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

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Multi-ethnic GWAS and fine-mapping of glycaemic traits identify novel loci in the PAGE Study
Diabetologia ( IF 8.4 ) Pub Date : 2021-12-24 , DOI: 10.1007/s00125-021-05635-9
Carolina G Downie ₁ , Sofia F Dimos ₁ , Stephanie A Bien ₂ , Yao Hu ₂ , Burcu F Darst ₃ , Linda M Polfus _{3,

4} , Yujie Wang ₁ , Genevieve L Wojcik ₅ , Ran Tao _{6,

7} , Laura M Raffield ₈ , Nicole D Armstrong ₉ , Hannah G Polikowsky ₁₀ , Jennifer E Below ₁₀ , Adolfo Correa ₁₁ , Marguerite R Irvin ₉ , Laura J F Rasmussen-Torvik ₁₂ , Christopher S Carlson ₂ , Lawrence S Phillips _{13,

14} , Simin Liu _{15,

16} , James S Pankow ₁₇ , Stephen S Rich ₁₈ , Jerome I Rotter ₁₉ , Steven Buyske ₂₀ , Tara C Matise ₂₁ , Kari E North ₁ , Christy L Avery ₁ , Christopher A Haiman ₃ , Ruth J F Loos ₂₂ , Charles Kooperberg ₂ , Mariaelisa Graff ₁ , Heather M Highland ₁

Affiliation

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Department of Preventive Medicine, Center for Genetic Epidemiology, University of Southern California, Los Angeles, CA, USA.
Ambry Genetics, Aliso Viejo, CA, USA.
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Medicine, Jackson Heart Study, University of Mississippi Medical Center, Jackson, MS, USA.
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Atlanta VA Medical Center, Decatur, GA, USA.
Department of Medicine, Division of Endocrinology, Emory University School of Medicine, Atlanta, GA, USA.
Department of Medicine, Division of Endocrinology, Warren Alpert School of Medicine, Brown University, Providence, RI, USA.
Department of Epidemiology, Brown School of Public Health, Providence, RI, USA.
Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN, USA.
Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
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.
Department of Statistics, Rutgers University, Piscataway, NJ, USA.
Department of Genetics, Rutgers University, Piscataway, NJ, USA.
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

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).

Graphical abstract

中文翻译：

多种族 GWAS 和血糖特征精细绘图确定了 PAGE 研究中的新位点

目标/假设

2 型糖尿病是一个日益严峻的全球公共卫生挑战。研究作为 2 型糖尿病进展早期标志的定量特征，包括空腹血糖、空腹胰岛素和 HbA _1c ，可能有助于更深入地了解 2 型糖尿病发展的遗传病因学。此前的全基因组关联研究 (GWAS) 已识别出 500 多个与 2 型糖尿病、血糖特征和胰岛素相关特征相关的基因座。然而，大多数这些发现仅基于欧洲血统的人群。为了弥补这一研究空白，我们使用基因组学和流行病学 (PAGE) 研究检查了不同人群结构参与者的空腹血糖、空腹胰岛素和 HbA _1c的遗传基础。