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

TitleMulti-ethnic GWAS and fine-mapping of glycaemic traits identify novel loci in the PAGE Study.
Publication TypePublication
Year2022
AuthorsDownie CG, Dimos SF, Bien SA, Hu Y, Darst BF, Polfus LM, Wang Y, Wojcik GL, Tao R, Raffield LM, Armstrong ND, Polikowsky HG, Below JE, Correa A, Irvin MR, Rasmussen-Torvik LJF, Carlson CS, Phillips LS, Liu S, Pankow JS, Rich SS, Rotter JI, Buyske S, Matise TC, North KE, Avery CL, Haiman CA, Loos RJF, Kooperberg C, Graff M, Highland HM
JournalDiabetologia
Volume65
Issue3
Pagination477-489
Date Published2022 Mar
ISSN1432-0428
KeywordsBlood Glucose, Diabetes Mellitus, Type 2, genome-wide association study, Genomics, Humans, Polymorphism, Single Nucleotide
Abstract

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

DOI10.1007/s00125-021-05635-9
Alternate JournalDiabetologia
PubMed ID34951656
PubMed Central IDPMC8810722
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MS#: 
0555
Manuscript Lead/Corresponding Author Affiliation: 
Coordinating Center - Collaborative Studies Coordinating Center - UNC at Chapel Hill
ECI: 
Yes
Manuscript Affiliation: 
Coordinating Center - Collaborative Studies Coordinating Center - UNC at Chapel Hill
Manuscript Status: 
Published