Multi-Ethnic GWAS and Fine-Mapping of Glycaemic Traits Identify Novel Loci in the Page Study

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Citation

Downie, Carolina G.; Dimos, Sofia F.; Bien, Stephanie A.; Hu, Yao; Darst, Burcu F.; Polfus, Linda M.; Wang, Yujie; Wojcik, Genevieve L.; Tao, Ran; & Raffield, Laura M., et al. (2022). Multi-Ethnic GWAS and Fine-Mapping of Glycaemic Traits Identify Novel Loci in the Page Study. Diabetologia, 65(3), 477-489. PMCID: PMC8810722

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.

URL

http://dx.doi.org/10.1007/s00125-021-05635-9

Reference Type

Journal Article

Year Published

2022

Journal Title

Diabetologia

Author(s)

Downie, Carolina G.
Dimos, Sofia F.
Bien, Stephanie A.
Hu, Yao
Darst, Burcu F.
Polfus, Linda M.
Wang, Yujie
Wojcik, Genevieve L.
Tao, Ran
Raffield, Laura M.
Armstrong, Nicole D.
Polikowsky, Hannah G.
Below, Jennifer E.
Correa, Adolfo
Irvin, Marguerite Ryan
Rasmussen-Torvik, Laura J.
Carlson, Christopher S.
Phillips, Lawrence S.
Liu, Simin
Pankow, James S.
Rich, Stephen S.
Rotter, Jerome I.
Buyske, Steven G.
Matise, Tara C.
North, Kari E.
Avery, Christy L.
Haiman, Christopher A.
Loos, Ruth J. F.
Kooperberg, Charles
Graff, Mariaelisa
Highland, Heather M.

Article Type

Regular

PMCID

PMC8810722

Data Set/Study

Atherosclerosis Risk in Communities (ARIC) Study
Ichan Mount Sinai School of Medicine’s BioMe
Biobank (BioMe)
Coronary Artery Risk Development in Young Adults (CARDIA) Study
Multiethnic Cohort (MEC) Study
Hispanic Community Health Study/Study of Latinos (HCHS/SOL)
Women's Health Study

Race/Ethnicity

African-American
Hispanic/Latinx
Asian
European
Native American

ORCiD

Avery - 0000-0002-1044-8162
Graff - 0000-0001-6380-1735