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Human Genetics

, Volume 120, Issue 4, pp 527–542 | Cite as

Association study on chromosome 20q11.21-13.13 locus and its contribution to type 2 diabetes susceptibility in Japanese

  • Toshihito Tanahashi
  • Dai Osabe
  • Kyoko Nomura
  • Shuichi Shinohara
  • Hitoshi Kato
  • Eiichiro Ichiishi
  • Naoto Nakamura
  • Toshikazu Yoshikawa
  • Yoichiro Takata
  • Tatsuro Miyamoto
  • Hiroshi Shiota
  • Parvaneh Keshavarz
  • Yuka Yamaguchi
  • Kiyoshi Kunika
  • Maki Moritani
  • Hiroshi Inoue
  • Mitsuo ItakuraEmail author
Original Investigation

Abstract

Several linkage studies have predicted that human chromosome 20q is closely related to type 2 diabetes, but there is no clear evidence that certain variant(s) or gene(s) have strong effects on the disease within this region. To examine disease susceptibility variant in Japanese, verified SNPs from the databases, with a minor allele frequency larger than 0.15, were selected at 10-kb intervals across a 19.31-Mb region (20q11.21-13.13), which contained 291 genes, including hepatocyte nuclear factor 4α (HNF4α). As a result, a total of 1,147 SNPs were genotyped with TaqMan assay using 1,818 Japanese samples. By searching for HNF4α as a representative disease-susceptible gene, no variants of HNF4α were strongly associated with disease. To identify other genetic variant related with disease, we designed an extensive two-stage association study (725 first and 1,093 second test samples). Although SNP1146 (rs220076) was selected as a landmark within the 19.31 Mb region, the magnitude of the nominal P value (P = 0.0023) was rather weak. Subsequently, a haplotype-based association study showed that two common haplotypes were weakly associated with disease. All of these tests resulted in non-significance after adjusting for Bonferroni’s correction and the false discovery rate to control for the impact of multiple testing. Contrary to the initial expectations, we could not conclude that certain SNPs had a major effect on this promising locus within the framework presented here. As a way to extend our observations, we emphasize the importance of a subsequent association study including replication and/or meta-analysis in multiple populations.

Keywords

Association Test Linkage Disequilibrium Block Linkage Peak Common Complex Disease SNPs Marker 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

FUSION

The Finland-United States Investigation of Non-insulin-dependent diabetes mellitus genetics

UTR

Untranslated region

JPT

Japanese in Tokyo

CHB

Han Chinese in Beijing

CEU

Utah residents with ancestry from northern and western Europe by the Centre d’Etude du Polymorphisme Humain

Notes

Acknowledgments

We are very grateful to Dr. Naoyuki Kamatani (Division of Statistical Genetics, Department of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University) for the critical reading of the manuscript and helpful comments. We thank the members of the Institute for Genome Research for helpful discussions and assistance. This study was supported by a grant from the Cooperative Link of Unique Science and Technology for Economy Revitalization (CLUSTER) and Takeda Science Foundation (Osaka, Japan).

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References

  1. Altshuler D, Brooks LD, Chakravarti A, Collins FS, Daly MJ, Donnelly P (2005) A haplotype map of the human genome. Nature 437:1299–1320CrossRefGoogle Scholar
  2. Bagwell AM, Bento JL, Mychaleckyj JC, Freedman BI, Langefeld CD, Bowden DW (2005) Genetic analysis of HNF4α polymorphisms in Caucasian-American type 2 diabetes. Diabetes 54:1185–1190PubMedGoogle Scholar
  3. Barroso I, Luan J, Middelberg RP, Harding AH, Franks PW, Jakes RW, Clayton D, Schafer AJ, O’Rahilly S, Wareham NJ (2003) Candidate gene association study in type 2 diabetes indicates a role for genes involved in beta-cell function as well as insulin action. PLoS Biol 1:E20PubMedCrossRefGoogle Scholar
  4. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Stat Soc Ser B 57:289–300Google Scholar
  5. Blomqvist ME, Reynolds C, Katzov H, Feuk L, Andreasen N, Bogdanovic N, Blennow K, Brookes AJ, Prince JA (2006) Towards compendia of negative genetic association studies: an example for Alzheimer disease. Hum Genet 119:29–37PubMedCrossRefGoogle Scholar
  6. Duggirala R, Blangero J, Almasy L, Arya R, Dyer TD, Williams KL, Leach RJ, O’Connell P, Stern MP (2001) A major locus for fasting insulin concentrations and insulin resistance on chromosome 6q with strong pleiotropic effects on obesity-related phenotypes in nondiabetic Mexican Americans. Am J Hum Genet 68:1149–1164PubMedCrossRefGoogle Scholar
  7. Edwards AO, Ritter R 3rd, Abel KJ, Manning A, Panhuysen C, Farrer LA (2005) Complement factor H polymorphism and age-related macular degeneration. Science 308:421–424PubMedCrossRefGoogle Scholar
  8. Freimer NB, Sabatti C (2005) Guidelines for association studies in human molecular genetics. Hum Mol Genet 14:2481–2483PubMedCrossRefGoogle Scholar
  9. Ghosh S, Watanabe RM, Hauser ER, Valle T, Magnuson VL, Erdos MR, Langefeld CD, Balow Jr J, Ally DS, Kohtamaki K, Chines P, Birznieks G, Kaleta HS, Musick A, Te C, Tannenbaum J, Eldridge W, Shapiro S, Martin C, Witt A, So A, Chang J, Shurtleff B, Porter R, Kudelko K, Unni A, Segal L, Sharaf R, Blaschak Harvan J, Eriksson J, Tenkula T, Vidgren G, Ehnholm C, Tuomilehto Wolf E, Hagopian W, Buchanan TA, Tuomilehto J, Bergman RN, Collins FS, Boehnke M (1999) Type 2 diabetes: evidence for linkage on chromosome 20 in 716 Finnish affected sib pairs. Proc Natl Acad Sci USA 96:2198–2203PubMedCrossRefGoogle Scholar
  10. Ghosh S, Watanabe RM, Valle TT, Hauser ER, Magnuson VL, Langefeld CD, Ally DS, Mohlke KL, Silander K, Kohtamaki K, Chines P, Balow Jr J, Birznieks G, Chang J, Eldridge W, Erdos MR, Karanjawala ZE, Knapp JI, Kudelko K, Martin C, Morales Mena A, Musick A, Musick T, Pfahl C, Porter R, Rayman JB (2000) The Finland-United States investigation of non-insulin-dependent diabetes mellitus genetics (FUSION) study. I. An autosomal genome scan for genes that predispose to type 2 diabetes. Am J Hum Genet 67:1174–1185PubMedGoogle Scholar
  11. Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, Styrkarsdottir U, Magnusson KP, Walters GB, Palsdottir E, Jonsdottir T, Gudmundsdottir T, Gylfason A, Saemundsdottir J, Wilensky RL, Reilly MP, Rader DJ, Bagger Y, Christiansen C, Gudnason V, Sigurdsson G, Thorsteinsdottir U, Gulcher JR, Kong A, Stefansson K (2006) Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 38:320–323PubMedCrossRefGoogle Scholar
  12. Hamada D, Takata Y, Osabe D, Nomura K, Shinohara S, Egawa H, Nakano S, Shinomiya F, Scafe CR, Reeve VM, Miyamoto T, Moritani M, Kunika K, Inoue H, Yasui N, Itakura M (2005) Association between single-nucleotide polymorphisms in the SEC8L1 gene, which encodes a subunit of the exocyst complex, and rheumatoid arthritis in a Japanese population. Arthritis Rheum 52:1371–1380PubMedCrossRefGoogle Scholar
  13. Hattersley AT, McCarthy MI (2005) What makes a good genetic association study? Lancet 366:1315–1323PubMedCrossRefGoogle Scholar
  14. Hill WG, Robertson A (1968) The effects of inbreeding at loci with heterozygote advantage. Genetics 60:615–628PubMedGoogle Scholar
  15. Hinds DA, Stuve LL, Nilsen GB, Halperin E, Eskin E, Ballinger DG, Frazer KA, Cox DR (2005) Whole-genome patterns of common DNA variation in three human populations. Science 307:1072–1079PubMedCrossRefGoogle Scholar
  16. Hirschhorn JN, Daly MJ (2005) Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 6:95–108PubMedCrossRefGoogle Scholar
  17. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O’Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent Puig P, Gower Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411:599–603PubMedCrossRefGoogle Scholar
  18. Iwasaki N, Cox NJ, Wang YQ, Schwarz PE, Bell GI, Honda M, Imura M, Ogata M, Saito M, Kamatani N, Iwamoto Y (2003) Mapping genes influencing type 2 diabetes risk and BMI in Japanese subjects. Diabetes 52:209–213PubMedGoogle Scholar
  19. Jinnai N, Sakagami T, Sekigawa T, Kakihara M, Nakajima T, Yoshida K, Goto S, Hasegawa T, Koshino T, Hasegawa Y, Inoue H, Suzuki N, Sano Y, Inoue I (2004) Polymorphisms in the prostaglandin E2 receptor subtype 2 gene confer susceptibility to aspirin-intolerant asthma: a candidate gene approach. Hum Mol Genet 13:3203–3217PubMedCrossRefGoogle Scholar
  20. Kato H, Nomura K, Osabe D, Shinohara S, Mizumori O, Katashima R, Iwasaki S, Nishimura K, Yoshino M, Kobori M, Ichiishi E, Nakamura N, Yoshikawa T, Tanahashi T, Keshavarz P, Kunika K, Moritani M, Kudo E, Tsugawa K, Takata Y, Hamada D, Yasui N, Miyamoto T, Shiota H, Inoue H, Itakura M (2006) Association of single-nucleotide polymorphisms in the suppressor of cytokine signaling 2 (SOCS2) gene with type 2 diabetes in the Japanese. Genomics 87:446–458PubMedCrossRefGoogle Scholar
  21. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, Henning AK, SanGiovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J (2005) Complement factor H polymorphism in age-related macular degeneration. Science 308:385–389PubMedCrossRefGoogle Scholar
  22. Lewontin RC (1964) The interaction of selection and linkage I. General considerations. Genetics 49:49–67Google Scholar
  23. Love Gregory LD, Wasson J, Ma J, Jin CH, Glaser B, Suarez BK, Permutt MA (2004) A common polymorphism in the upstream promoter region of the hepatocyte nuclear factor-4 alpha gene on chromosome 20q is associated with type 2 diabetes and appears to contribute to the evidence for linkage in an Ashkenazi Jewish population. Diabetes 53:1134–1140PubMedGoogle Scholar
  24. Luo TH, Zhao Y, Li G, Yuan WT, Zhao JJ, Chen JL, Huang W, Luo M (2001) A genome-wide search for type II diabetes susceptibility genes in Chinese Hans. Diabetologia 44:501–506PubMedCrossRefGoogle Scholar
  25. McIntyre LM, Martin ER, Simonsen KL, Kaplan NL (2000) Circumventing multiple testing: a multilocus Monte Carlo approach to testing for association. Genet Epidemiol 19:18–29PubMedCrossRefGoogle Scholar
  26. Mori Y, Otabe S, Dina C, Yasuda K, Populaire C, Lecoeur C, Vatin V, Durand E, Hara K, Okada T, Tobe K, Boutin P, Kadowaki T, Froguel P (2002) Genome-wide search for type 2 diabetes in Japanese affected sib-pairs confirms susceptibility genes on 3q, 15q, and 20q and identifies two new candidate Loci on 7p and 11p. Diabetes 51:1247–1255PubMedGoogle Scholar
  27. Nawata H, Shirasawa S, Nakashima N, Araki E, Hashiguchi J, Miyake S, Yamauchi T, Hamaguchi K, Yoshimatsu H, Takeda H, Fukushima H, Sasahara T, Yamaguchi K, Sonoda N, Sonoda T, Matsumoto M, Tanaka Y, Sugimoto H, Tsubouchi H, Inoguchi T, Yanase T, Wake N, Narazaki K, Eto T, Umeda F, Nakazaki M, Ono J, Asano T, Ito Y, Akazawa S, Hazegawa I, Takasu N, Shinohara M, Nishikawa T, Nagafuchi S, Okeda T, Eguchi K, Iwase M, Ishikawa M, Aoki M, Keicho N, Kato N, Yasuda K, Yamamoto K, Sasazuki T (2004) Genome-wide linkage analysis of type 2 diabetes mellitus reconfirms the susceptibility locus on 11p13-p12 in Japanese. J Hum Genet 49:629–634PubMedCrossRefGoogle Scholar
  28. Ng MC, So WY, Cox NJ, Lam VK, Cockram CS, Critchley JA, Bell GI, Chan JC (2004) Genome-wide scan for type 2 diabetes loci in Hong Kong Chinese and confirmation of a susceptibility locus on chromosome 1q21-q25. Diabetes 53:1609–1613PubMedGoogle Scholar
  29. Ohmori H, Ando Y, Makita Y, Onouchi Y, Nakajima T, Saraiva MJ, Terazaki H, Suhr O, Sobue G, Nakamura M, Yamaizumi M, Munar Ques M, Inoue I, Uchino M, Hata A (2004) Common origin of the Val30Met mutation responsible for the amyloidogenic transthyretin type of familial amyloidotic polyneuropathy. J Med Genet 41:e51PubMedCrossRefGoogle Scholar
  30. O’Rahilly S, Barroso I, Wareham NJ (2005) Genetic factors in type 2 diabetes: the end of the beginning? Science 307:370–373PubMedCrossRefGoogle Scholar
  31. Ozaki K, Ohnishi Y, Iida A, Sekine A, Yamada R, Tsunoda T, Sato H, Sato H, Hori M, Nakamura Y, Tanaka T (2002) Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction. Nat Genet 32:650–654PubMedCrossRefGoogle Scholar
  32. Permutt MA, Wasson J, Cox N (2005) Genetic epidemiology of diabetes. J Clin Invest 115:1431–1439PubMedCrossRefGoogle Scholar
  33. Permutt MA, Wasson J, Suarez BK, Lin J, Thomas J, Meyer J, Lewitzky S, Rennich JS, Parker A, DuPrat L, Maruti S, Chayen S, Glaser B (2001) A genome scan for type 2 diabetes susceptibility loci in a genetically isolated population. Diabetes 50:681–685PubMedGoogle Scholar
  34. Permutt MA, Wasson J, Love Gregory LD, Ma J, Skolnick G, Suarez B, Lin J, Glaser B (2002) Searching for type 2 diabetes genes on chromosome 20. Diabetes 51(Suppl 3):S308–S315PubMedGoogle Scholar
  35. Reich DE, Schaffner SF, Daly MJ, McVean G, Mullikin JC, Higgins JM, Richter DJ, Lander ES, Altshuler D (2002) Human genome sequence variation and the influence of gene history, mutation and recombination. Nat Genet 32:135–142PubMedCrossRefGoogle Scholar
  36. Shiffman D, Ellis SG, Rowland CM, Malloy MJ, Luke MM, Iakoubova OA, Pullinger CR, Cassano J, Aouizerat BE, Fenwick RG, Reitz RE, Catanese JJ, Leong DU, Zellner C, Sninsky JJ, Topol EJ, Devlin JJ, Kane JP (2005) Identification of four gene variants associated with myocardial infarction. Am J Hum Genet 77:596–605PubMedCrossRefGoogle Scholar
  37. Silander K, Mohlke KL, Scott LJ, Peck EC, Hollstein P, Skol AD, Jackson AU, Deloukas P, Hunt S, Stavrides G, Chines PS, Erdos MR, Narisu N, Conneely KN, Li C, Fingerlin TE, Dhanjal SK, Valle TT, Bergman RN, Tuomilehto J, Watanabe RM, Boehnke M, Collins FS (2004) Genetic variation near the hepatocyte nuclear factor-4 alpha gene predicts susceptibility to type 2 diabetes. Diabetes 53:1141–1149PubMedGoogle Scholar
  38. Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989PubMedCrossRefGoogle Scholar
  39. Storey J (2002) A direct approach to false discovery rates. J Roy Stat Soc Ser B 64:479–498CrossRefGoogle Scholar
  40. Storey J, Tibshirani R (2003) Statistical significance for genomewide studies. Proc Natl Acad Sci USA 100:9440–9445PubMedCrossRefGoogle Scholar
  41. Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, Nagasaki M, Nakayama Hamada M, Kawaida R, Ono M, Ohtsuki M, Furukawa H, Yoshino S, Yukioka M, Tohma S, Matsubara T, Wakitani S, Teshima R, Nishioka Y, Sekine A, Iida A, Takahashi A, Tsunoda T, Nakamura Y, Yamamoto K (2003) Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 34:395–402PubMedCrossRefGoogle Scholar
  42. Togawa K, Moritani M, Yaguchi H, Itakura M (2006) Multidimensional genome scans identify the combinations of genetic loci linked to diabetes-related phenotypes in mice. Hum Mol Genet 15:113–128PubMedCrossRefGoogle Scholar
  43. Vaxillaire M, Dina C, Lobbens S, Dechaume A, Vasseur Delannoy V, Helbecque N, Charpentier G, Froguel P (2005) Effect of common polymorphisms in the HNF4α promoter on susceptibility to type 2 diabetes in the French Caucasian population. Diabetologia 48:440–444PubMedCrossRefGoogle Scholar
  44. Vionnet N, Hani El H, Dupont S, Gallina S, Francke S, Dotte S, De Matos F, Durand E, Lepretre F, Lecoeur C, Gallina P, Zekiri L, Dina C, Froguel P (2000) Genomewide search for type 2 diabetes-susceptibility genes in French whites: evidence for a novel susceptibility locus for early-onset diabetes on chromosome 3q27-qter and independent replication of a type 2-diabetes locus on chromosome 1q21-q24. Am J Hum Genet 67:1470–1480PubMedCrossRefGoogle Scholar
  45. Wall JD, Pritchard JK (2003) Haplotype blocks and linkage disequilibrium in the human genome. Nat Rev Genet 4:587–597PubMedCrossRefGoogle Scholar
  46. Wang WY, Barratt BJ, Clayton DG, Todd JA (2005) Genome-wide association studies: theoretical and practical concerns. Nat Rev Genet 6:109–118PubMedCrossRefGoogle Scholar
  47. Winckler W, Graham RR, de Bakker PI, Sun M, Almgren P, Tuomi T, Gaudet D, Hudson TJ, Ardlie KG, Daly MJ, Hirschhorn JN, Groop L, Altshuler D (2005) Association testing of variants in the hepatocyte nuclear factor 4alpha gene with risk of type 2 diabetes in 7,883 people. Diabetes 54:886–892PubMedGoogle Scholar
  48. Xiang K, Wang Y, Zheng T, Jia W, Li J, Chen L, Shen K, Wu S, Lin X, Zhang G, Wang C, Wang S, Lu H, Fang Q, Shi Y, Zhang R, Xu J, Weng Q (2004) Genome-wide search for type 2 diabetes/impaired glucose homeostasis susceptibility genes in the Chinese: significant linkage to chromosome 6q21-q23 and chromosome 1q21-q24. Diabetes 53:228–234PubMedGoogle Scholar
  49. World Health Organization (1985) Diabetes mellitus: report of a WHO study group. Geneva World Health Org, Tech. Rep. Ser., no. 727Google Scholar
  50. Zhu Q, Yamagata K, Miura A, Shihara N, Horikawa Y, Takeda J, Miyagawa J, Matsuzawa Y (2003) T130I mutation in HNF-4alpha gene is a loss-of-function mutation in hepatocytes and is associated with late-onset Type 2 diabetes mellitus in Japanese subjects. Diabetologia 46:567–573PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Toshihito Tanahashi
    • 1
  • Dai Osabe
    • 2
  • Kyoko Nomura
    • 2
  • Shuichi Shinohara
    • 3
  • Hitoshi Kato
    • 4
  • Eiichiro Ichiishi
    • 5
  • Naoto Nakamura
    • 6
  • Toshikazu Yoshikawa
    • 6
  • Yoichiro Takata
    • 7
  • Tatsuro Miyamoto
    • 8
  • Hiroshi Shiota
    • 8
  • Parvaneh Keshavarz
    • 1
  • Yuka Yamaguchi
    • 1
  • Kiyoshi Kunika
    • 1
  • Maki Moritani
    • 1
  • Hiroshi Inoue
    • 1
  • Mitsuo Itakura
    • 1
    Email author
  1. 1.Division of Genetic Information, Institute for Genome ResearchThe University of TokushimaTokushimaJapan
  2. 2.Department of Bioinformatics, Division of Life Science SystemsFujitsu LimitedTokyoJapan
  3. 3.Division of R&D SolutionFujitsu Nagano Systems Engineering LimitedNaganoJapan
  4. 4.Haplopharma Inc.TokyoJapan
  5. 5.New Industry Creation Hatchery CenterTohoku UniversityMiyagiJapan
  6. 6.Department of Endocrinology and MetabolismKyoto Prefectural University of Medicine Graduate School of Medical SciencesKyotoJapan
  7. 7.Department of Orthopedics, Institute for Health BiosciencesThe University of TokushimaTokushimaJapan
  8. 8.Department of Ophthalmology and Visual Neuroscience, Institute for Health BiosciencesThe University of TokushimaTokushimaJapan

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