Autism and Increased Paternal Age

Reference work entry

Abstract

With today’s population living longer, there is a trend in many modern societies to delay parenthood until the prospective parents have completed their education and established their careers. This has resulted in an increase in children born to parents of advanced age, which has been linked to several disorders of brain development including mental retardation, schizophrenia, and autism. The underlying mechanisms for this relationship are believed to be complex and likely differ between maternal and paternal age effects. Maternal age has been associated with an increase in genetic disorders such as Down syndrome caused by duplication of chromosome 21. All of a female’s oocytes are present at birth, wherefore oocytes in older women have increased time to undergo genetic rearrangements and duplications. This is not true for fathers whose spermatocytes are continuously produced throughout life. Suggested mechanisms for an effect of advanced paternal age on autism and other disorders include de novo (new) mutations in older fathers’ DNA and multiple epigenetic mechanisms including changes in DNA methylation, histone modifications, and noncoding RNAs. Evidence for genetic and epigenetic mechanisms is reviewed herein and important areas for future research are highlighted.

References

  1. Adkins RM, Thomas F, Tylavsky FA, Krushkal J. Parental ages and levels of DNA methylation in the newborn are correlated. BMC Med Genet. 2011;12:47.PubMedCrossRefGoogle Scholar
  2. Alter MD, Hen R. Is there a genomic tone? Implications for understanding development, adaptation and treatment. Dev Neurosci. 2009;31:351–7.PubMedCrossRefGoogle Scholar
  3. Alter MD, Rubin DB, Ramsey K, et al. Variation in the large-scale organization of gene expression levels in the hippocampus relates to stable epigenetic variability in behavior. PLoS One. 2008;6:e3344.CrossRefGoogle Scholar
  4. Alter MD, Kharkar R, Ramsey KE, et al. Autism and increased paternal age related changes in global levels of gene expression regulation. PLoS One. 2011;6:e16715.PubMedCrossRefGoogle Scholar
  5. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999;23:185–8.PubMedCrossRefGoogle Scholar
  6. Asaka Y, Jugloff DG, Zhang L, Eubanks JH, Fitzsimonds RM. Hippocampal synaptic plasticity is impaired in the Mecp2-null mouse model of Rett syndrome. Neurobiol Dis. 2006;21:217–27.PubMedCrossRefGoogle Scholar
  7. Auroux M. Decrease of learning capacity in offspring with increasing paternal age in the rat. Teratology. 1983;27:141–8.PubMedCrossRefGoogle Scholar
  8. Bailey A, Le Couteur A, Gottesman I, et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med. 1995;25:63–77.PubMedCrossRefGoogle Scholar
  9. Berg J, Lin KK, Sonnet, et al. Imprinted genes that regulate early mammalian growth are coexpressed in somatic stem cells. PLoS One. 2011;6:e26410.PubMedCrossRefGoogle Scholar
  10. Beydoun A, D’Souza J. Treatment of idiopathic generalized epilepsy – a review of the evidence. Expert Opin Pharmacother. 2012;13:1283–98.PubMedCrossRefGoogle Scholar
  11. Bouchard Jr TJ, Heston L, Eckert E, Keyes M, Resnick S. The Minnesota study of twins reared apart: project description and sample results in the developmental domain. Prog Clin Biol Res. 1981;69:227–33.PubMedGoogle Scholar
  12. Byrne M, Agerbo E, Ewald H, Eaton WW, Mortensen PB. Parental age and risk of schizophrenia: a case control study. Arch Gen Psychiatry. 2003;60:673–8.PubMedCrossRefGoogle Scholar
  13. Cardno AG, Gottesman II. Twin studies of schizophrenia: from bow-and-arrow concordances to star wars Mx and functional genomics. Am J Med Genet. 2000;97:12–7.PubMedCrossRefGoogle Scholar
  14. Cheng LC, Pastrana E, Tavazoie M, Doetsch F. miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nat Neurosci. 2009;12:399–408.PubMedCrossRefGoogle Scholar
  15. Dalman C, Allbeck P. Paternal age and schizophrenia: further support for an association. Am J Psychiatry. 2002;159:1591–2.PubMedCrossRefGoogle Scholar
  16. Dempster EL, Pidsley R, Schalkwyk LC, et al. Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder. Hum Mol Genet. 2011;20:4786–96.PubMedCrossRefGoogle Scholar
  17. Driscoll DA, Gross S. Clinical practice. Prenatal screening for aneuploidy. N Engl J Med. 2009;360:2556–62.PubMedCrossRefGoogle Scholar
  18. Elbe D, Lalani Z. Review of the pharmacotherapy of irritability of autism. J Can Acad Child Adolesc Psychiatry. 2012;21:130–46.PubMedGoogle Scholar
  19. Festenstein R, Aragon L. Decoding the epigenetic effects of chromatin. Genome Biol. 2003;4:342.PubMedCrossRefGoogle Scholar
  20. Flatscher-Bader T, Foldi CJ, Chong S, et al. Increased de novo copy number variants in the offspring of older males. Transl Psychiatry. 2011;1:e34.PubMedCrossRefGoogle Scholar
  21. Foldi CJ, Eyles DW, McGrath JJ, Burne TH. Advanced paternal age is associated with alterations in discrete behavioural domains and cortical neuroanatomy of C57BL/6J mice. Eur J Neurosci. 2010;31:556–64.PubMedCrossRefGoogle Scholar
  22. Fombonne E. The changing epidemiology of autism. J Appl Res Intellect Disabil. 2005;18:281–94.CrossRefGoogle Scholar
  23. Fraga MF, Ballestar E, Paz MF, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA. 2005;102:10604–9.PubMedCrossRefGoogle Scholar
  24. Frans EM, Sandin S, Reichenberg A, Lichtenstein P, Långström N, Hultman CM. Advancing paternal age and bipolar disorder. Arch Gen Psychiatry. 2008;65:1034–40.PubMedCrossRefGoogle Scholar
  25. Gandal M, Nesbitt AM, McCurdy, Alter M. Modulation of cellular plasticity is related to power-law scaling of stereotyped gene expression programs. PLoS One. 2012;7:412–15.[ahead of print].Google Scholar
  26. García-Palomares S, Pertusa JF, Miñarro J, et al. Long-term effects of delayed fatherhood in mice on postnatal development and behavioral traits in offspring. Biol Reprod. 2009;80:337–42.PubMedCrossRefGoogle Scholar
  27. Gärtner K, Baunack E. Is the similarity of monozygotic twins due to genetic factors alone? Nature. 1981;292:646–7.PubMedCrossRefGoogle Scholar
  28. Gillis RF, Rouleau GA. The ongoing dissection of the genetic architecture of autistic spectrum disorder. Mol Autism. 2011;2:12.PubMedCrossRefGoogle Scholar
  29. Giraldez AJ, Cinalli RM, Glasner ME, et al. MicroRNAs regulate brain morphogenesis in zebrafish. Science. 2005;308:833–8.PubMedCrossRefGoogle Scholar
  30. Goriely A, McVean GA, Röjmyr M, Ingemarsson B, Wilkie AO. Evidence for selective advantage of pathogenic FGFR2 mutations in the male germ line. Science. 2003;301:643–6.PubMedCrossRefGoogle Scholar
  31. Gregory SC, Connelly JJ, Towers AJ, et al. Genomic and epigenetic evidence for oxytocin deficiency in autism. BMC Med. 2009;7:62.PubMedCrossRefGoogle Scholar
  32. Haddad PM, Das A, Ashfaq M, Wieck A. A review of valproate in psychiatric practice. Expert Opin Drug Metab Toxicol. 2009;5:539–51.PubMedCrossRefGoogle Scholar
  33. Hastings PJ, Lupski JR, Rosenberg SM, Ira G. Mechanisms of change in gene copy number. Nat Rev Genet. 2009;10:551–64.PubMedCrossRefGoogle Scholar
  34. Hehir-Kwa JY, Rodríguez-Santiago B, Vissers LE, et al. De novo copy number variants associated with intellectual disability have a paternal origin and age bias. J Med Genet. 2011;48:776–8.PubMedCrossRefGoogle Scholar
  35. Heyn H, Li N, Ferreira HJ, et al. Distinct DNA methylomes of newborns and centenarians. Proc Natl Acad Sci USA. 2012;109:10522–7.[ahead of print].PubMedCrossRefGoogle Scholar
  36. Hogart A, Wu D, LaSalle JM, Schanen NC. The comorbidity of autism with the genomic disorders of chromosome 15q11.2-q13. Neurobiological Disord. 2010;38:181–91.CrossRefGoogle Scholar
  37. Houston I, Peter CJ, Mitchell A, Straubhaar J, Rogaev E, Akbarian S. Epigenetics in the human brain. Neuropsychopharmacology. 2012;38:183–97. doi:10.1038/npp.2012.78.PubMedCrossRefGoogle Scholar
  38. Hultman CM, Sandin S, Levine SZ, Lichtenstein P, Reichenberg A. Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies. Mol Psychiatry. 2011;16:1203–12.PubMedCrossRefGoogle Scholar
  39. Im HI, Kenny PJ. MicroRNAs in neuronal function and dysfunction. Trends Neurosci. 2012;35:325–34.PubMedCrossRefGoogle Scholar
  40. Kurahashi H, Bolor H, Kato T, et al. Recent advance in our understanding of the molecular nature of chromosomal abnormalities. J Hum Genet. 2009;54:253–60.PubMedCrossRefGoogle Scholar
  41. Lehmann K, Löwel S. Age-dependent ocular dominance plasticity in adult mice. PLoS One. 2008;3:e3120.PubMedCrossRefGoogle Scholar
  42. Levenson JM, Sweatt JD. Epigenetic mechanisms: a common theme in vertebrate and invertebrate memory formation. Cell Mol Life Sci. 2006;63:1009–16.PubMedCrossRefGoogle Scholar
  43. Levenson JM, O’Riordan KJ, Brown KD, Trinh MA, Molfese DL, Sweatt JD. Regulation of histone acetylation during memory formation in the hippocampus. J Biol Chem. 2004;279:40545–59.PubMedCrossRefGoogle Scholar
  44. Li H, Zhong X, Chau KF, Williams EC, Chang Q. Loss of activity-induced phosphorylation of MeCP2 enhances synaptogenesis, LTP and spatial memory. Nat Neurosci. 2011;14:1001–8.PubMedCrossRefGoogle Scholar
  45. Li J, Harris RA, Cheung SW, et al. Genomic hypomethylation in the human germline associates with selective structural mutability in the human genome. PLoS Genet. 2012;8:e1002692.PubMedCrossRefGoogle Scholar
  46. MacDonald WA. Epigenetic mechanisms of genomic imprinting: common themes in the regulation of imprinted regions in mammals, plants, and insects. Genet Res Int.2012;2012:585024PubMedGoogle Scholar
  47. Malaspina D, Harlap S, Fennig S, et al. Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry. 2001;58:361–7.PubMedCrossRefGoogle Scholar
  48. Malaspina D, Reichenberg A, Weiser M, et al. Paternal age and intelligence: implications for age-related genomic changes in male germ cells. Psychiatr Genet. 2005;15:117–25.PubMedCrossRefGoogle Scholar
  49. Margolis R, Ross C. Genetics of childhood disorders: IX. Triplet repeat disorders. Development and neurobiology. J Am Acad Child Adolesc Psychiatry. 1999;38:1598–600.PubMedCrossRefGoogle Scholar
  50. Maric NP, Svrakic DM. Why schizophrenia genetics needs epigenetics: a review. Psychiatr Danub. 2012;24:2–18.PubMedGoogle Scholar
  51. Mefford HC, Batshaw ML, Hoffman EP. Genomics, intellectual disability, and autism. N Engl J Med. 2012;366:733–43.PubMedCrossRefGoogle Scholar
  52. Menezes PR, Lewis G, Rasmussen F, et al. Paternal and maternal ages at conception and risk of bipolar affective disorder in their offspring. Psychol Med. 2010;40:477–85.PubMedCrossRefGoogle Scholar
  53. Mill J, Tang T, Kaminsky Z, et al. Epigenetic profiling reveals DNA-methylation changes associated with major psychosis. Am J Hum Genet. 2008;82:696–711.PubMedCrossRefGoogle Scholar
  54. Moore S, Kelleher E, Corvin A. The shock of the new: progress in schizophrenia genomics. Curr Genomics. 2011;12:516–24.PubMedCrossRefGoogle Scholar
  55. Morris KV. Non-coding RNAs, epigenetic memory and the passage of information to progeny. RNA Biol. 2009;6:242–7.PubMedCrossRefGoogle Scholar
  56. Muhle R, Trentacoste SV, Rapin I. The genetics of autism. Pediatrics. 2004;113:472–86.CrossRefGoogle Scholar
  57. Nan X, Campoy FJ, Bird A. MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell. 1997;88:471–81.PubMedCrossRefGoogle Scholar
  58. Nguyen A, Rauch TA, Pfeifer GP, Hu VW. Global methylation profiling of lymphoblastoid cell lines reveals epigenetic contributions to autism spectrum disorders and a novel autism candidate gene, RORA, whose protein product is reduced in autistic brain. FASEB J. 2010;24:3036–51.PubMedCrossRefGoogle Scholar
  59. Oakes CC, Smiraglia DJ, Plass C, Trasler JM, Robaire B. Aging results in hypermethylation of ribosomal DNA in sperm and liver of male rats. Proc Natl Acad Sci USA. 2003;100:1775–80.PubMedCrossRefGoogle Scholar
  60. Olde Loohuis NF, Kos A, Martens GJ, Van Bokhoven H, Nadif Kasri N, Aschrafi A. MicroRNA networks direct neuronal development and plasticity. Cell Mol Life Sci. 2012;69:89–102.PubMedCrossRefGoogle Scholar
  61. Olynik BM, Rastegar M. The genetic and epigenetic journey of embryonic stem cells into mature neural cells. Front Genet. 2012;3:81.PubMedCrossRefGoogle Scholar
  62. Penrose LS. Parental age and mutation. Lancet. 1955;269:312–3.PubMedCrossRefGoogle Scholar
  63. Perrin MC, Brown AS, Malaspina D. Aberrant epigenetic regulation could explain the relationship of paternal age to schizophrenia. Schizophr Bull. 2007;33:1270–3.PubMedCrossRefGoogle Scholar
  64. Petronis A. The origin of schizophrenia: genetic thesis, epigenetic antithesis and resolving synthesis. Biol Psychiatry. 2004;55:965–70.PubMedCrossRefGoogle Scholar
  65. Razin A, Cedar H. DNA methylation and gene expression. Microbiol Rev. 1991;55:451–8.PubMedGoogle Scholar
  66. Reichenberg A, Gross R, Weiser M, et al. Advancing paternal age and autism. Arch Gen Psychiatry. 2006;63:1026–32.PubMedCrossRefGoogle Scholar
  67. Sandhu KS. Systems properties of proteins encoded by imprinted genes. Epigenetics. 2010;5:627–36.PubMedCrossRefGoogle Scholar
  68. Sebat J, Lakshmi B, Troge J, et al. Large-scale copy number polymorphism in the human genome. Science. 2004;305:525–8.PubMedCrossRefGoogle Scholar
  69. Shelton JF, Tancredi DJ, Hertz-Picciotto I. Independent and dependent contributions of advanced maternal and paternal ages to autism risk. Autism Res. 2010;3:30–9.PubMedCrossRefGoogle Scholar
  70. Sipos A, Rasmussen F, Harrison G, et al. Paternal age and schizophrenia: a population based cohort study. BMJ. 2004;329:1070.PubMedCrossRefGoogle Scholar
  71. Smith RG, Kember RL, Mill J, et al. Advancing paternal Age is associated with deficits in social and exploratory behaviors in the offspring: a mouse model. PLoS One. 2009;4:e8456.PubMedCrossRefGoogle Scholar
  72. Stoneking M. Single nucleotide polymorphisms. From the evolutionary past. Nature. 2001;409:821–2.PubMedCrossRefGoogle Scholar
  73. Strathern JN, Shafer BK, McGill CB. DNA synthesis errors associated with double-strand-break repair. Genetics. 1995;140:965–72.PubMedGoogle Scholar
  74. Swisshelm K, Disteche CM, Thorvaldsen J, Nelson A, Salk D. Age-related increase in methylation of ribosomal genes and inactivation of chromosome-specific rRNA gene clusters in mouse. Mutat Res. 1990;237:131–46.PubMedCrossRefGoogle Scholar
  75. Templado C, Donate A, Giraldo J, Bosch M, Estop A. Advanced age increases chromosome structure abnormalities in human spermatozoa. Eur J Hum Genet. 2011;19:145–51.PubMedCrossRefGoogle Scholar
  76. Tiemann-Boege I, Navidi W, Grewal R, et al. The observed human sperm mutation frequency cannot explain the achondroplasia paternal age effect. Proc Natl Acad Sci USA. 2002;99:14952–7.PubMedCrossRefGoogle Scholar
  77. Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci. 2006;9:519–25.PubMedCrossRefGoogle Scholar
  78. Tsankova N, Renthal W, Kumar A, Nestler EJ. Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci. 2007;8:355–67.PubMedCrossRefGoogle Scholar
  79. Turner BM. The adjustable nucleosome: an epigenetic signaling molecule. Trends Genet. 2012;28:436–444.[ahead of print].CrossRefGoogle Scholar
  80. Van Buggenhout G, Fryns JP. Angelman syndrome (AS, MIM 105830). Eur J Hum Genet. 2009;17:1367–73.PubMedCrossRefGoogle Scholar
  81. van Engeland M, Derks S, Smits KM, Meijer GA, Herman JG. Colorectal cancer epigenetics: complex simplicity. J Clin Oncol. 2011;29:1382–91.PubMedCrossRefGoogle Scholar
  82. Vincent A, Van Seuningen I. Epigenetics, stem cells and epithelial cell fate. Differentiation. 2009;78:99–107.PubMedCrossRefGoogle Scholar
  83. Vo NK, Cambronne XA, Goodman RH. MicroRNA pathways in neural development and plasticity. Curr Opin Neurobiol. 2010;20:457–65.PubMedCrossRefGoogle Scholar
  84. Weaver IC, Champagne FA, Brown SE, et al. Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life. J Neurosci. 2005;25:11045–54.PubMedCrossRefGoogle Scholar
  85. Weaver IC, Meaney MJ, Szyf M. Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood. Proc Natl Acad Sci USA. 2006;103:3480–5.PubMedCrossRefGoogle Scholar
  86. Wilkinson LS, Davies W, Isles AR. Genomic imprinting effects on brain development and function. Nat Rev Neurosci. 2007;8:832–43.PubMedCrossRefGoogle Scholar
  87. Wong AH, Gottesman II, Petronis A. Phenotypic differences in genetically identical organisms: the epigenetic perspective. Hum Mol Genet. 2005;14(Spec 1):R11–8.PubMedCrossRefGoogle Scholar
  88. Zeschnigk M, Schmitz B, Dittrich B, Buiting K, Horsthemke B, Doerfler W. Imprinted segments in the human genome: different DNA methylation patterns in the Prader-Willi/Angelman syndrome region as determined by the genomic sequencing method. Hum Mol Genet. 1997;6:387–95.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of PsychiatryUniversity of Pennsylvania, Center for Neurobiology and BehaviorPhiladelphiaUSA
  2. 2.Department of PsychiatryUniversity of Pennsylvania, Perelman School of MedicinePhiladelphiaUSA

Personalised recommendations