TY - JOUR
T1 - Multi-ethnic GWAS and fine-mapping of glycaemic traits identify novel loci in the PAGE Study
AU - Downie, Carolina G.
AU - Dimos, Sofia F.
AU - Bien, Stephanie A.
AU - Hu, Yao
AU - Darst, Burcu F.
AU - Polfus, Linda M.
AU - Wang, Yujie
AU - Wojcik, Genevieve L.
AU - Tao, Ran
AU - Raffield, Laura M.
AU - Armstrong, Nicole D.
AU - Polikowsky, Hannah G.
AU - Below, Jennifer E.
AU - Correa, Adolfo
AU - Irvin, Marguerite R.
AU - Rasmussen-Torvik, Laura J.F.
AU - Carlson, Christopher S.
AU - Phillips, Lawrence S.
AU - Liu, Simin
AU - Pankow, James S.
AU - Rich, Stephen S.
AU - Rotter, Jerome I.
AU - Buyske, Steven
AU - Matise, Tara C.
AU - North, Kari E.
AU - Avery, Christy L.
AU - Haiman, Christopher A.
AU - Loos, Ruth J.F.
AU - Kooperberg, Charles
AU - Graff, Mariaelisa
AU - Highland, Heather M.
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2022/3
Y1 - 2022/3
N2 - 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.]
AB - 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.]
KW - Fine-mapping
KW - Genome-wide association study
KW - Glucose
KW - Glycaemic traits
KW - HbA
KW - Insulin
KW - Transethnic population
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U2 - 10.1007/s00125-021-05635-9
DO - 10.1007/s00125-021-05635-9
M3 - Article
C2 - 34951656
AN - SCOPUS:85121608065
SN - 0012-186X
VL - 65
SP - 477
EP - 489
JO - Diabetologia
JF - Diabetologia
IS - 3
ER -