Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Imprinting detection by extending a regression-based QTL analysis method


We present an extension of a regression-based quantitative-trait linkage analysis method to incorporate parent-of-origin effects. We separately regressed total, paternal, and maternal IBD sharing on traits’ squared sums and differences. We also developed a test for imprinting that indicates whether there is any difference between the paternal and maternal regression coefficients. Since this method treats the identity-by-descent information as the dependent variable that is conditioned on the trait, it can be readily applied to data from complex ascertainment processes. We performed a simulation study to examine the performance of the method. We found that when using empirical critical values, the method shows identical or higher power compared to existing methods for evaluation of parent-of-origin effect in linkage analysis of quantitative traits. Missing parental genotypes increase the type I error rate of the linkage test and decrease the power of the imprinting test. When the major gene has a low heritability, the power of the method decreases considerably, but the statistical tests still perform well. We also applied a permutation algorithm, which ensures the appropriate type I error rate for the test for imprinting. The method was applied to a data from a study of 6 body size related measures and 23 loci on chromosome 7 for 255 nuclear families. Multipoint identities-by-descent (IBD) were obtained using a modification of the SIMWALK 2 program. A parent-of-origin effect consistent with maternal imprinting was suggested at 99.67–111.26 Mb for body mass index, bioelectrical impedance analysis, waist circumference, and leptin concentration.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2


  1. Amos CI (1994) Robust variance-components approach for assessing genetic linkage in pedigrees. Am J Hum Genet 54:535–543

  2. Amos CI, de Andrade M (2001) Genetic linkage methods for quantitative traits. Stat Methods Med Res 10:3–25

  3. Bartolomei MS, Tilghman SM (1997) Genomic imprinting in mammals. Annu Rev Genet 31:493–525

  4. Blackwelder WC, Elston RC (1985) A comparison of sib-pair linkage tests for disease susceptibility loci. Genet Epidemiol 2:85–97

  5. Chumlea WC, Guo SS, Kuczmarski RJ, Flegal KM, Johnson CL, Heymsfield SB, Lukaski HC, Friedl K, Hubbard VS (2002) Body composition estimates from NHANES III bioelectrical impedance data. Int J Obes Relat Metab Disord 26:1596–1609

  6. Ferguson-Smith AC, Cattanach BM, Barton SC, Beechey CV, Surani MA (1991) Embryological and molecular investigations of parental imprinting on mouse chromosome 7. Nature 351:667–670

  7. Freeman MS, Mansfield MW, Barrett JH, Grant PJ (2002) Heritability of features of the insulin resistance syndrome in a community-based study of healthy families. Diabet Med 19:994–999

  8. Fulker DW, Cherny SS (1996) An improved multipoint sib-pair analysis of quantitative traits. Behav Genet 26:527–532

  9. Gorlova OY, Amos CI, Wang NW, Shete S, Turner ST, Boerwinkle E (2003) Genetic linkage and imprinting effects on body mass index in children and young adults. Eur J Hum Genet 11:425–432

  10. Greally JM (2002) Short interspersed transposable elements (SINEs) are excluded from imprinted regions in the human genome. Proc Natl Acad Sci USA 99:327–332

  11. Hanson RL, Kobes S, Lindsay RS, Knowler WC (2001) Assessment of parent-of-origin effects in linkage analysis of quantitative traits. Am J Hum Genet 68:951–962

  12. Haseman JK, Elston RC (1972) The investigation of linkage between a quantitative trait and a marker locus. Behav Genet 2:3–19

  13. Iyengar S, Calafell F, Kidd KK (1997) Detection of major genes underlying several quantitative traits associated with a common disease using different ascertainment schemes. Genet Epidemiol 14:809–814

  14. Knapp M, Strauch K (2004) Affected-sib-pair test for linkage based on constraints for identical-by-descent distributions corresponding to disease models with imprinting. Genet Epidemiol 26:273–285

  15. Kobayashi S, Kohda T, Miyoshi N, Kuroiwa Y, Aisaka K, Tsutsumi O, Kaneko-Ishino T, Ishino F (1997) Human PEG1/MEST, an imprinted gene on chromosome 7. Hum Mol Genet 6:781–786

  16. Langenberg C, Hardy R, Kuh D, Brunner E, Wadsworth M (2003) Central and total obesity in middle aged men and women in relation to lifetime socioeconomic status: evidence from a national birth cohort. J Epidemiol Community Health 57:816–822

  17. Li WD, Li D, Wang S, Zhang S, Zhao H, Price RA (2003) Linkage and linkage disequilibrium mapping of genes influencing human obesity in chromosome region 7q22.1–7q35. Diabetes 52:1557–1561

  18. Luke A, Guo X, Adeyemo AA, Wilks R, Forrester T, Lowe W Jr, Comuzzie AG, Martin LJ, Zhu X, Rotimi CN, Cooper RS (2001) Heritability of obesity-related traits among Nigerians, Jamaicans and US black people. Int J Obes Relat Metab Disord 25:1034–1041

  19. Nakabayashi K, Bentley L, Hitchins MP, Mitsuya K, Meguro M, Minagawa S, Bamforth JS, Stanier P, Preece M, Weksberg R, Oshimura M, Moore GE, Scherer SW (2002) Identification and characterization of an imprinted antisense RNA (MESTIT1) in the human MEST locus on chromosome 7q32. Hum Mol Genet 11:1743–1756

  20. Okita C, Meguro M, Hoshiya H, Haruta M, Sakamoto YK, Oshimura M (2003) A new imprinted cluster on the human chromosome 7q21-q31, identified by human–mouse monochromosomal hybrids. Genomics 81:556–559

  21. Peng B, Yu R, DeHoff K, Amos C (2007) Normalizing a large number of quantitative traits using empirical normal quantile transformation. BMC Genetics (in press)

  22. Ruhl CE, Everhart JE (2001) Leptin concentrations in the United States: relations with demographic and anthropometric measures. Am J Clin Nutr 74:295–301

  23. Sham PC, Purcell S, Cherny SS, Abecasis GR (2002) Powerful regression-based quantitative-trait linkage analysis of general pedigrees. Am J Hum Genet 71:238–253

  24. Shete S, Amos CI (2002) Testing for genetic linkage in families by a variance-components approach in the presence of genomic imprinting. Am J Hum Genet 70:751–757

  25. Shete S, Zhou X, Amos CI (2003) Genomic imprinting and linkage test for quantitative-trait Loci in extended pedigrees. Am J Hum Genet 73:933–938

  26. Smith FM, Garfield AS, Ward A (2006) Regulation of growth and metabolism by imprinted genes. Cytogenet Genome Res 113:279–291

  27. Strauch K, Fimmers R, Kurz T, Deichmann KA, Wienker TF, Baur MP (2000) Parametric and nonparametric multipoint linkage analysis with imprinting and two-locus-trait models: application to mite sensitization. Am J Hum Genet 66:1945–1957

  28. Terwilliger JD, Speer M, Ott J (1993) Chromosome-based method for rapid computer simulation in human genetic linkage analysis. Genet Epidemiol 10:217–224

  29. Tilghman SM (1999) The sins of the fathers and mothers: genomic imprinting in mammalian development. Cell 96:185–193

  30. Vincent Q, Alcais A, Alter A, Schurr E, Abel L (2006) Quantifying genomic imprinting in the presence of linkage. Biometrics 62:1071–1080

  31. Wilkins JF, Haig D (2003) What good is genomic imprinting: the function of parent-specific gene expression. Nat Rev Genet 4:359–368

  32. Wu CC, Shete S, Amos CI (2005) Linkage analysis of affected sib pairs allowing for parent-of-origin effects. Ann Hum Genet 69:113–126

  33. Yamasaki K, Hayashida S, Miura K, Masuzaki H, Ishimaru T, Niikawa N, Kishino T (2000) The novel gene, gamma2-COP (COPG2), in the 7q32 imprinted domain escapes genomic imprinting. Genomics 68:330–335

Download references


The work was supported by the National Institutes of Health grant ES09912. We thank Drs. Pak C. Sham and Goncalo R. Abecasis for their help regarding the regression model and its implementation in Merlin-Regress, and Mrs. Wei Chen for her help with the simulation setup.

Author information

Correspondence to Olga Y. Gorlova.

Additional information

An erratum to this article can be found at http://dx.doi.org/10.1007/s00439-007-0426-z

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM1 (DOC 142 kb)



Electronic-Database Information

The URLs for data presented herein are as follows: American Diabetes Association, http://www.diabetes.org/about-diabetes.jspOnline Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/. The software developed in this study is available from the author free of charge upon request.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gorlova, O.Y., Lei, L., Zhu, D. et al. Imprinting detection by extending a regression-based QTL analysis method. Hum Genet 122, 159–174 (2007). https://doi.org/10.1007/s00439-007-0387-2

Download citation


  • Waist Circumference
  • Standard Normal Distribution
  • Parental Genotype
  • Base Case Scenario
  • Linkage Test