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Trans-ethnic fine mapping identifies a novel independent locus at the 3' end of CDKAL1 and novel variants of several susceptibility loci for type 2 diabetes in a Han Chinese population.

ABSTRACT: Candidate gene and genome-wide association studies have identified ?60 susceptibility loci for type 2 diabetes. A majority of these loci have been discovered and tested only in European populations. The aim of this study was to assess the presence and extent of trans-ethnic effects of these loci in an East Asian population.A total of 9,335 unrelated Chinese Han individuals, including 4,535 with type 2 diabetes and 4,800 non-diabetic ethnically matched controls, were genotyped using the Illumina 200K Metabochip. We tested 50 established loci for type 2 diabetes and related traits (fasting glucose, fasting insulin, 2 h glucose). Disease association with the additive model of inheritance was analysed with logistic regression.We found that 14 loci significantly transferred to the Chinese population, with two loci (p?=?5.7?×?10(-12) for KCNQ1; p?=?5.0?×?10(-8) for CDKN2A/B-CDKN2BAS) reaching independent genome-wide statistical significance. Five of these 14 loci had similar lead single-nucleotide polymorphisms (SNPs) as were found in the European studies while the other nine were different. Further stepwise conditional analysis identified a total of seven secondary signals and an independent novel locus at the 3' end of CDKAL1.These results suggest that many loci associated with type 2 diabetes are commonly shared between European and Chinese populations. Identification of population-specific SNPs may increase our understanding of the genetic architecture underlying type 2 diabetes in different ethnic populations.

SUBMITTER: Kuo JZ

PROVIDER: S-EPMC3825282 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Trans-ethnic fine mapping identifies a novel independent locus at the 3' end of CDKAL1 and novel variants of several susceptibility loci for type 2 diabetes in a Han Chinese population.

Kuo Jane Z JZ Sheu Wayne Huey-Herng WH Assimes Themistocles L TL Hung Yi-Jen YJ Absher Devin D Chiu Yen-Feng YF Mak Jordan J Wang Jun-Sing JS Kwon Soonil S Hsu Chih-Cheng CC Goodarzi Mark O MO Lee I-Te IT Knowles Joshua W JW Miller Brittany E BE Lee Wen-Jane WJ Juang Jyh-Ming J JM Wang Tzung-Dau TD Guo Xiuqing X Taylor Kent D KD Chuang Lee-Ming LM Hsiung Chao A CA Quertermous Thomas T Rotter Jerome I JI Chen Yii-Der I YD

Diabetologia 20130908 12

<h4>Aims/hypothesis</h4>Candidate gene and genome-wide association studies have identified ∼60 susceptibility loci for type 2 diabetes. A majority of these loci have been discovered and tested only in European populations. The aim of this study was to assess the presence and extent of trans-ethnic effects of these loci in an East Asian population.<h4>Methods</h4>A total of 9,335 unrelated Chinese Han individuals, including 4,535 with type 2 diabetes and 4,800 non-diabetic ethnically matched cont ...[more]

PMID: 24013783

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Project description:Aims/hypothesisType 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.MethodsWe 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.ResultsFour 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/interpretationOur findings provide new insights into the genetic architecture of glycaemic traits and highlight the continued importance of conducting genetic studies in diverse populations.Data availabilityFull 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 ).

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Dataset Information

Trans-ethnic fine mapping identifies a novel independent locus at the 3' end of CDKAL1 and novel variants of several susceptibility loci for type 2 diabetes in a Han Chinese population.

Publications

Trans-ethnic fine mapping identifies a novel independent locus at the 3' end of CDKAL1 and novel variants of several susceptibility loci for type 2 diabetes in a Han Chinese population.

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