A Genome-Wide Association Study of Gestational Diabetes Mellitus in Korean Women

Knowledge regarding the genetic risk loci for gestational diabetes mellitus (GDM) is still limited. In this study, we performed a two-stage genome-wide association analysis in Korean women. In the stage 1 genome scan, 468 women with GDM and 1,242 nondiabetic control women were compared using 2.19 million genotyped or imputed markers. We selected 11 loci for further genotyping in stage 2 samples of 931 case and 783 control subjects. The joint effect of stage 1 plus stage 2 studies was analyzed by meta-analysis. We also investigated the effect of known type 2 diabetes variants in GDM. Two loci known to be associated with type 2 diabetes had a genome-wide significant association with GDM in the joint analysis. rs7754840, a variant in CDKAL1, had the strongest association with GDM (odds ratio 1.518; P = 6.65 × 10−16). A variant near MTNR1B, rs10830962, was also significantly associated with the risk of GDM (1.454; P = 2.49 × 10−13). We found that there is an excess of association between known type 2 diabetes variants and GDM above what is expected under the null hypothesis. In conclusion, we have confirmed that genetic variants in CDKAL1 and near MTNR1B are strongly associated with GDM in Korean women. There seems to be a shared genetic basis between GDM and type 2 diabetes.

[1]  B. Metzger.  Summary and Recommendations of the Third International Workshop-Conference on Gestational Diabetes Mellitus , 1991, Diabetes.

[2]  P. Gorden,et al.  O-Linked Oligosaccharides on Insulin Receptor , 1991, Diabetes.

[3]  B. Metzger,et al.  Prepregnancy Weight and Antepartum Insulin Secretion Predict Glucose Tolerance Five Years After Gestational Diabetes Mellitus , 1993, Diabetes Care.

[4]  B. Metzger,et al.  Screening for gestational diabetes mellitus in Korea , 1995, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[5]  International Human Genome Sequencing Consortium.  Initial sequencing and analysis of the human genome , 2001, Nature.

[6]  L. Jovanovič,et al.  Gestational diabetes mellitus. , 2001, JAMA.

[7]  T. Buchanan.  Pancreatic B-cell defects in gestational diabetes: implications for the pathogenesis and prevention of type 2 diabetes. , 2001, The Journal of clinical endocrinology and metabolism.

[8]  J. V. Moran,et al.  Initial sequencing and analysis of the human genome. , 2001, Nature.

[9]  Catherine Kim,et al.  Gestational diabetes and the incidence of type 2 diabetes: a systematic review. , 2002, Diabetes care.

[10]  R. Qi,et al.  Identification of a Neuronal Cdk5 Activator-binding Protein as Cdk5 Inhibitor* , 2002, The Journal of Biological Chemistry.

[11]  S. Del Prato,et al.  Intermediate metabolism in normal pregnancy and in gestational diabetes , 2003, Diabetes/metabolism research and reviews.

[12]  R. Turner,et al.  Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man , 1985, Diabetologia.

[13]  G. Abecasis,et al.  Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies , 2006, Nature Genetics.

[14]  P. Donnelly,et al.  A new multipoint method for genome-wide association studies by imputation of genotypes , 2007, Nature Genetics.

[15]  J. Gulcher,et al.  A variant in CDKAL1 influences insulin response and risk of type 2 diabetes , 2007, Nature Genetics.

[16]  Xueying Gu,et al.  Menin Controls Growth of Pancreatic ß-Cells in Pregnant Mice and Promotes Gestational Diabetes Mellitus , 2007, Science.

[17]  T. Hudson,et al.  A genome-wide association study identifies novel risk loci for type 2 diabetes , 2007, Nature.

[18]  M. McCarthy,et al.  Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes , 2007, Science.

[19]  Marcia M. Nizzari,et al.  Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels , 2007, Science.

[20]  Simon C. Potter,et al.  Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls , 2007, Nature.

[21]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[22]  G. Abecasis,et al.  A Genome-Wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants , 2007, Science.

[23]  M. McCarthy,et al.  Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes , 2008, Nature Genetics.

[24]  B. Metzger,et al.  Prevalence of type 2 diabetes among women with a previous history of gestational diabetes mellitus. , 2008, Diabetes research and clinical practice.

[25]  H. Shin,et al.  Type 2 diabetes-associated genetic variants discovered in the recent genome-wide association studies are related to gestational diabetes mellitus in the Korean population , 2009, Diabetologia.

[26]  H. Shin,et al.  Implication of Genetic Variants Near TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, and FTO in Type 2 Diabetes and Obesity in 6,719 Asians , 2008, Diabetes.

[27]  Judy H. Cho,et al.  Finding the missing heritability of complex diseases , 2009, Nature.

[28]  G. Abecasis,et al.  Genotype imputation. , 2009, Annual review of genomics and human genetics.

[29]  D. Altshuler,et al.  Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion , 2009, Nature Genetics.

[30]  T. Hansen,et al.  Common type 2 diabetes risk gene variants associate with gestational diabetes. , 2009, The Journal of clinical endocrinology and metabolism.

[31]  Mark I. McCarthy,et al.  Type 2 Diabetes Risk Alleles Are Associated With Reduced Size at Birth , 2009, Diabetes.

[32]  Taesung Park,et al.  A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits , 2009, Nature Genetics.

[33]  Inês Barroso,et al.  Variants in MTNR1B influence fasting glucose levels , 2009, Nature Genetics.

[34]  P. Elliott,et al.  A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk , 2009, Nature Genetics.

[35]  Ayellet V. Segrè,et al.  Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis , 2010, Nature Genetics.

[36]  S. Kwak,et al.  Polymorphisms in KCNQ1 Are Associated with Gestational Diabetes in a Korean Population , 2010, Hormone Research in Paediatrics.

[37]  H. Shin,et al.  Melatonin receptor 1 B polymorphisms associated with the risk of gestational diabetes mellitus , 2011, BMC Medical Genetics.

[38]  Christian Gieger,et al.  New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk , 2010, Nature Genetics.

[39]  Michael Boehnke,et al.  LocusZoom: regional visualization of genome-wide association scan results , 2010, Bioinform..

[40]  H. Kang,et al.  Variance component model to account for sample structure in genome-wide association studies , 2010, Nature Genetics.

[41]  Fuu-Jen Tsai,et al.  A Genome-Wide Association Study Identifies Susceptibility Variants for Type 2 Diabetes in Han Chinese , 2010, PLoS genetics.

[42]  G. Morahan,et al.  Faculty Opinions recommendation of Serotonin regulates pancreatic beta cell mass during pregnancy. , 2010 .

[43]  Yun Li,et al.  METAL: fast and efficient meta-analysis of genomewide association scans , 2010, Bioinform..

[44]  E. Peschke,et al.  New evidence for a role of melatonin in glucose regulation. , 2010, Best practice & research. Clinical endocrinology & metabolism.

[45]  Yusuke Nakamura,et al.  A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B , 2010, Nature Genetics.

[46]  P. Butler,et al.  Cyclin-Dependent Kinase 5 Promotes Pancreatic β-Cell Survival via Fak-Akt Signaling Pathways , 2011, Diabetes.

[47]  David Haussler,et al.  ENCODE whole-genome data in the UCSC genome browser (2011 update) , 2010, Nucleic Acids Res..

[48]  H. Jang.  Gestational Diabetes in Korea: Incidence and Risk Factors of Diabetes in Women with Previous Gestational Diabetes , 2011, Diabetes & metabolism journal.

[49]  D. Haussler,et al.  ENCODE whole-genome data in the UCSC Genome Browser: update 2012 , 2011, Nucleic Acids Res..

[50]  Wei Lu,et al.  Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians , 2011, Nature Genetics.

[51]  D. Coustan,et al.  Gestational diabetes mellitus. , 2013, Clinical chemistry.