Statistical Approaches for Detecting Transgenerational Genetic Effects in Humans

  • Janet S. Sinsheimer
  • Michelle M. Creek


Transgenerational genetic effects occur when the genes of one generation influence the phenotype of subsequent generations without Mendelian transmission of alleles, possibly through inherited epigenetic effects. The evidence for transgenerational genetic effects in humans comes predominantly from genetic epidemiology studies, which thus presents a number of statistical challenges to their analysis and interpretation. In this chapter, we outline some of the genetic epidemiologic study designs and statistical analysis approaches that have been used to detect these effects and discuss their strengths and weaknesses.


Assisted Reproductive Technology Transgenerational Effect Transmission Disequilibrium Test Mendelian Randomization Variance Component Model 
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.



We thank the editors for their comments on this chapter. This review was supported in part by NIH grants GM53275 and T32-HG002536.


  1. Ainsworth HF, Unwin J, Jamison DL, Cordell HJ (2011) Investigation of maternal effects, maternal-fetal interactions and parent-of-origin effects (imprinting), using mothers and their offspring. Genet Epidemiol 35:19–45PubMedCrossRefGoogle Scholar
  2. Bell JT, Spector TD (2012) DNA methylation studies using twins: what are they telling us? Genome Biol 13:172PubMedCrossRefGoogle Scholar
  3. Benyshek DC, Martin JF, Johnston CS (2001) A reconsideration of the origins of the type 2 diabetes epidemic among Native Americans and the implications for intervention policy. Med Anthropol 20:25–64PubMedCrossRefGoogle Scholar
  4. Bjornsson HT, Sigurdsson MI, Fallin MD, Irizarry RA, Aspelund T, Cui H, Yu W, Rongione MA, Ekstrum TJ, Harris TB, Launer LJ, Eiriksdottir G, Leppert MF, Sapienza C, Gudnason V, Feinberg AP (2008) Intra-individual change over time in DNA methylation with familial clustering. JAMA 299:2877–2883PubMedCrossRefGoogle Scholar
  5. Bocklandt S, Lin W, Sehl ME, Sanchez FJ, Sinsheimer JS, Horvath S, Vilain E (2011) Epigenetic predictor of age. PLoS One 6:e14821PubMedCrossRefGoogle Scholar
  6. Cannon M, Jones P, Murray R (2002) Obstetric complications and schizophrenia: historical and meta-analytic review. Am J Psychiatry 159:1080–1092PubMedCrossRefGoogle Scholar
  7. Chen J, Zheng H, Wilson ML (2009) Likelihood ratio tests for maternal and fetal genetic effects on obstetric complications. Genet Epidemiol 33:526–538PubMedCrossRefGoogle Scholar
  8. Childs EJ, Palmer CG, Lange K, Sinsheimer JS (2010) Modeling maternal-offspring gene-gene interactions: the extended MFG test. Genet Epidemiol 34:512–521PubMedCrossRefGoogle Scholar
  9. Childs EJ, Sobel EM, Palmer CG, Sinsheimer JS (2011) Detection of intergenerational genetic effects with applications to HLA-B matching as a risk factor for schizophrenia. Hum Hered 72:161–172PubMedCrossRefGoogle Scholar
  10. Cordell HJ, Barratt BJ, Clayton DG (2004) Case/pseudocontrol analysis in genetic association studies: a unified framework for detection of genotype and haplotype associations, gene-gene and gene-environment interactions, and parent-of-origin effects. Genet Epidemiol 26:167–185PubMedCrossRefGoogle Scholar
  11. Cordell HJ (2004) Properties of case/pseudocontrol analysis for genetic association studies: effects of recombination, ascertainment, and multiple affected offspring. Genet Epidemiol 26:186–205PubMedCrossRefGoogle Scholar
  12. Cortessis VK, Thomas DC, Levine AJ, Breton CV, Mack TM, Siegmund KD, Haile RW, Laird PW (2012) Environmental epigenetics: prospects for studying epigenetic mediation of exposure-response relationships. Hum Genet 131:1565–1589PubMedCrossRefGoogle Scholar
  13. Dahlquist GG, Patterson G, Soltesz G (1999) Perinatal risk factors for childhood type 1 diabetes in Europe. The EURODIAB substudy 2 study group. Diabetes Care 22:1698–1702PubMedCrossRefGoogle Scholar
  14. Edwards TL, Gao X (2012) Methods for detecting and correcting for population stratification. Curr Protoc Hum Genet Chap1:1.22.1–14Google Scholar
  15. Gluckman PD, Hanson MA, Beedle AS (2007) Non-Genomic transgenerational inheritance of disease risk. BioEssays 29:145–154PubMedCrossRefGoogle Scholar
  16. Gorlova OY, Lei L, Zhu D, Weng SF, Shete S, Zhang Y, Li WD, Price RA, Amos CI (2007) Imprinting detection by extending a regression-based QTL analysis method. Hum Genet 122:159–174PubMedCrossRefGoogle Scholar
  17. Guilmatre A, Sharp AJ (2012) Parent of origin effects. Clin Genet 81:201–209PubMedCrossRefGoogle Scholar
  18. Guyton AC (1981) Textbook of medical physiology. W. B. Saunders, Philadelphia, PAGoogle Scholar
  19. Harney S, Newton J, Milicic A, Brown MA, Wordsworth BP (2003) Non-inherited maternal HLA alleles are associated with rheumatoid arthritis. Rheumatology 42:171–174PubMedCrossRefGoogle Scholar
  20. Hollister J, Laing P, Mednick S (1996) Rhesus incompatibility as a risk factor for schizophrenia in male adults. Arch Gen Psychiatry 53:19–24PubMedCrossRefGoogle Scholar
  21. Hsieh H, Palmer CGS, Sinsheimer JS (2006a) Allowing for missing data at highly polymorphic genes when testing for maternal, offspring and maternal–fetal genotype incompatibility effects. Hum Hered 62:165–174PubMedCrossRefGoogle Scholar
  22. Hsieh HJ, Palmer CG, Harney S, Chen HW, Bauman L, Brown MA, Sinsheimer JS (2007) Using the maternal–fetal genotype incompatibility test to assess non-inherited maternal HLA-DRB1 antigen coding alleles as rheumatoid arthritis risk factors. BMC Proc 1:S124PubMedCrossRefGoogle Scholar
  23. Hsieh HJ, Palmer CG, Harney S, Newton JL, Wordsworth P, Brown MA, Sinsheimer JS (2006b) The v-MFG test: investigating maternal, offspring and maternal–fetal genetic incompatibility effects on disease and viability. Genet Epidemiol 30:333–347PubMedCrossRefGoogle Scholar
  24. Insel BJ, Brown AS, Bresnahan MA, Schaefer CA, Susser ES (2005) Maternal–fetal blood incompatibility and the risk of schizophrenia in offspring. Schizophr Res 80:331–342PubMedCrossRefGoogle Scholar
  25. Juul-Dam N, Townsend J, Courchesne E (2001) Prenatal, perinatal, and neonatal factors in autism, pervasive developmental disorder-not otherwise specified, and the general population. Pediatrics 107:e63PubMedCrossRefGoogle Scholar
  26. Kangas-Kontio T, Kakko S, Tamminen M, von Rohr P, Hoeschele I, Juvonen T, Kere J, Savolainen MJ (2010) Genome scan for loci regulating HDL cholesterol levels in Finnish extended pedigrees with early coronary heart disease. Eur J Hum Genet 18:604–613PubMedCrossRefGoogle Scholar
  27. Khoury MJ, Beaty TH, Cohen BH (1993) Fundamentals of genetic epidemiology. Oxford University Press, OxfordGoogle Scholar
  28. Kistner EO, Weinberg CR (2004) Method for using complete and incomplete trios to identify genes related to a quantitative trait. Genet Epidemiol 27:33–42PubMedCrossRefGoogle Scholar
  29. Klip H, Verloop J, van Gool JD, Koster ME, Burger CW, van Leeuwen FE, OMEGA Project Group (2002) Hypospadias in sons of women exposed to diethylstilbestrol in utero: a cohort study. Lancet 35:1102–1107CrossRefGoogle Scholar
  30. Kraft P, Hsieh H-J, Cordell HJ, Sinsheimer J (2005) A conditional-on-exchangeable parental-genotypes likelihood that remains unbiased at the causal locus under multiple-affected-sibling ascertainment. Genet Epidemiol 29:87–90PubMedCrossRefGoogle Scholar
  31. Kraft P, Palmer CGS, Woodward AJ, Turunen JA, Minassian S, Paunio T, Lonnqvist J, Peltonen L, Sinsheimer JS (2004) RHD maternal–fetal genotype incompatibility and schizophrenia: extending the MFG test to include multiple siblings and birth order. Eur J Hum Gen 12:192–198CrossRefGoogle Scholar
  32. Laird NM, Lange C (2010) The fundamentals of modern statistical genetics. Springer Verlag, New York, NYGoogle Scholar
  33. Laird PW (2010) Principles and challenges of genomewide DNA methylation analysis. Nat Rev Genet 11:191–203PubMedCrossRefGoogle Scholar
  34. Lange K (2002) Mathematical and statistical methods for genetic analysis, 2nd edn. Springer Verlag, New York, NYCrossRefGoogle Scholar
  35. Lange K, Papp JC, Sinsheimer JS, Sripracha R, Zhou H, Sobel EM (2013) Mendel: the Swiss army knife of genetic analysis programs. Bioinformatics 29:1568–1570PubMedCrossRefGoogle Scholar
  36. Li H, Lu L, Manly KF, Chesler EJ, Bao L, Wang J, Zhou M, Williams RW, Cui Y (2005) Inferring gene transcriptional modulator relations: a genetical genomics approach. Hum Mol Genet 14:1119–1125PubMedCrossRefGoogle Scholar
  37. Minassian SL, Palmer CGS, Turunen JA, Paunio T, Lonnqvist J, Peltonen L, Woodward AJ, Sinsheimer JS (2006) Incorporating serotypes into family based association studies using the MFG test. Ann Human Gen 70:541–553CrossRefGoogle Scholar
  38. Morris NJ, Gray-McGuire C, Stein CM (2009) Mendelian randomization in family data. BMC Proc 15:S7, S45Google Scholar
  39. Morris NJ, Elston RC, Stein CM (2010) A framework for structural equation models (SEM) in general pedigrees. Hum Hered 70:278–286PubMedCrossRefGoogle Scholar
  40. Nadeau JH (2009) Transgenerational genetic effects on phenotypic variation and disease risk. Hum Mol Genet 18:R202–R210PubMedCrossRefGoogle Scholar
  41. Ott J (1974) Estimation of the recombination fraction in human pedigrees: efficient computation of the likelihood for human linkage studies. Am J Hum Genet 26:588–597PubMedGoogle Scholar
  42. Palmer CGS, Hsieh H, Reed EF, Lonnqvist J, Peltonen L, Woodward JA, Sinsheimer JS (2006) HLA-B maternal–fetal genotype matching increases risk of schizophrenia. Am J Hum Genet 79:710–715PubMedCrossRefGoogle Scholar
  43. Palmer CGS, Turunen JA, Sinsheimer JS, Minassian S, Paunio T, Lonnqvist J, Peltonen L, Woodward JA (2002) RHD maternal–fetal genotype incompatibility increases schizophrenia susceptibility. Am J Hum Genet 71:1312–1319PubMedCrossRefGoogle Scholar
  44. Relton CL, Davey Smith G (2012) Two-step epigenetic Mendel randomization: a strategy for establishing the causal role of epigenetic processes in pathways to disease. Int J Epidemiol 41:161–176PubMedCrossRefGoogle Scholar
  45. Robson EB (1955) Birth weight in cousins. Annals Hum Genet 262–8Google Scholar
  46. Sham PC, Curtis D (1995) An extended transmission/disequilibrium test (TDT) for multi-allele marker loci. Ann Hum Genet 59:323–336PubMedCrossRefGoogle Scholar
  47. Sinsheimer JS, Blangero J, Lange K (2000) Gamete-competition models. Am J Hum Genet 66:1168–1172PubMedCrossRefGoogle Scholar
  48. Sinsheimer JS, Palmer CGS, Woodward AJ (2003) The maternal–fetal genotype incompatibility test: detecting genotype combinations that increase risk for disease. Genet Epidemiol 24:1–13PubMedCrossRefGoogle Scholar
  49. Spielman RS, McGinnis RE, Ewens WJ (1993) Transmission test for linkage disequilibrium: the insulin gene region and insulin dependent diabetes mellitus (IDDM). Am J Hum Genet 52: 506–516PubMedGoogle Scholar
  50. Stratchen T, Reed A (2003) Human molecular genetics, 3rd edn. Garland Science/Taylor & Francis Group, OxfordGoogle Scholar
  51. Stubbs EG, Ritvo ER, Mason-Brothers A (1985) Autism and shared parental HLA antigens. J Am Acad Child Psych 24:182–185CrossRefGoogle Scholar
  52. Terwilliger JD, Ott J (1992) A haplotype based ‘haplotype relative risk' approach to detecting allelic associations. Hum Hered 42:337–346PubMedCrossRefGoogle Scholar
  53. Thapar A, Harold G, Rice F, Ge X, Boivin J, Hay D, van den Bree M, Lewis A (2007) Do intrauterine or genetic influences explain the foetal origins of chronic disease? A novel experimental method for disentangling effects. BMC Med Res Methodol 7:25PubMedCrossRefGoogle Scholar
  54. Thomas DC (2004) Statistical methods in genetic epidemiology. Oxford University Press, OxfordGoogle Scholar
  55. Thomas DC, Conti DV (2004) Commentary: the concept of ‘Mendelian Randomization’. Int J Epidemiol 33:21–25PubMedCrossRefGoogle Scholar
  56. Vermeulen SH, Shi M, Weinberg CR, Umbach DM (2009) A hybrid design: case-parent triads supplemented by control-mother dyads. Genet Epidemiol 33:136–144PubMedCrossRefGoogle Scholar
  57. Watanabe RM, Valle T, Hauser ER, Ghosh S, Eriksson J, Kohtamèki K, Ehnholm C, Tuomilehto J, Collins FS, Bergman RN, Boehnke M (1999) Familiality of quantitative metabolic traits in Finnish families with non-insulin-dependent diabetes mellitus. Finland-United States Investigation of NIDDM Genetics (FUSION) Study investigators. Hum Hered 49:159–168PubMedCrossRefGoogle Scholar
  58. Wheeler E, Cordell HJ (2007) Quantitative trait association in parent offspring trios: extension of case/pseudocontrol method and comparison of prospective and retrospective approaches. Genet Epidemiol 31:813–833PubMedCrossRefGoogle Scholar
  59. Weinberg CR, Wilcox AJ, Lie RT (1998) A log-linear approach to case-parent-triad data: assessing effects of disease genes that act either directly or through maternal effects and that may be subject to parental imprinting. Am J Hum Genet 62:969–978PubMedCrossRefGoogle Scholar
  60. Zhou JJ, Pelka S, Lange K, Palmer CG, Sinsheimer JS (2011) Dissecting prenatal, postnatal and inherited effects: ART and design. Genet Epidemiol 35:437–446PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Human GeneticsDavid Geffen School of Medicine at UCLALos AngelesUSA
  2. 2.Department of BiostatisticsUCLA Fielding School of Public HealthLos AngelesUSA

Personalised recommendations