Multi-ethnic GWAS and fine-mapping of glycaemic traits identify novel loci in the PAGE Study

Carolina G Downie¹, Sofia F Dimos², Stephanie A Bien³, Yao Hu³, Burcu F Darst⁴, Linda M Polfus^{4

5}, Yujie Wang², Genevieve L Wojcik⁶, Ran Tao^{7

8}, Laura M Raffield⁹, Nicole D Armstrong¹⁰, Hannah G Polikowsky¹¹, Jennifer E Below¹¹, Adolfo Correa¹², Marguerite R Irvin¹⁰, Laura J F Rasmussen-Torvik¹³, Christopher S Carlson³, Lawrence S Phillips^{14

15}, Simin Liu^{16

17}, James S Pankow¹⁸, Stephen S Rich¹⁹, Jerome I Rotter²⁰, Steven Buyske²¹, Tara C Matise²², Kari E North², Christy L Avery², Christopher A Haiman⁴, Ruth J F Loos²³, Charles Kooperberg³, Mariaelisa Graff², Heather M Highland²

Affiliations

¹ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. cdownie@live.unc.edu.
² Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁴ Department of Preventive Medicine, Center for Genetic Epidemiology, University of Southern California, Los Angeles, CA, USA.
⁵ Ambry Genetics, Aliso Viejo, CA, USA.
⁶ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁷ Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
⁹ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁰ Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
¹¹ Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹² Department of Medicine, Jackson Heart Study, University of Mississippi Medical Center, Jackson, MS, USA.
¹³ Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
¹⁴ Atlanta VA Medical Center, Decatur, GA, USA.
¹⁵ Department of Medicine, Division of Endocrinology, Emory University School of Medicine, Atlanta, GA, USA.
¹⁶ Department of Medicine, Division of Endocrinology, Warren Alpert School of Medicine, Brown University, Providence, RI, USA.
¹⁷ Department of Epidemiology, Brown School of Public Health, Providence, RI, USA.
¹⁸ Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN, USA.
¹⁹ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
²⁰ Department of Pediatrics, Genome Outcomes, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
²¹ Department of Statistics, Rutgers University, Piscataway, NJ, USA.
²² Department of Genetics, Rutgers University, Piscataway, NJ, USA.
²³ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

PMID: 34951656
PMCID: PMC8810722
DOI: 10.1007/s00125-021-05635-9

Meta-Analysis

Multi-ethnic GWAS and fine-mapping of glycaemic traits identify novel loci in the PAGE Study

Carolina G Downie et al. Diabetologia. 2022 Mar.

. 2022 Mar;65(3):477-489.

doi: 10.1007/s00125-021-05635-9. Epub 2021 Dec 24.

Authors

Affiliations

¹ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. cdownie@live.unc.edu.
² Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁴ Department of Preventive Medicine, Center for Genetic Epidemiology, University of Southern California, Los Angeles, CA, USA.
⁵ Ambry Genetics, Aliso Viejo, CA, USA.
⁶ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁷ Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
⁹ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁰ Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
¹¹ Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹² Department of Medicine, Jackson Heart Study, University of Mississippi Medical Center, Jackson, MS, USA.
¹³ Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
¹⁴ Atlanta VA Medical Center, Decatur, GA, USA.
¹⁵ Department of Medicine, Division of Endocrinology, Emory University School of Medicine, Atlanta, GA, USA.
¹⁶ Department of Medicine, Division of Endocrinology, Warren Alpert School of Medicine, Brown University, Providence, RI, USA.
¹⁷ Department of Epidemiology, Brown School of Public Health, Providence, RI, USA.
¹⁸ Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN, USA.
¹⁹ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
²⁰ Department of Pediatrics, Genome Outcomes, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
²¹ Department of Statistics, Rutgers University, Piscataway, NJ, USA.
²² Department of Genetics, Rutgers University, Piscataway, NJ, USA.
²³ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

PMID: 34951656
PMCID: PMC8810722
DOI: 10.1007/s00125-021-05635-9

Abstract

Aims/hypothesis: Type 2 diabetes is a growing global public health challenge. Investigating quantitative traits, including fasting glucose, fasting insulin and HbA_1c, 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 HbA_1c 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 HbA_1c (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 ).

Keywords: Fine-mapping; Genome-wide association study; Glucose; Glycaemic traits; HbA1c; Insulin; Transethnic population.

PubMed Disclaimer

Figures

**Fig. 1**
Manhattan plots for glycaemic trait association analyses in PAGE, adjusting for BMI. (a) Fasting insulin transethnic meta-analysis results. (b) HbA_1c transethnic meta-analysis results. (c) Fasting glucose transethnic meta-analysis results. (d) Fasting glucose AA-specific meta-analysis results. Known loci are shown in grey; novel loci with p value < 1 × 10⁻⁶ are shown in purple; novel loci with p value < 5 × 10⁻⁹ are shown in pink

**Fig. 2**
Forest plots of primary GWAS and replication transethnic and population-specific meta-analysis effect estimates and 95% CIs for the four novel variants identified in the PAGE Study. (a) Fasting glucose variant rs571025315 at *LRRC37A5P* locus, which was genome-wide significant (*p <* 5 × 10⁻⁹) only in AA-specific meta-analysis. Effective n < 30 for all other populations in the primary analysis, indicated by sample size n = NA in the primary analysis panel. (b) Fasting insulin variant rs9472142 at *VEGFA* locus. (c) Fasting insulin variant rs35131928 at *CASC8*/*CASC21* locus; EA REGARDS replication data used proxy variant rs10956361 in lieu of rs35131928 (D′ = 1 and r² = 1 with rs35131928 in EA PAGE data). (d) Fasting insulin variant rs10887773 at *PTEN* locus. PAGE Study GWAS results for transethnic and population-specific meta-analyses are shown against a white background; transethnic and population-specific meta-analyses of replication results are shown against a grey background. Replication data sources, by population, are as follows: AA, JHS, REGARDS; EA, REGARDS, MESA, MAGIC; HA, MESA, CCHC; and ASN, MESA, CHNS

See this image and copyright information in PMC

References

1. Cowie C, Casagrande S, Geiss L (2018) Prevalence and incidence of type 2 diabetes and prediabetes. In: Cowie C, Casagrande S, Menke A et al. (eds) Diabetes in America: 3rd edition, vol 17–1468. National Institutes of Health, Bethesda, MD
1. Tancredi M, Rosengren A, Svensson AM et al. (2015) Excess mortality among persons with type 2 diabetes. N Engl J Med 373(18):1720–1732. 10.1056/NEJMoa1504347 - DOI - PubMed
1. Rowley WR, Bezold C, Arikan Y, Byrne E, Krohe S (2017) Diabetes 2030: insights from yesterday, today, and future trends. Popul Health Manag 20(1):6–12. 10.1089/pop.2015.0181 - DOI - PMC - PubMed
1. Huang ES, Basu A, O’Grady M, Capretta JC (2009) Projecting the future diabetes population size and related costs for the U.S. Diabetes Care 32(12):2225–2229. 10.2337/dc09-0459 - DOI - PMC - PubMed
1. Dupuis J, Langenberg C, Prokopenko I et al. (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42(2):105–116. 10.1038/ng.520 - DOI - PMC - PubMed

Publication types

Actions
Actions
Actions
Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Multi-ethnic GWAS and fine-mapping of glycaemic traits identify novel loci in the PAGE Study

Affiliations

Multi-ethnic GWAS and fine-mapping of glycaemic traits identify novel loci in the PAGE Study

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous