Human Genetics

, 125:1 | Cite as

Genome-wide association scan for stature in Chinese: evidence for ethnic specific loci

  • Shu-Feng Lei
  • Tie-Lin Yang
  • Li-Jun Tan
  • Xiang-Ding Chen
  • Yan Guo
  • Yan-Fang Guo
  • Liang Zhang
  • Xiao-Gang Liu
  • Han Yan
  • Feng Pan
  • Zhi-Xin Zhang
  • Yu-Mei Peng
  • Qi Zhou
  • Li-Na He
  • Xue-Zhen Zhu
  • Jing Cheng
  • Yao-Zhong Liu
  • Christopher J. Papasian
  • Hong-Wen Deng
Original Investigation

Abstract

In Caucasian, several studies have identified some common variants associated with human stature variation. However, no such study was performed in Chinese, which is the largest population in the world and evidently differs from Caucasian in genetic background. To identify common or ethnic specific genes for stature in Chinese, an initial GWAS and follow-up replication study were performed. Our initial GWAS study found that a group of 13 contiguous SNPs, which span a region of ~150 kb containing two neighboring genes, zinc finger protein (ZNP) 510 and ZNP782, achieved strong signals for association with stature, with P values ranging from 9.71 × 10−5 to 3.11 × 10−6. After false discovery rate correction for multiple testing, 9 of the 13 SNPs remain significant (FDR q = 0.036−0.046). The follow-up replication study in an independent 2,953 unrelated southern Chinese confirmed the association of rs10816533 with stature (P = 0.029). All the13 SNPs were in consistently strong linkage disequilibrium (D′ > 0.99) and formed a single perfect haplotype block. The minor allele frequencies for the 13 contiguous SNPs have evidently ethnic difference, which range from 0.21 to 0.33 in Chinese but have as low as ~0.017 reported in dbSNP database in Caucasian. The present results suggest that the genomic region containing the ZNP510 and ZNP782 genes is an ethnic specific locus associated with stature variation in Chinese.

References

  1. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265PubMedCrossRefGoogle Scholar
  2. Braun A, Roth R, McGinniss MJ (2003) Technology challenges in screening single gene disorders. Eur J Pediatr 162(Suppl 1):S13–S16PubMedCrossRefGoogle Scholar
  3. Carmichael CM, McGue M (1995) A cross-sectional examination of height, weight, and body mass index in adult twins. J Gerontol A Biol Sci Med Sci 50:B237–B244PubMedGoogle Scholar
  4. Deng HW, Xu FH, Liu YZ, Shen H, Deng H, Huang QY, Liu YJ, Conway T, Li JL, Davies KM, Recker RR (2002) A whole-genome linkage scan suggests several genomic regions potentially containing QTLs underlying the variation of stature. Am J Med Genet 113:29–39PubMedCrossRefGoogle Scholar
  5. Devlin B, Roeder K (1999) Genomic control for association studies. Biometrics 55:997–1004PubMedCrossRefGoogle Scholar
  6. Dvornyk V, Liu XH, Shen H, Lei SF, Zhao LJ, Huang QR, Qin YJ, Jiang DK, Long JR, Zhang YY, Gong G, Recker RR, Deng HW (2003) Differentiation of Caucasians and Chinese at bone mass candidate genes: implication for ethnic difference of bone mass. Ann Hum Genet 67:216–227PubMedCrossRefGoogle Scholar
  7. Dvornyk V, Liu PY, Long JR, Zhang YY, Lei SF, Recker RR, Deng HW (2005) Contribution of genotype and ethnicity to bone mineral density variation in Caucasians and Chinese: a test for five candidate genes for bone mass. Chin Med J (Engl) 118:1235–1244Google Scholar
  8. Fisher KA, Miles R (2008) Modeling the acoustic radiation force in microfluidic chambers. J Acoust Soc Am 123:1862–1865PubMedCrossRefGoogle Scholar
  9. Ganss B, Jheon A (2004) Zinc finger transcription factors in skeletal development. Crit Rev Oral Biol Med 15:282–297PubMedCrossRefGoogle Scholar
  10. Goring HH, Terwilliger JD (2000) Linkage analysis in the presence of errors III: marker loci and their map as nuisance parameters. Am J Hum Genet 66:1298–1309PubMedCrossRefGoogle Scholar
  11. Gudbjartsson DF, Walters GB, Thorleifsson G, Stefansson H, Halldorsson BV, Zusmanovich P, Sulem P, Thorlacius S, Gylfason A, Steinberg S, Helgadottir A, Ingason A, Steinthorsdottir V, Olafsdottir EJ, Olafsdottir GH, Jonsson T, Borch-Johnsen K, Hansen T, Andersen G, Jorgensen T, Pedersen O, Aben KK, Witjes JA, Swinkels DW, Heijer MD, Franke B, Verbeek AL, Becker DM, Yanek LR, Becker LC, Tryggvadottir L, Rafnar T, Gulcher J, Kiemeney LA, Kong A, Thorsteinsdottir U, Stefansson K (2008) Many sequence variants affecting diversity of adult human height. Nat Genet 40:609–615PubMedCrossRefGoogle Scholar
  12. Hirschhorn JN, Lindgren CM, Daly MJ, Kirby A, Schaffner SF, Burtt NP, Altshuler D, Parker A, Rioux JD, Platko J, Gaudet D, Hudson TJ, Groop LC, Lander ES (2001) Genomewide linkage analysis of stature in multiple populations reveals several regions with evidence of linkage to adult height. Am J Hum Genet 69:106–116PubMedCrossRefGoogle Scholar
  13. Lei SF, Deng FY, Liu XH, Huang QR, Qin Y, Zhou Q, Jiang DK, Li YM, Mo XY, Liu MY, Chen XD, Wu XS, Shen H, Dvornyk V, Zhao L, Recker RR, Deng HW (2003) Polymorphisms of four bone mineral density candidate genes in Chinese populations and comparison with other populations of different ethnicity. J Bone Miner Metab 21:34–42PubMedCrossRefGoogle Scholar
  14. Lei SF, Chen Y, Xiong DH, Li LM, Deng HW (2006) Ethnic difference in osteoporosis-related phenotypes and its potential underlying genetic determination. J Musculoskelet Neuronal Interact 6:36–46PubMedGoogle Scholar
  15. Lettre G, Jackson AU, Gieger C, Schumacher FR, Berndt SI, Sanna S, Eyheramendy S, Voight BF, Butler JL, Guiducci C, Illig T, Hackett R, Heid IM, Jacobs KB, Lyssenko V, Uda M, Boehnke M, Chanock SJ, Groop LC, Hu FB, Isomaa B, Kraft P, Peltonen L, Salomaa V, Schlessinger D, Hunter DJ, Hayes RB, Abecasis GR, Wichmann HE, Mohlke KL, Hirschhorn JN (2008) Identification of ten loci associated with height highlights new biological pathways in human growth. Nat Genet 40:584–591PubMedCrossRefGoogle Scholar
  16. Li MX, Liu PY, Li YM, Qin YJ, Liu YZ, Deng HW (2004) A major gene model of adult height is suggested in Chinese. J Hum Genet 49:148–153PubMedCrossRefGoogle Scholar
  17. Liu YZ, Xu FH, Shen H, Liu YJ, Zhao LJ, Long JR, Zhang YY, Xiao P, Xiong DH, Dvornyk V, Li JL, Conway T, Davies KM, Recker RR, Deng HW (2004) Genetic dissection of human stature in a large sample of multiplex pedigrees. Ann Hum Genet 68:472–488PubMedCrossRefGoogle Scholar
  18. Liu YZ, Guo YF, Xiao P, Xiong DH, Zhao LJ, Shen H, Liu YJ, Dvornyk V, Long JR, Deng HY, Li JL, Deng HW (2006a) Epistasis between loci on chromosomes 2 and 6 influences human height. J Clin Endocrinol Metab 91:3821–3825PubMedCrossRefGoogle Scholar
  19. Liu YZ, Xiao P, Guo YF, Xiong DH, Zhao LJ, Shen H, Liu YJ, Dvornyk V, Long JR, Deng HY, Li JL, Recker RR, Deng HW (2006b) Genetic linkage of human height is confirmed to 9q22 and Xq24. Hum Genet 119:295–304PubMedCrossRefGoogle Scholar
  20. Luo ZC, Bertsson-Wikland K, Karlberg J (1998) Target height as predicted by parental heights in a population-based study. Pediatr Res 44:563–571PubMedCrossRefGoogle Scholar
  21. Marchini J, Howie B, Myers S, McVean G, Donnelly P (2007) A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet 39:906–913PubMedCrossRefGoogle Scholar
  22. Momeni P, Glockner G, Schmidt O, von HD, Albrecht B, Gillessen-Kaesbach G, Hennekam R, Meinecke P, Zabel B, Rosenthal A, Horsthemke B, Ludecke HJ (2000) Mutations in a new gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal syndrome type I. Nat Genet 24:71–74PubMedCrossRefGoogle Scholar
  23. Mukhopadhyay N, Finegold DN, Larson MG, Cupples LA, Myers RH, Weeks DE (2003) A genome-wide scan for loci affecting normal adult height in the Framingham Heart Study. Hum Hered 55:191–201PubMedCrossRefGoogle Scholar
  24. Mundlos S, Otto F, Mundlos C, Mulliken JB, Aylsworth AS, Albright S, Lindhout D, Cole WG, Henn W, Knoll JH, Owen MJ, Mertelsmann R, Zabel BU, Olsen BR (1997) Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89:773–779PubMedCrossRefGoogle Scholar
  25. Perola M, Ohman M, Hiekkalinna T, Leppavuori J, Pajukanta P, Wessman M, Koskenvuo M, Palotie A, Lange K, Kaprio J, Peltonen L (2001) Quantitative-trait-locus analysis of body-mass index and of stature, by combined analysis of genome scans of five Finnish study groups. Am J Hum Genet 69:117–123PubMedCrossRefGoogle Scholar
  26. Phillips K, Matheny AP Jr (1990) Quantitative genetic analysis of longitudinal trends in height: preliminary results from the Louisville Twin Study. Acta Genet Med Gemellol (Roma) 39:143–163Google Scholar
  27. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38:904–909PubMedCrossRefGoogle Scholar
  28. Pritchard JK, Stephens M, Donnelly P (2000) Inference of population structure using multilocus genotype data. Genetics 155:945–959PubMedGoogle Scholar
  29. Sanna S, Jackson AU, Nagaraja R, Willer CJ, Chen WM, Bonnycastle LL, Shen H, Timpson N, Lettre G, Usala G, Chines PS, Stringham HM, Scott LJ, Dei M, Lai S, Albai G, Crisponi L, Naitza S, Doheny KF, Pugh EW, Ben-Shlomo Y, Ebrahim S, Lawlor DA, Bergman RN, Watanabe RM, Uda M, Tuomilehto J, Coresh J, Hirschhorn JN, Shuldiner AR, Schlessinger D, Collins FS, Davey SG, Boerwinkle E, Cao A, Boehnke M, Abecasis GR, Mohlke KL (2008) Common variants in the GDF5-UQCC region are associated with variation in human height. Nat Genet 40:198–203PubMedCrossRefGoogle Scholar
  30. Storey JD, Tibshirani R (2003) Statistical significance for genomewide studies. Proc Natl Acad Sci USA 100:9440–9445PubMedCrossRefGoogle Scholar
  31. Weedon MN, Lettre G, Freathy RM, Lindgren CM, Voight BF, Perry JR, Elliott KS, Hackett R, Guiducci C, Shields B, Zeggini E, Lango H, Lyssenko V, Timpson NJ, Burtt NP, Rayner NW, Saxena R, Ardlie K, Tobias JH, Ness AR, Ring SM, Palmer CN, Morris AD, Peltonen L, Salomaa V, Davey SG, Groop LC, Hattersley AT, McCarthy MI, Hirschhorn JN, Frayling TM (2007) A common variant of HMGA2 is associated with adult and childhood height in the general population. Nat Genet 39:1245–1250PubMedCrossRefGoogle Scholar
  32. Weedon MN, Lango H, Lindgren CM, Wallace C, Evans DM, Mangino M, Freathy RM, Perry JR, Stevens S, Hall AS, Samani NJ, Shields B, Prokopenko I, Farrall M, Dominiczak A, Johnson T, Bergmann S, Beckmann JS, Vollenweider P, Waterworth DM, Mooser V, Palmer CN, Morris AD, Ouwehand WH, Zhao JH, Li S, Loos RJ, Barroso I, Deloukas P, Sandhu MS, Wheeler E, Soranzo N, Inouye M, Wareham NJ, Caulfield M, Munroe PB, Hattersley AT, McCarthy MI, Frayling TM (2008) Genome-wide association analysis identifies 20 loci that influence adult height. Nat Genet 40:575–583PubMedCrossRefGoogle Scholar
  33. Wiltshire S, Frayling TM, Hattersley AT, Hitman GA, Walker M, Levy JC, O’Rahilly S, Groves CJ, Menzel S, Cardon LR, McCarthy MI (2002) Evidence for linkage of stature to chromosome 3p26 in a large UK Family data set ascertained for type 2 diabetes. Am J Hum Genet 70:543–546PubMedCrossRefGoogle Scholar
  34. Wu X, Cooper RS, Boerwinkle E, Turner ST, Hunt S, Myers R, Olshen RA, Curb D, Zhu X, Kan D, Luke A (2003) Combined analysis of genomewide scans for adult height: results from the NHLBI Family Blood Pressure Program. Eur J Hum Genet 11:271–274PubMedCrossRefGoogle Scholar
  35. Xu J, Bleecker ER, Jongepier H, Howard TD, Koppelman GH, Postma DS, Meyers DA (2002) Major recessive gene(s) with considerable residual polygenic effect regulating adult height: confirmation of genomewide scan results for chromosomes 6, 9, and 12. Am J Hum Genet 71:646–650PubMedCrossRefGoogle Scholar
  36. Yuan HY, Chiou JJ, Tseng WH, Liu CH, Liu CK, Lin YJ, Wang HH, Yao A, Chen YT, Hsu CN (2006) FASTSNP: an always up-to-date and extendable service for SNP function analysis and prioritization. Nucleic Acids Res 34:W635–W641PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Shu-Feng Lei
    • 1
    • 4
  • Tie-Lin Yang
    • 2
  • Li-Jun Tan
    • 1
  • Xiang-Ding Chen
    • 1
  • Yan Guo
    • 2
  • Yan-Fang Guo
    • 2
  • Liang Zhang
    • 3
  • Xiao-Gang Liu
    • 2
    • 4
  • Han Yan
    • 2
  • Feng Pan
    • 2
  • Zhi-Xin Zhang
    • 2
  • Yu-Mei Peng
    • 2
  • Qi Zhou
    • 2
  • Li-Na He
    • 2
  • Xue-Zhen Zhu
    • 2
  • Jing Cheng
    • 3
  • Yao-Zhong Liu
    • 4
  • Christopher J. Papasian
    • 4
  • Hong-Wen Deng
    • 1
    • 4
  1. 1.Laboratory of Molecular and Statistical Genetics and Key Laboratory of Protein Chemistry and Developmental Biology of Ministry of Education, College of Life SciencesHunan Normal UniversityChangshaPeople’s Republic of China
  2. 2.The Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and TechnologyXi’an Jiaotong UniversityXi’anPeople’s Republic of China
  3. 3.National Engineering Research Center for Beijing Biochip TechnologyBeijingPeople’s Republic of China
  4. 4.School of Medicine University of Missouri-Kansas CityKansas CityUSA

Personalised recommendations