Genetics of type 2 diabetes: the GWAS era and future perspectives [Review].

Genome-wide association studies (GWAS) have facilitated a substantial and rapid rise in the number of confirmed genetic susceptibility variants for type 2 diabetes (T2D). Approximately 40 variants have been identified so far, many of which were discovered through GWAS. This success has led to widespread hope that the findings will translate into improved clinical care for the increasing numbers of patients with diabetes. Potential areas or clinical translation include risk prediction and subsequent disease prevention, pharmacogenetics, and the development of novel therapeutics. However, the genetic loci so far identified account for only a small fraction (approximately 10%) of the overall heritable risk for T2D. Uncovering the missing heritability is essential to the progress of T2D genetic studies and to the translation of genetic information into clinical practice.

[1]  D. Mccormick.  Sequence the Human Genome , 1986, Bio/Technology.

[2]  J. Lehmann,et al.  An Antidiabetic Thiazolidinedione Is a High Affinity Ligand for Peroxisome Proliferator-activated Receptor γ (PPARγ) (*) , 1995, The Journal of Biological Chemistry.

[3]  J. Lehmann,et al.  An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). , 1995, The Journal of biological chemistry.

[4]  L. Groop,et al.  Metabolic Consequences of a Family History of NIDDM (The Botnia Study): Evidence for Sex-Specific Parental Effects , 1996, Diabetes.

[5]  P. Poulsen,et al.  Heritability of Type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance – a population-based twin study , 1999, Diabetologia.

[6]  E S Lander,et al.  The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. , 2000, Nature genetics.

[7]  Eric S. Lander,et al.  The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes , 2000, Nature Genetics.

[8]  T. Kadowaki,et al.  The Pro12Ala Polymorphism in PPAR γ2 May Confer Resistance to Type 2 Diabetes , 2000 .

[9]  Tom H. Lindner,et al.  Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus , 2000, Nature Genetics.

[10]  T. Kadowaki,et al.  The Pro12Ala polymorphism in PPAR gamma2 may confer resistance to type 2 diabetes. , 2000, Biochemical and biophysical research communications.

[11]  M. Kasuga,et al.  The Pro12 -->Ala substitution in PPAR-gamma is associated with resistance to development of diabetes in the general population: possible involvement in impairment of insulin secretion in individuals with type 2 diabetes. , 2001, Diabetes.

[12]  G I Bell,et al.  Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. , 2001, The New England journal of medicine.

[13]  Timothy B. Stockwell,et al.  The Sequence of the Human Genome , 2001, Science.

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

[15]  J. Gulcher,et al.  Localization of a susceptibility gene for type 2 diabetes to chromosome 5q34-q35.2. , 2003, American journal of human genetics.

[16]  M. McCarthy,et al.  Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. , 2003, Diabetes.

[17]  A. Hattersley,et al.  Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy. , 2004, Diabetes.

[18]  A. Favier,et al.  Identification and cloning of a beta-cell-specific zinc transporter, ZnT-8, localized into insulin secretory granules. , 2004, Diabetes.

[19]  M. Olivier.  A haplotype map of the human genome , 2003, Nature.

[20]  Lu Qi,et al.  Variant of Transcription Factor 7-Like 2 (TCF7L2) Gene and the Risk of Type 2 Diabetes in Large Cohorts of U.S. Women and Men , 2006, Diabetes.

[21]  H. Stefánsson,et al.  Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes , 2006, Nature Genetics.

[22]  David M Nathan,et al.  TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. , 2006, The New England journal of medicine.

[23]  K. Silver,et al.  Polymorphisms in the Transcription Factor 7-Like 2 (TCF7L2) Gene Are Associated With Type 2 Diabetes in the Amish , 2006, Diabetes.

[24]  Steven Wiltshire,et al.  Association Analysis of 6,736 U.K. Subjects Provides Replication and Confirms TCF7L2 as a Type 2 Diabetes Susceptibility Gene With a Substantial Effect on Individual Risk , 2006, Diabetes.

[25]  Kristin G Ardlie,et al.  Common Single Nucleotide Polymorphisms in TCF7L2 Are Reproducibly Associated With Type 2 Diabetes and Reduce the Insulin Response to Glucose in Nondiabetic Individuals , 2006, Diabetes.

[26]  Laura J. Scott,et al.  Association of Transcription Factor 7-Like 2 (TCF7L2) Variants With Type 2 Diabetes in a Finnish Sample , 2006, Diabetes.

[27]  P. Froguel,et al.  A genetic variation of the transcription factor 7-like 2 gene is associated with risk of type 2 diabetes in the Japanese population , 2007, Diabetologia.

[28]  D. Melzer,et al.  A common haplotype of the glucokinase gene alters fasting glucose and birth weight: association in six studies and population-genetics analyses. , 2006, American journal of human genetics.

[29]  R. Scharfmann,et al.  Transcription Factor TCF7L2 Genetic Study in the French Population , 2006, Diabetes.

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

[31]  M. McCarthy,et al.  Common variants in WFS1 confer risk of type 2 diabetes , 2007, Nature Genetics.

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

[33]  P. Froguel,et al.  Variations in the HHEX gene are associated with increased risk of type 2 diabetes in the Japanese population , 2007, Diabetologia.

[34]  M. McCarthy,et al.  Common Variants of the Novel Type 2 Diabetes Genes CDKAL1 and HHEX/IDE Are Associated With Decreased Pancreatic β-Cell Function , 2007, Diabetes.

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

[36]  Y. Iwamoto,et al.  Replication study for the association of TCF7L2 with susceptibility to type 2 diabetes in a Japanese population , 2007, Diabetologia.

[37]  D. Gudbjartsson,et al.  Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes , 2007, Nature Genetics.

[38]  T. Hansen,et al.  Studies of Association of Variants Near the HHEX, CDKN2A/B, and IGF2BP2 Genes With Type 2 Diabetes and Impaired Insulin Release in 10,705 Danish Subjects , 2007, Diabetes.

[39]  H. Shiota,et al.  SNPs in the KCNJ11-ABCC8 gene locus are associated with type 2 diabetes and blood pressure levels in the Japanese population , 2007, Journal of Human Genetics.

[40]  Kristin G Ardlie,et al.  Evaluation of Common Variants in the Six Known Maturity-Onset Diabetes of the Young (MODY) Genes for Association With Type 2 Diabetes , 2007, Diabetes.

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

[42]  N. Stefan,et al.  Polymorphisms within Novel Risk Loci for Type 2 Diabetes Determine β-Cell Function , 2007, PloS one.

[43]  K. Taylor,et al.  Genome-Wide Association , 2007, Diabetes.

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

[45]  D. Lawlor,et al.  Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels. , 2008, The Journal of clinical investigation.

[46]  Jean Tichet,et al.  A Polymorphism Within the G6PC2 Gene Is Associated with Fasting Plasma Glucose Levels , 2008, Science.

[47]  M. McCarthy,et al.  Genome-wide association studies for complex traits: consensus, uncertainty and challenges , 2008, Nature Reviews Genetics.

[48]  L. Groop,et al.  Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus , 2008, Nature Genetics.

[49]  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.

[50]  T. Sanke,et al.  Polymorphisms in the IDE-KIF11-HHEX gene locus are reproducibly associated with type 2 diabetes in a Japanese population. , 2008, The Journal of clinical endocrinology and metabolism.

[51]  E. Kang,et al.  Association between polymorphisms in SLC30A8, HHEX, CDKN2A/B, IGF2BP2, FTO, WFS1, CDKAL1, KCNQ1 and type 2 diabetes in the Korean population , 2008, Journal of Human Genetics.

[52]  K. Mossman.  The Wellcome Trust Case Control Consortium, U.K. , 2008 .

[53]  Nicholette D. Palmer,et al.  Quantitative Trait Analysis of Type 2 Diabetes Susceptibility Loci Identified From Whole Genome Association Studies in the Insulin Resistance Atherosclerosis Family Study , 2008, Diabetes.

[54]  F. Zhang,et al.  A common variant in the FTO gene is associated with obesity in the Uyghur population , 2008, Journal of endocrinological investigation.

[55]  Yusuke Nakamura,et al.  Association of CDKAL1, IGF2BP2, CDKN2A/B, HHEX, SLC30A8, and KCNJ11 With Susceptibility to Type 2 Diabetes in a Japanese Population , 2008, Diabetes.

[56]  T. Hansen,et al.  SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations , 2008, Nature Genetics.

[57]  Mark I. McCarthy,et al.  Assessing the Combined Impact of 18 Common Genetic Variants of Modest Effect Sizes on Type 2 Diabetes Risk , 2008, Diabetes.

[58]  Peter Almgren,et al.  Clinical risk factors, DNA variants, and the development of type 2 diabetes. , 2008, The New England journal of medicine.

[59]  R. D'Agostino,et al.  Genotype score in addition to common risk factors for prediction of type 2 diabetes. , 2008, The New England journal of medicine.

[60]  M. Kasuga,et al.  Replication of genome-wide association studies of type 2 diabetes susceptibility in Japan. , 2008, The Journal of clinical endocrinology and metabolism.

[61]  Weiping Jia,et al.  Diabetes in Asia: epidemiology, risk factors, and pathophysiology. , 2009, JAMA.

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

[63]  Jean Tichet,et al.  Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia , 2009, Nature Genetics.

[64]  J. Chan,et al.  Construction of a prediction model for type 2 diabetes mellitus in the Japanese population based on 11 genes with strong evidence of the association , 2009, Journal of Human Genetics.

[65]  Zhuoyou Chen,et al.  Variants in KCNQ1 are associated with susceptibility to type 2 diabetes in the population of mainland China , 2009, Diabetologia.

[66]  E. Tai,et al.  Genetic Variation in KCNQ1 Associates With Fasting Glucose andβ-Cell Function , 2009, Diabetes.

[67]  J. Florez,et al.  The clinical application of genetic testing in type 2 diabetes: a patient and physician survey , 2009, Diabetologia.

[68]  E. Tai,et al.  Genetic variation in KCNQ1 associates with fasting glucose and beta-cell function: a study of 3,734 subjects comprising three ethnicities living in Singapore. , 2009, Diabetes.

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

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

[71]  K. Xiang,et al.  Variations in KCNQ1 are associated with type 2 diabetes and beta cell function in a Chinese population , 2009, Diabetologia.

[72]  P. Elliott,et al.  Genetic Variant in HK1 Is Associated With a Proanemic State and A1C but Not Other Glycemic Control–Related Traits , 2009, Diabetes.

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

[74]  S. Humphries,et al.  Utility of genetic and non-genetic risk factors in prediction of type 2 diabetes: Whitehall II prospective cohort study , 2010, BMJ : British Medical Journal.

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

[76]  Richard W. Grant,et al.  Genetic Risk Reclassification for Type 2 Diabetes by Age Below or Above 50 Years Using 40 Type 2 Diabetes Risk Single Nucleotide Polymorphisms , 2010, Diabetes Care.

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

[78]  大森 慎太郎.  Replication study for the association of new meta-analysis-derived risk loci with susceptibility to type 2 diabetes in 6,244 Japanese individuals , 2010 .

[79]  Y. J. Kim,et al.  Identification of New Genetic Risk Variants for Type 2 Diabetes , 2010, PLoS genetics.

[80]  Alex Doney,et al.  Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge , 2010, Nature Genetics.

[81]  K. Kohara,et al.  The GCKR rs780094 polymorphism is associated with susceptibility of type 2 diabetes, reduced fasting plasma glucose levels, increased triglycerides levels and lower HOMA-IR in Japanese population , 2010, Journal of Human Genetics.

[82]  D. Altshuler,et al.  A map of human genome variation from population-scale sequencing , 2010, Nature.

[83]  T. Hansen,et al.  The diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 variant impairs glucose-stimulated insulin response in 5,722 non-diabetic Danish individuals , 2011, Diabetologia.

[84]  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.

[85]  Peter Donnelly,et al.  Edinburgh Research Explorer Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes , 2022 .

[86]  E. Lander.  Initial impact of the sequencing of the human genome , 2011, Nature.

[87]  M. Guyer,et al.  Charting a course for genomic medicine from base pairs to bedside , 2011, Nature.