825. HMH is also funded by NHLBI training grants T32 HL007055 and T32 HL129982-03, and ADA grant no. 1–19-PDF-045. KEN is also supported by R01HG010297-01. LMR is supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant KL2T2002490 and by R01HG010297. JEB and HGP are supported by R01HL142302-01; HGP is also supported by U01HG007416. CK is supported by S10OD028685. RJFL is supported by R01HG010297 and R01HL151152. MRI is supported by R01HL136666. SB and TCM are supported by U01HG007419. LSP is supported by Veterans Administration (VA) awards CSP no. 2008, I01 CX001899, I01 CX001737 and HSR&D IIR 07-138, and by NIH awards R21 DK099716, R18 DK066204, R03 AI133172, R21 AI156161, U01 DK091958, U01 DK098246 and UL1 TR002378. (10) The CCHC is supported by MD000170 P20 funded from the National Center on Minority Health and Health Disparities (NCMHD), the University of Texas Houston Health Sciences Center, Center for Clinical and Translational Science CCTS-CTSA award UL1 TR00371 from NCATS. (5) The WHI programme is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, and US Department of Health and Human Services through contracts 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, 75N92021D00005. (12) Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute (NHLBI) grant R01HL105756.
Keywords
- Fine-mapping
- Genome-wide association study
- Glucose
- Glycaemic traits
- HbA
- Insulin
- Transethnic population
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism
