Biochemical Genetics

, Volume 56, Issue 1–2, pp 22–55 | Cite as

Genetic Approaches to the Study of Gene Variants and Their Impact on the Pathophysiology of Type 2 Diabetes

  • Monica SzaboEmail author
  • Beáta Máté
  • Katalin Csép
  • Theodora Benedek


Diabetes mellitus is an incurable progressive disease, characterized by elevated blood glucose levels, which lead to the development of micro- and macrovascular complications. Although the etiopathology of the disease remains unclear, it seems to be multifactorial, with an important interaction between genetics and environmental causes. Currently, the genetics of type 2 diabetes (T2D) is poorly understood. The recent advance of the genetic technologies and with a better understanding of genetics, more than 120 distinct genetic loci, with more than 150 variants, have been identified that may be involved in the pathogenesis of T2D. However, as these variants can account for only approximately 20% of the heritability of T2D, there is an obvious need for additional approaches to identify susceptibility genes or genetic mechanisms involved in the development of this disease. There is a growing number of genes found to be related to T2D; however, their individual impact on the pathogenesis of the disease appears to be low, while silencing of protective genes may also contribute to the development of this disease. The present review attempts to summarize our current knowledge in the field of genetics of T2D, highlighting the possible practical applications for each approach.


Type 2 diabetes-associated genes Gene–gene interaction Protective genes Genetic Risk network 


  1. Albrechtsen A, Grarup N, Li Y, Sparso T, Tian G, Cao H, Jiang T, Kim SY, Korneliussen T, Li Q et al (2013) Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes. Diabetologia 56:298–310. PubMedCrossRefGoogle Scholar
  2. Ali O (2013) Genetics of type 2 diabetes. World J Diabetes 15(4):114–123. CrossRefGoogle Scholar
  3. Asahara S, Etoh H, Inoue H, Teruyama K, Shibutani Y, Ihara Y, Kawada Y, Bartolome A, Hashimoto N, Matsuda T, Koyanagi-Kimura M, Kanno A, Hirota Y, Hosooka T, Nagashima K, Nishimura W, Matsumoto M, Higgins M, Yasuda K, Inagaki N, Seino S, Kasuga M, Kido Y (2015) Paternal allelic mutation at the Kcnq1 locus reduces pancreatic β-cell mass by epigenetic modification of Cdkn1c. PNAS 112(27):8332–8337. PubMedPubMedCentralCrossRefGoogle Scholar
  4. Baier LJ, Muller YL, Remedi MS et al (2015) ABCC8 R1420H loss-of-function variant in a Southwest American Indian community: association with increased birth weight and doubled risk of type 2 diabetes. Diabetes 64(12):4322–4332. PubMedPubMedCentralCrossRefGoogle Scholar
  5. Basile KJ, Guy VC, Schwartz S, Grant SF (2014) Overlap of genetic susceptibility to type 1 diabetes, type 2 diabetes, and latent autoimmune diabetes in adults. CurrDiab Rep 14(11):550–555. Google Scholar
  6. Boj SF, van Es JH, Huch M, Li VS, José A, Hatzis P, Mokry M, Haegebarth A, van den Born M, Voshol Chambon P, Dor Y, Cuppen E, Fillat C, Clevers H (2012) Diabetes risk gene and Wnt effector Tcf7l2/TCF4 controls hepatic response to perinatal and adult metabolic demand. Cell 151(7):1595–1607. PubMedCrossRefGoogle Scholar
  7. Bouatia-Naji N, Bonnefond A, Cavalcanti-Proenca C et al (2009) A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk. Nat Genet 41(1):89–94. PubMedCrossRefGoogle Scholar
  8. Brown AE, Williams CJ, Rocha N, Richards JB, Semple R, Walker M (2010) Expression of ARL15, a type 2 diabetes risk variant, is increased in cultured human skeletal muscle cells from insulin-resistant type 2 diabetes patients. Diabetologia 53(1 Supplement):S125–S126Google Scholar
  9. Cantrell QW, Silva J, Nguyen C, Hildebrand LD, Rivas T, Shoemaker R, Rojas A, Cuajungco MP (2016) Transmembrane (TMEM)-163 protein is a novel zinc transporter. FASEB J 30(1 Supplement):878Google Scholar
  10. Cauchi S, Meyre D, Durand E, Proença C, Marre M, Hadjadj S, Choquet H, De Graeve F, Gaget S, Allegaert F, Delplanque J, Permutt MA, Wasson J, Blech I, Charpentier G, Balkau B, Vergnaud AC, Czernichow S, Patsch W, Chikri M, Glaser B, Sladek R, Froguel P (2008) Post genome-wide association studies of novel genes associated with type 2 diabetes show gene–ene interaction and high predictive value. PLoS ONE 3(5):e2031. PubMedPubMedCentralCrossRefGoogle Scholar
  11. Chen R, Mias GI, Li-Pook-Than J, Jiang L, Lam HY, Chen R, Miriami E, Karczewski KJ, Hariharan M, Dewey FE, Cheng Y, Clark MJ, Im H, Habegger L, Balasubramanian S, O’Huallachain M, Dudley JT, Hillenmeyer S, Haraksingh R, Sharon D, Euskirchen G, Lacroute P, Bettinger K, Boyle AP, Kasowski M, Grubert F, Seki S, Garcia M, Whirl-Carrillo M, Gallardo M, Blasco MA, Greenberg PL, Snyder P, Klein TE, Altman RB, Butte AJ, Ashley EA, Gerstein M, Nadeau KC, Tang H, Snyder M (2012) Personal omics profiling reveals dynamic molecular and medical phenotypes. Cell 148(6):1293–1307PubMedPubMedCentralCrossRefGoogle Scholar
  12. Chen G, Zhang Z, Adebamowo SN, Liu G, Adeyemo A, Zhou Y et al (2017) Common and rare exonic MUC5B variants associated with type 2 diabetes in Han Chinese. PLoS ONE 12(3):e0173784. PubMedPubMedCentralCrossRefGoogle Scholar
  13. Cho YS, Chen CH, Hu C, Long J, Ong RT, Sim X, Takeuchi F, Wu Y, Go MJ, Chang Yamauchi T, Kwak SH, Ma RCW, Yamamoto K, Adair LS, Aung T, Cai Q et al (2012) Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in East Asians. Nat Genet 44(1):67–72. CrossRefGoogle Scholar
  14. Connor SC, Hansen MK, Corner A, Smith RF, Ryan TE (2010) Integration of metabolomics and transcriptomics data to aid biomarker discovery in Type 2 diabetes. Mol BioSyst 6(5):909–912PubMedCrossRefGoogle Scholar
  15. Connor AE, Baumgartner RN, Baumgartner KB, Kerber RA, Pinkston C, John EM, Torres-Mejia G, Hines L, Giuliano A, Wolff RK, Slattery ML (2012) Associations between TCF7L2 polymorphisms and risk of breast cancer among Hispanic and non-Hispanic white women: the Breast Cancer Health Disparities Study. Breast Cancer Res Treat 136(2):593–602. PubMedPubMedCentralCrossRefGoogle Scholar
  16. Consortium Sigma Type 2 Diabetes, Williams AL, Jacobs SB, Moreno-Macias H, Huerta-Chagoya A, Churchhouse C, Marquez-Luna C, Garcia-Ortiz H, Gomez-Vazquez MJ, Burtt NP, Aguilar-Salinas CA, González-Villalpando C, Florez JC, Orozco L, Haiman CA, Tusié-Luna T, Altshuler D (2014) Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico. Nature 506(7486):97–101. Google Scholar
  17. Dai XP, Huang Q, Yin JY, Guo Y, Gong CZ, Lei MX, Jiang TJ, Zhou HH, Liu ZQ (2012) KCNQ1 gene polymorphisms are associated with the therapeutic efficacy of repaglinide in Chinese Type 2 diabetic patients. ClinExpPharmacolPhysiol 39(5):462–468. Google Scholar
  18. Daly AK, Day CP (2001) Candidate gene case-control association studies: advantages and potential pitfalls. Br J Clin Pharmacol 52(5):489–499. PubMedPubMedCentralCrossRefGoogle Scholar
  19. Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes of BioMedical Research, Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, Chen H, Roix JJ, Kathiresan S, Hirschhorn JN, Daly MJ, Hughes TE, Groop L et al (2007) Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316(5830):1331–1336. CrossRefGoogle Scholar
  20. DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium, South Asian Type 2 Diabetes (SAT2D) Consortium, Mexican American Type 2 Diabetes (MAT2D) Consortium, Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples (T2D-GENES) Consortium, Go MJ, Zhang W, Below JE, Gaulton KJ et al (2014) Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nat Genet 46(3):234–244. CrossRefGoogle Scholar
  21. Dorajoo R, Liu J, Boehm BO (2015) Genetics of type 2 diabetes and clinical utility. Genes 6(2):372–384. PubMedPubMedCentralCrossRefGoogle Scholar
  22. Dupuis J, Langenberg C, Prokopenko I et al (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42(2):105–116. PubMedPubMedCentralCrossRefGoogle Scholar
  23. Ehret GB, Munroe PB, Rice KM, Bochud M, International Consortium for Blood Pressure Genome-Wide Association Studies et al (2011) Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478(7367):103–109. PubMedCrossRefGoogle Scholar
  24. Estrada K, Aukrust I, Bjørkhaug L, SIGMA Type 2 Diabetes Consortium et al (2014) Association of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population. JAMA 311(22):2305–2314PubMedCrossRefGoogle Scholar
  25. Farook V, Coletta DK, Puppala S, Schneider J, Chittor G, DeFronzo RA et al (2013) Linkage of Type 2 diabetes on chromosome 9p24 in Mexican Americans: additional evidence from the Veterans Administration Genetic Epidemiology Study (VAGES). Hum Hered 76(1):36–46. PubMedPubMedCentralCrossRefGoogle Scholar
  26. Ferreira MA (2004) Linkage analysis: principles and methods for the analysis of human quantitative traits. Twin Res 7(5):513–530. PubMedCrossRefGoogle Scholar
  27. Flannick J, Thorleifsson G, Beer NL, Jacobs SB, Grarup N, Burtt NP, Mahajan A, Fuchsberger C, Atzmon G, Benediktsson R et al (2014) Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nat Genet 46(4):357–363. PubMedPubMedCentralCrossRefGoogle Scholar
  28. Fuchsberger C, Flannick J, Teslovich TM, Mahajan A, Agarwala V et al (2016) The genetic architecture of type 2 diabetes. Nature 536(7614):41–47. PubMedPubMedCentralCrossRefGoogle Scholar
  29. Furuta H, Furuta M, Sanke T, Ekawa K, Hanabusa T, Nishi M, Sasaki H, Nanjo K (2002) Nonsense and missense mutations in the human hepatocyte nuclear factor-1 beta gene (TCF2) and their relation to type 2 diabetes in Japanese. J ClinEndocrinolMetab 87(8):3859–3863. Google Scholar
  30. Gan W, Walters RG, Holmes MV, Bragg F, Millwood I, Banasik K, Chen Y, Du H, Iona A, Mahajan A, Yang L, Bian Z, Guo Y, Clarke RJ, Li L, McCarthy M, Chen Z, on behalf of the China Kadoorie Biobank Collaborative Group (2016) Evaluation of type 2 diabetes genetic risk variants in Chinese adults: findings from 93,000 individuals from the China Kadoorie Biobank. Diabetologia 59(4):1446–1457. PubMedPubMedCentralCrossRefGoogle Scholar
  31. Gloyn AL, Weedon MN, Owen KR, Turner MJ, Knight BA, Hitman G, Walker M, Levy JC, Sampson M, Halford S et al (2003) Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir62 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23 K variant is associated with type 2 diabetes. Diabetes 52(2):568–572. PubMedCrossRefGoogle Scholar
  32. Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A et al (2006) Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 38(3):320–323. PubMedCrossRefGoogle Scholar
  33. Gu HF (2015) Genetic, epigenetic and biological effects of zinc transporter (SLC30A8) in type 1 and type 2 diabetes. Curr Diabetes Rev 12:1–9CrossRefGoogle Scholar
  34. Gudmundsson J, Sulem P, Steinthorsdottir V, Bergthorsson JT, Thorleifsson G, Manolescu A, Rafnar T, Gudbjartsson D, Agnarsson BA, Baker A et al (2007) Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat Genet 39(8):977–983. PubMedCrossRefGoogle Scholar
  35. Hale PJ, López-Yunez AM, Chen JY (2012) Genome-wide meta-analysis of genetic susceptible genes for type 2 diabetes. BMC SystBiol 6(3):S16. CrossRefGoogle Scholar
  36. Hanson RL, Rong R, Kobes S, Muller YL, Weil EI, Curtis JM, Nelson RG, Baier LG (2015) Role of established type 2 diabetes–susceptibility genetic variants in a high prevalence American Indian Population. Diabetes 64(12):2646–2657. PubMedPubMedCentralCrossRefGoogle Scholar
  37. Hara K, Fujita H, Johnson TA et al (2014) Genome-wide association study identifies three novel loci for type 2 diabetes. Hum Mol Genet 23(1):239–246. PubMedCrossRefGoogle Scholar
  38. Hegele RA, Cao H, Harris SB, Hanley AJ, Zinman B (1999) The hepatic nuclear factor-1alpha G319S variant is associated with early-onset type 2 diabetes in Canadian Oji-Cree. J ClinEndocrinolMetab 84(3):1077–1082Google Scholar
  39. Hood L, Flores M (2012) A personal view on systems medicine and the emergence of proactive P4 medicine: predictive, preventive, personalized and participatory. N Biotechnol 29(6):613–624PubMedCrossRefGoogle Scholar
  40. Horikawa Y, Oda N, Cox NJ, Li X, Orho-Melander M, Hara M, Hinokio Y et al (2000) Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 26(2):163–175. PubMedCrossRefGoogle Scholar
  41. Hu C, Wang Zhang R et al (2009) Variations in KCNQ1 are associated with type 2 diabetes and beta cell function in a Chinese population. Diabetologia 52(7):1322–1325. PubMedCrossRefGoogle Scholar
  42. Imamura M, Maeda S, Yamauchi T, Hara K, Yasuda K et al (2012) A single nucleotide polymorphism in ANK1 is associated with susceptibility to type 2 diabetes. Hum Mol Genet 21(13):3042–3049. PubMedCrossRefGoogle Scholar
  43. International Diabetes Federation (2015) IDF Diabetes Atlas, 7th ed. Brussels, Belgium: International Diabetes Federation. Accessed 14 January 2017
  44. Jang WY, Bae KB, Kim SH, Yu DH, Kim HJ, Rae Y et al (2014) Overexpression of Jazf1 reduces body weight gain and regulates lipid metabolism in high fat diet. Biochem Biophys Res Commun 444(3):296–301. PubMedCrossRefGoogle Scholar
  45. Kaprio J, Tuomilehto J, Koskenvuo M, Romanov K, Reunanen A, Eriksson J, Stengard J, Kesaniemi YA (1992) Concordance for type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finnland. Diabetologia 35(11):1060–1067. PubMedCrossRefGoogle Scholar
  46. Kitabchi AE, Temprosa M, Knowler WC et al (2005) Role of insulin secretion and sensitivity in the evolution of type 2 diabetes in the diabetes prevention program: effects of lifestyle intervention and metformin. Diabetes 54(8):2404–2414PubMedCrossRefGoogle Scholar
  47. Klonoff DC (2008) Personalized medicine for diabetes. J Diabetes Sci Technol 2(3):335–341PubMedPubMedCentralCrossRefGoogle Scholar
  48. Köbberling J, Tillil H (1982) Empirical risk figures for first-degree relatives of non-insulin dependent diabetics. In: Köbberling J, Tillil H (eds) The genetics of diabetes mellitus. Academic Press, London, pp 201–209Google Scholar
  49. Kong A, Steinthorsdottir V, Masson G, Thorleifsson G, Sulem P, Besenbacher S, Jonasdottir A, Sigurdssonet A et al (2009) Parental origin of sequence variants associated with complex diseases. Nature 462(7275):868–874. PubMedPubMedCentralCrossRefGoogle Scholar
  50. Kong Y, Sharma RB, Nwosu BU, Alonso LC (2016) Islet biology, the CDKN2A/B locus and type 2 diabetes risk. Diabetologia 59(8):1579–1583. PubMedPubMedCentralCrossRefGoogle Scholar
  51. Kooner JS, Saleheen D, Sim X, Sehmi J, Zhang W, Frossard P, Been LF, Chia KS, Dimas AS, Hassanali N et al (2011) Genome-wide association study in individuals of south Asian ancestry identifies six new type 2 diabetes susceptibility loci. Nat Genet 43:984–989. PubMedPubMedCentralCrossRefGoogle Scholar
  52. Kwak SH, Jung CH, Ahn CH, Park J, Chae J et al (2016) Clinical whole exome sequencing in early onset diabetes patients. Diabetes Res Clin Pract 122(12):71–77. PubMedCrossRefGoogle Scholar
  53. Le Fur S, Le Stunff C, Bougnères P (2002) Increased insulin resistance in obese children who have both 972 IRS-1 and 1057 IRS-2 polymorphisms. Diabetes 51(3):S304–S307PubMedCrossRefGoogle Scholar
  54. Lefebvre B, Vandewalle B, Balavoine AS, Queniat G, Moerman E, Vantyghem MC, Le Bacquer O, Gmyr V, Pawlowski V, Kerr-Conte J et al (2012) Regulation and functional effects of ZNT8 in human pancreatic islets. J Endocrinol 214(8):225–232. PubMedCrossRefGoogle Scholar
  55. Li X, Li Y, Song B, Guo S, Chu S, Jia N, Niu W (2012) Hematopoietically-expressed homeobox gene three widely-evaluated polymorphisms and risk for diabetes: a meta-analysis. PLoS ONE 7:e49917PubMedPubMedCentralCrossRefGoogle Scholar
  56. Li H, Gan W, Lu L, Dong X, Han X, Hu C, Yang Z, Sun L, Bao W, Li P, He M, Sun L, Wang Y, Zhu J, Ning Q, Tang Y, Zhang R, Wen J et al (2013) A genome-wide association study identifies RK5 and RASGRP1 as type 2 diabetes loci in Chinese Hans. Diabetes 62(1):291–298. PubMedCrossRefGoogle Scholar
  57. Li J, Wei J, Xu P, Yan M, Li J, Chen Z, Jin T (2016) Impact of diabetes-related gene polymorphisms on the clinical characteristics of type 2 diabetes Chinese Han population. Oncotarget 7(51):85464–85471. PubMedPubMedCentralGoogle Scholar
  58. Li Q, Tang T, Jiang W, Zhang R, Chen M, Yin J et al (2017) Polymorphisms of the KCNQ1 gene are associated with the therapeutic responses of sulfonylureas in Chinese patients with type 2 diabetes. Acta Pharmacol Sin 38(1):80–89. PubMedCrossRefGoogle Scholar
  59. Liu S, Song Y (2010) Building genetic scores to predict risk of complex diseases in humans: is It possible? Diabetes 59(11):2729–2731. PubMedPubMedCentralCrossRefGoogle Scholar
  60. Liu NJ, Xiong Q, Wu HH, Li YL, Yang Z, Tao XM, Lu B, Hu RM, Wang XC, Wen J (2016) The association analysis polymorphism of CDKAL1 and diabetic retinopathy in Chinese Han population. Int J Ophthalmol 9(5):707–712. PubMedPubMedCentralGoogle Scholar
  61. Look AHEAD Research Group (2015) Prospective association of a genetic risk score and lifestyle intervention with cardiovascular morbidity and mortality among individuals with type 2 diabetes: the Look AHEAD randomised controlled trial. Diabetologia 58(8):1803–1813. CrossRefGoogle Scholar
  62. Lyssenko V, Jonsson A, Almgren P et al (2008) Clinical risk factors, DNA variants and the development of Type 2 diabetes. N Eng J Med 359:2220–2232. CrossRefGoogle Scholar
  63. Ma RC, Hu C, Tam CH et al (2013) Genome-wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4. Diabetologia 56(6):1291–1305. PubMedPubMedCentralCrossRefGoogle Scholar
  64. Mega JL, Stitziel NO, Smith JG, Chasman DI, Caulfield MJ, Devlin JJ, Nordio F, Hyde CL, Cannon CP, Sacks FM, Poulter NR, Sever PS, Ridker PM, Braunwald E, Melander O, Kathiresan S, Sabatine MS (2015) Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials. Lancet 385(9984):2264–2271. PubMedPubMedCentralCrossRefGoogle Scholar
  65. Meigs JB, Cupples LA, Wilson PW (2000) Parental transmission of type 2 diabetes: the Framingham offspring study. Diabetes 49(12):2201–2207PubMedCrossRefGoogle Scholar
  66. Moltke I, Grarup N, Jørgensen ME, Bjerregaard P, Treebak JT, Fumagalli M et al (2014) A common Greenlandic TBC1D4 variant confers muscle insulin resistance and type 2 diabetes. Nature 512(7513):190–193. PubMedCrossRefGoogle Scholar
  67. Morris AP, Voight BF, Teslovich TM, Ferreira T, Segre AV, Steinthorsdottir V, Strawbridge RJ, Khan H, Grallert H, Mahajan A et al (2012) Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet 44(9):981–990. PubMedPubMedCentralCrossRefGoogle Scholar
  68. Najmi LA, Aukrust I, Flannick J, Molnes J, Burtt N et al (2017) Functional investigations of HNF1A identify rare variants as risk factors for type 2 diabetes in the general population. Diabetes 66(2):335–346. PubMedCrossRefGoogle Scholar
  69. Ng MC, Shriner D, Chen BH, Li J, Chen WM, Guo X, Liu J, Bielinski SJ, Yanek LR, Nalls MA et al (2014) Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes. PLoS Genet 10:e1004517. PubMedPubMedCentralCrossRefGoogle Scholar
  70. Ohshige T, Tanka Y, Araki S et al (2010) A single nucleotide polymorphism in KCNQ1 is associated with susceptibility to diabetic nephropathy in Japanese subject with type 2 diabetes. Diabetes Care 33(4):842–846. PubMedPubMedCentralCrossRefGoogle Scholar
  71. Palmer ND, McDonough CW, Hicks PJ, Roh BH, Wing MR, An SS, Hester JM, Cooke JN, Bostrom MA, Rudock ME, Talbert ME, Lewis JP, DIAGRAM Consortium; MAGIC Investigators, Ferrara A et al (2012) A genome-wide association search for type 2 diabetes genes in African Americans. PLoS ONE 7(1):e29202. PubMedPubMedCentralCrossRefGoogle Scholar
  72. Parra EJ, Below JE, Krithika S, Valladares A, Barta JL, Cox NJ, Hanis CL, Wacher N, Garcia-Mena J, Hu P et al (2011) Genome-wide association study of type 2 diabetes in a sample from Mexico City and a meta-analysis of a Mexican-American sample from star county,Texas. Diabetologia 54:2038–2046. PubMedCrossRefGoogle Scholar
  73. Pascoe L, Tura A, Patel SK, Ibrahim IM, Ferrannini E, The RISC Consortium, The UK Type 2 Diabetes Genetics Consortium, Zeggini E, Weedon MN, Mari A, Hattersley AT, McCarthy MI, Frayling TM, Walker M (2007) Common variants of the novel type 2 diabetes genes, CDKAL1 and HHEX/IDE, are associated with decreased pancreatic β-cell function. Diabetes 56(12):3101–3104. PubMedCrossRefGoogle Scholar
  74. Patnala R, Clements J, Batra J (2013) Candidate gene association studies: a comprehensive guide to useful in silicotools. BMC Genet 14:39. PubMedPubMedCentralCrossRefGoogle Scholar
  75. Peng F, Hu D, Gu C, Xiaobo L et al (2013) The relationship between five widely-evaluated variants in CDKN2A/B and CDKAL1 genes and the risk of type 2 diabetes: a meta-analysis. Gene 531(2):435–443. PubMedCrossRefGoogle Scholar
  76. Perry JRB, Voight BF, Yengo L, Amin N, Dupuis J et al (2012) Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases. PLoS Genet 8(5):e1002741. PubMedPubMedCentralCrossRefGoogle Scholar
  77. Phillips PC (2008) Epistasis—the essential role of gene interactions in the structure and evolution of genetic systems. Nat Rev Genet 9:855–867. PubMedPubMedCentralCrossRefGoogle Scholar
  78. Poulsen P, Kyvik KO, Vaag A, Beck-Nielsen H (1999) Heritability of type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance-a population-based twin study. Diabetologia 42(2):139–145PubMedCrossRefGoogle Scholar
  79. Prasad RB, Groop L (2015) Genetics of Type 2 Diabetes- Pitfalls and Possibilities. Genes 6(1):87–123. PubMedPubMedCentralCrossRefGoogle Scholar
  80. Prasad RB, Lessmark A, Almgren P et al (2016) Excess maternal transmission of variants in the THADA gene to offspring with type 2 diabetes. Diabetologia 59:1702. PubMedCrossRefGoogle Scholar
  81. Prokopenko I, Langenberg C, Florez JC, Saxena R, Soranzo N, Thorleifsson G, Loos RJ, Manning AK, Jackson AU, Aulchenko Y et al (2009) Variants in MTNR1B influence fasting glucose levels. Nat Genet 41:77–81. PubMedCrossRefGoogle Scholar
  82. Qi L, Cornelis MC, Kraft P et al (2010) Genetic variants at 2q24 are associated with susceptibility to type 2 diabetes. Hum Mol Genet 19(13):2706–2715. PubMedPubMedCentralCrossRefGoogle Scholar
  83. Ren Q, Han X, Zhang S, Cai X, Ji L (2016) Combined influence of genetic variants and gene–gene interaction on sulfonylurea efficacy in type 2 diabetic patients. Exp Clin Endocrinol Diabetes 124(3):157–162. PubMedCrossRefGoogle Scholar
  84. Rosengren AH, Jokubka R, Tojjar D, Granhall C, Hansson O, Li DQ, Nagaraj V, Reinbothe TM, Tuncel J, Eliasson L et al (2010) Overexpression of alpha2a-adrenergic receptors contributes to type 2 diabetes. Science 327:217–220. PubMedCrossRefGoogle Scholar
  85. Ruchat SM, Weisnagel SJ, Vohl MC, RankinenT Bouchard C, Pérusse L (2009) Evidence for interaction between PPARG Pro12Ala and PPARGC1A Gly482Ser polymorphisms in determining type 2 diabetes intermediate phenotypes in overweight subjects. Exp Clin Endocrinol Diabetes 117:455–459. PubMedCrossRefGoogle Scholar
  86. Rung J, Cauchi S, Albrechtsen A, Shen L, Rocheleau G, Cavalcanti-Proença C, Bacot F, Balkau B, Belisle A, Borch-Johnsen K, Charpentier G, Dina C, Durand E, Elliott P et al (2009) Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia. Nat Genet 41(10):1110–1115. PubMedCrossRefGoogle Scholar
  87. Sale MM, Smith SG, Mychaleckyj JC, Keene KL, Langefeld CD, Leak TS, Hicks PJ, Bowden DW, Rich SS, Freedman BI (2007) Variants of the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in an African–American population enriched for nephropathy. Diabetes 56:2638–2642. PubMedCrossRefGoogle Scholar
  88. Sandhu MS, Weedon MN, Fawcett KA, Wasson J, Debenham SL, Daly A, Lango H, Frayling TM, Neumann RJ, Sherva R et al (2007) Common variants in WFS1confer risk of type 2 diabetes. Nat Genet 39:951–953. PubMedPubMedCentralCrossRefGoogle Scholar
  89. Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, Chen H, Roix JJ, Kathiresan S, Hirschhorn JN, Daly MJ, Hughes TE, Groop L, Altshuler D, Almgren P et al (2007) Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316:1331–1334. PubMedCrossRefGoogle Scholar
  90. Saxena R, Elbers CC, Guo Y, Peter I, Gaunt TR, Mega JL, Lanktree MB, Tare A, Castillo BA, Li YR et al (2012) Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci. Am J Hum Genet 90:410–425. PubMedPubMedCentralCrossRefGoogle Scholar
  91. Saxena R, Saleheen D, Been LF, Garavito ML, Braun T, Bjonnes A, Young R, Ho WK, Rasheed A, Frossard P et al (2013) Genome-wide association study identifies a novel locus contributing to type 2 diabetes susceptibility in sikhs of punjabi origin from India. Diabetes 62:1746–1755. PubMedPubMedCentralCrossRefGoogle Scholar
  92. Scott LJ et al (2007) A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316:1341–1345. PubMedPubMedCentralCrossRefGoogle Scholar
  93. Shtir C, Aldahmesh MA, Al-Dahmash S et al (2016) Exome-based case–control association study using extreme phenotype design reveals novel candidates with protective effect in diabetic retinopathy. Hum Genet 135:193–196. PubMedCrossRefGoogle Scholar
  94. Shu XO, Long J, Cai Q et al (2010) Identification of new genetic risk variants for type 2 diabetes. PLoS Genet 6(9):e1001127. PubMedPubMedCentralCrossRefGoogle Scholar
  95. Sim X, Ong RT, Suo C, Tay WT, Liu J, Ng DP, Boehnke M, Chia KS, Wong TY, Seielstad M et al (2011) Transferability of type 2 diabetes implicated loci in multi-ethnic cohorts from Southeast Asia. PLoS Genet 7:e1001363. PubMedPubMedCentralCrossRefGoogle Scholar
  96. Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, Boutin P, Vincent D, Belisle A, Hadjadj S et al (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445:881–885. PubMedCrossRefGoogle Scholar
  97. Steinthorsdottir V, Thorleifsson G, Reynisdottir I, Benediktsson R, Jonsdottir T, Walters GB, Styrkarsdottir U, Gretarsdottir S et al (2007) A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet 39(6):770–775. PubMedCrossRefGoogle Scholar
  98. Steinthorsdottir V, Thorleifsson G, Sulem P, Helgason H, Grarup N, Sigurdsson A, Helgadottir HT, Johannsdottir H, Magnusson OT, Gudjonsson SA et al (2014) Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes. Nat Genet 46:294–298. PubMedCrossRefGoogle Scholar
  99. Strawbridge RJ, Dupuis J, Prokopenko I, Barker A, Ahlqvist E, Rybin D, Petrie JR, Travers ME, Bouatia-Naji N, Dimas AS et al (2011) Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes. Diabetes 60:2624–2634. PubMedPubMedCentralCrossRefGoogle Scholar
  100. Sun X, Yu W, Hu C (2014) Genetics of type 2 diabetes: insights into the pathogenesis and its clinical application. Bio Med Res Int 8:926713. Google Scholar
  101. Tabassum R, Chauhan G, Dwivedi OP, Mahajan A, Jaiswal A, Kaur I, Bandesh K, Singh T, Mathai BJ, Pandey Y et al (2013) Genome-wide association study for type 2 diabetes in Indians identifies a new susceptibility locus at 2q21. Diabetes 62:977–986. PubMedPubMedCentralCrossRefGoogle Scholar
  102. Takeuchi F, Serizawa M, Yamamoto K, Fujisawa T, Nakashima E, Ohnaka K, Ikegami H, Sugiyama T et al (2009) Confirmation of multiple risk loci and genetic impacts by a genome-wide association Study of Type 2 Diabetes in the Japanese Population. Diabetes 58(7):1690–1699. PubMedPubMedCentralCrossRefGoogle Scholar
  103. Tang Y, Axelsson AS, Spégel P, Andersson LE, Mulder H, Groop LC, Renström E, Rosengren AH (2014) Genotype-based treatment of type 2 diabetes with an α2A-adrenergic receptor antagonist. Sci Transl Med 6(257):257ra139. PubMedCrossRefGoogle Scholar
  104. Teer JK, Mullikin JC (2010) Exome sequencing: the sweet spot before whole genomes. Hum Mol Genet 19:145–151CrossRefGoogle Scholar
  105. Thomas PP, Alshehri SM, van Kranen H, Ambrosino E (2016) The impact of personalized medicine of Type 2 diabetes mellitus in the global health context. Personalized Medicine 13:381–393. CrossRefGoogle Scholar
  106. Thomsen SK, Ceroni A, van de Bunt M, Burrows C, Barrett A, Scharfmann R, Ebner D, McCarthy MI, Gloyn AL (2016) Systematic functional characterization of candidate causal genes for type 2 diabetes risk variants. Diabetes 65:3805–3811. PubMedPubMedCentralCrossRefGoogle Scholar
  107. Thorleifsson G, Walters GB, Gudbjartsson DF, Steinthorsdottir V, Sulem P, Helgadottir A, Styrkarsdottir U, Gretarsdottir S, Thorlacius S, Jonsdottir I et al (2009) Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet 41:18–24. PubMedCrossRefGoogle Scholar
  108. Topol EJ (2014) Individualized medicine from prewomb to tomb. Cell 157(1):241–253PubMedPubMedCentralCrossRefGoogle Scholar
  109. Tsai FJ, Yang CF, Chen CC, Chuang LM, Lu CH, Chang CT, Wang TY, Chen RH, Shiu CF, Liu YM et al (2010) A genome-wide association study identifies susceptibility variants for type 2 diabetes in Han Chinese. PLoS Genet 6(2):e1000847. PubMedPubMedCentralCrossRefGoogle Scholar
  110. Ueyama M, Nishida N, Korenaga M et al (2016) The impact of PNPLA3 and JAZF1 on hepatocellular carcinoma in non-viral hepatitis patients with type 2 diabetes mellitus. J Gastroenterol 51:370. PubMedCrossRefGoogle Scholar
  111. Van de Bunt M, Manning Fox JE, Dai X et al (2015) Transcript expression data from human islets links regulatory signals from genome-wide association studies for type 2 diabetes and glycemic traits to their downstream effectors. PLoS Genet 11:e1005694. PubMedPubMedCentralCrossRefGoogle Scholar
  112. Visscher PM, Hill WG, Wray NR (2008) Heritability in the genomics era—concepts and misconceptions. Nat Rev Genet 9:255–266. PubMedCrossRefGoogle Scholar
  113. Visscher PM, Brown MA, McCarthy MI et al (2012) Five years of GWAS discovery. Am J Hum Genet 90(1):7–24. PubMedPubMedCentralCrossRefGoogle Scholar
  114. Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP, Zeggini E, Huth C, Aulchenko YS, Thorleifsson G et al (2010) Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 42:579–589. PubMedPubMedCentralCrossRefGoogle Scholar
  115. Wagner MJ (2013) Rare-variant genome-wide association studies: a new frontier in genetic analysis of complex traits. Pharmacogenomics 14(4):413–424. PubMedCrossRefGoogle Scholar
  116. Weedon MN, Schwarz PE, Horikawa Y, Iwasaki N, Illig T, Holle R, Rathmann W, Selisko T, Schulze J, Owen KR et al (2003) Meta-analysis and a large association study confirm a role for calpain-10 variation in type 2 diabetes susceptibility. Am J Hum Genet 73:1208–1212. PubMedPubMedCentralCrossRefGoogle Scholar
  117. Wellcome Trust Case Control Consortium, Burton PR, Clayton DG, Cardon LR et al (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3000 shared controls. Nature 447(7145):661–678.CrossRefGoogle Scholar
  118. Weston AD, Hood L (2004) Systems biology, proteomics, and the future of health care: toward predictive, preventative, and personalized medicine. J Proteome Res 3(2):179–196PubMedCrossRefGoogle Scholar
  119. World Health Organization (2016) Global report on diabetes, Geneva.
  120. Yaghootkar H, Scott RA, White CC, Zhang W, Speliotes E, Munroe PB, Ehret GB, Bis JC, Fox CS, Frayling TM et al (2014) Genetic evidence for a normal-weight “metabolically obese” phenotype linking insulin resistance, hypertension, coronary artery disease, and type 2 diabetes. Diabetes 63(12):4369–4377. PubMedPubMedCentralCrossRefGoogle Scholar
  121. Yaghootkar H, Stancáková A, Freathy RM, Vangipurapu J, Weedon MN, XieW Frayling TM et al (2015) Association analysis of 29,956 individuals confirms that a low-frequency variant at CCND2 halves the risk of type 2 diabetes by enhancing insulin secretion. Diabetes 64(6):2279–2285. PubMedCrossRefGoogle Scholar
  122. Yamauchi T, Hara K, Maeda S, Yasuda K, Takahashi A, Horikoshi M, Nakamura M, Fujita H, Grarup N, Cauchi S, Ng DP, Ma RC, Tsunoda T, Kubo M, Watada H, Maegawa H et al (2010) A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B. Nat Genet 42(10):864–868. PubMedCrossRefGoogle Scholar
  123. Yasuda K, Miyake K, Horikawa Y, Hara K, Osawa H, Furuta H, Hirota Y, Mori H, Jonsson A, Sato Y et al (2008) Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nat Genet 40:1092–1097. PubMedCrossRefGoogle Scholar
  124. Zeggini E, WeedonMN LindgrenCM, Frayling TM et al (2007) Multiple type 2 diabetes susceptibility genes following genome-wide association scan in UK samples. Science 316(5829):1336–1341. PubMedPubMedCentralCrossRefGoogle Scholar
  125. Zeggini E, Scott LJ, Saxena R, Voight BF et al (2008) Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 40(5):638–645. PubMedPubMedCentralCrossRefGoogle Scholar
  126. Zhang J, McKenna LB, Bogue CW, Kaestner KH (2014) The diabetes gene Hhex maintains δ-cell differentiation and islet function. Genes Dev 28:829–834. PubMedPubMedCentralCrossRefGoogle Scholar
  127. Zhu Z, Tong X, Zhu Z, Liang M, Cui W, Su K, Li MD, Zhu J (2013) Development of GMDR-GPU for gene–gene interaction analysis and its application to WTCCC GWAS data for type 2 diabetes. PLoS ONE 8(4):e61943. PubMedPubMedCentralCrossRefGoogle Scholar
  128. Zuk O, Hechter E, Sunyaev SR, Lander ES (2012) The mystery of missing heritability: genetic interactions create phantom heritability. PNAS 109:1193–1198. PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Monica Szabo
    • 1
    Email author
  • Beáta Máté
    • 1
  • Katalin Csép
    • 1
  • Theodora Benedek
    • 1
  1. 1.University of Medicine and Pharmacy Tg MureşTârgu MureşRomania

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