Advancing Paternal Age and Autism | Autism Spectrum Disorders | JAMA Psychiatry | JAMA Network
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1.
Bailey  APhillips  WRutter  M Autism: towards an integration of clinical, genetic, neuropsychological, and neurobiological perspectives.  J Child Psychol Psychiatry 1996;3789- 126PubMedGoogle ScholarCrossref
2.
Rapin  I Autism.  N Engl J Med 1997;33797- 104PubMedGoogle ScholarCrossref
3.
Rapin  I The autistic-spectrum disorders.  N Engl J Med 2002;347302- 303PubMedGoogle ScholarCrossref
4.
Volkmar  FRPauls  D Autism.  Lancet 2003;3621133- 1141PubMedGoogle ScholarCrossref
5.
Fombonne  E The prevalence of autism.  JAMA 2003;28987- 89PubMedGoogle ScholarCrossref
6.
Fombonne  E The epidemiology of autism: a review.  Psychol Med 1999;29769- 786PubMedGoogle ScholarCrossref
7.
Croen  LAGrether  JKHoogstrate  JSelvin  S The changing prevalence of autism in California.  J Autism Dev Disord 2002;32207- 215PubMedGoogle ScholarCrossref
8.
Newschaffer  CJFallin  DLee  NL Heritable and nonheritable risk factors for autism spectrum disorders.  Epidemiol Rev 2002;24137- 153PubMedGoogle ScholarCrossref
9.
Penrose  LS The effects of change in maternal age distribution upon the incidence of mongolism.  J Ment Defic Res 1967;1154- 57PubMedGoogle Scholar
10.
Durkin  MVKaveggia  EGPendleton  ENeuhauser  GOpitz  JM Analysis of etiologic factors in cerebral palsy with severe mental retardation, I: analysis of gestational, parturitional and neonatal data.  Eur J Pediatr 1976;12367- 81PubMedGoogle ScholarCrossref
11.
Gillberg  C Maternal age and infantile autism.  J Autism Dev Disord 1980;10293- 297PubMedGoogle ScholarCrossref
12.
Croen  LAGrether  JKSelvin  S The epidemiology of mental retardation of unknown cause.  Pediatrics 2001;107E86PubMedGoogle ScholarCrossref
13.
Eaton  WWMortensen  PBThomsen  PHFrydenberg  M Obstetric complications and risk for severe psychopathology in childhood.  J Autism Dev Disord 2001;31279- 285PubMedGoogle ScholarCrossref
14.
Gillberg  CGillberg  IC Infantile autism: a total population study of reduced optimality in the pre-, peri-, and neonatal period.  J Autism Dev Disord 1983;13153- 166PubMedGoogle ScholarCrossref
15.
Burd  LSeverud  RKerbeshian  JKlug  MG Prenatal and perinatal risk factors for autism.  J Perinat Med 1999;27441- 450PubMedGoogle Scholar
16.
Cryan  EByrne  MO’Donovan  AO’Callaghan  E A case-control study of obstetric complications and later autistic disorder.  J Autism Dev Disord 1996;26453- 460PubMedGoogle ScholarCrossref
17.
Hultman  CMSparen  PCnattingius  S Perinatal risk factors for infantile autism.  Epidemiology 2002;13417- 423PubMedGoogle ScholarCrossref
18.
Larsson  HJEaton  WWMadsen  KMVestergaard  MOlesen  AVAgerbo  ESchendel  DThorsen  PMortensen  PB Risk factors for autism: perinatal factors, parental psychiatric history, and socioeconomic status.  Am J Epidemiol 2005;161916- 928PubMedGoogle ScholarCrossref
19.
Glasson  EJBower  CPetterson  BDe Klerk  NChaney  GHallmayer  JF Perinatal factors and the development of autism: a population study.  Arch Gen Psychiatry 2004;61618- 627PubMedGoogle ScholarCrossref
20.
Croen  LAGrether  JKSelvin  S Descriptive epidemiology of autism in a California population: who is at risk?  J Autism Dev Disord 2002;32217- 224PubMedGoogle ScholarCrossref
21.
Tolarova  MMHarris  JAOrdway  DEVargervik  K Birth prevalence, mutation rate, sex ratio, parents' age, and ethnicity in Apert syndrome.  Am J Med Genet 1997;72394- 398PubMedGoogle ScholarCrossref
22.
Singer  SBower  CSouthall  PGoldblatt  J Craniosynostosis in Western Australia, 1980-1994: a population-based study.  Am J Med Genet 1999;83382- 387PubMedGoogle ScholarCrossref
23.
Lian  ZHZack  MMErickson  JD Paternal age and the occurrence of birth defects.  Am J Hum Genet 1986;39648- 660PubMedGoogle Scholar
24.
Polednak  AP Paternal age in relation to selected birth defects.  Hum Biol 1976;48727- 739PubMedGoogle Scholar
25.
Perry  TBFraser  FC Paternal age and congenital cleft lip and cleft palate.  Teratology 1972;6241- 246PubMedGoogle ScholarCrossref
26.
Savitz  DASchwingl  PJKeels  MA Influence of paternal age, smoking, and alcohol consumption on congenital anomalies.  Teratology 1991;44429- 440PubMedGoogle ScholarCrossref
27.
Malaspina  DHarlap  SFennig  SHeiman  DNahon  DFeldman  DSusser  ES Advancing paternal age and the risk of schizophrenia.  Arch Gen Psychiatry 2001;58361- 367PubMedGoogle ScholarCrossref
28.
Brown  ASSchaefer  CAWyatt  RJBegg  MDGoetz  RBresnahan  MAHarkavy-Friedman  JGorman  JMMalaspina  DSusser  ES Paternal age and risk of schizophrenia in adult offspring.  Am J Psychiatry 2002;1591528- 1533PubMedGoogle ScholarCrossref
29.
Auroux  MRMayaux  MJGuihard-Moscato  MLFromantin  MBarthe  JSchwartz  D Paternal age and mental functions of progeny in man.  Hum Reprod 1989;4794- 797PubMedGoogle Scholar
30.
Malaspina  DReichenberg  AWeiser  MFennig  SDavidson  MHarlap  SWolitzky  RRabinowitz  JSusser  EKnobler  HY Paternal age and intelligence: implications for age-related genomic changes in male germ cells.  Psychiatr Genet 2005;15117- 125PubMedGoogle ScholarCrossref
31.
Moloney  DMSlaney  SFOldridge  MWall  SASahlin  PStenman  GWilkie  AO Exclusive paternal origin of new mutations in Apert syndrome.  Nat Genet 1996;1348- 53PubMedGoogle ScholarCrossref
32.
Allen  JDeMeyer  MKNorton  JAPontius  WYang  E Intellectuality in parents of psychotic, subnormal, and normal children.  J Autism Child Schizophr 1971;1311- 326PubMedGoogle ScholarCrossref
33.
Treffert  DA Epidemiology of infantile autism.  Arch Gen Psychiatry 1970;22431- 438PubMedGoogle ScholarCrossref
34.
Mouridsen  SERich  BIsager  T Brief report: parental age in infantile autism, autistic-like conditions, and borderline childhood psychosis.  J Autism Dev Disord 1993;23387- 396PubMedGoogle ScholarCrossref
35.
Gillberg  C Parental age in child psychiatric clinic attenders.  Acta Psychiatr Scand 1982;66471- 478PubMedGoogle Scholar
36.
Weiser  MReichenberg  ARabinowitz  JKaplan  ZMark  MBodner  ENahon  DDavidson  M Association between nonpsychotic psychiatric diagnoses in adolescent males and subsequent onset of schizophrenia.  Arch Gen Psychiatry 2001;58959- 964PubMedGoogle ScholarCrossref
37.
Schopler  EReichler  RJDeVellis  RFDaly  K Toward objective classification of childhood autism: Childhood Autism Rating Scale (CARS).  J Autism Dev Disord 1980;1091- 103PubMedGoogle ScholarCrossref
38.
Steinhausen  HCGobel  DBreinlinger  MWohlleben  B Maternal age and autistic children.  J Dev Behav Pediatr 1984;5343- 345PubMedGoogle ScholarCrossref
39.
Lin  DYPsaty  BMKronmal  RA Assessing the sensitivity of regression results to unmeasured confounders in observational studies.  Biometrics 1998;54948- 963PubMedGoogle ScholarCrossref
40.
Penrose  LS Parental age and mutation.  Lancet 1955;269312- 313http://linkinghub.elsevier.com/retrieve/pii/S0140673655923059Google ScholarCrossref
41.
Crow  JF The high spontaneous mutation rate: is it a health risk?  Proc Natl Acad Sci U S A 1997;948380- 8386PubMedGoogle ScholarCrossref
42.
Green  RELewis  BPHillman  RTBlanchette  MLareau  LFGarnett  ATRio  DCBrenner  SE Widespread predicted nonsense-mediated mRNA decay of alternatively-spliced transcripts of human normal and disease genes.  Bioinformatics 2003;19 ((suppl 1)) i118- i121Google ScholarCrossref
43.
Hannon  GJRossi  JJ Unlocking the potential of the human genome with RNA interference.  Nature 2004;431371- 378PubMedGoogle ScholarCrossref
44.
Malaspina  D Paternal factors and schizophrenia risk: de novo mutations and imprinting.  Schizophr Bull 2001;27379- 393PubMedGoogle ScholarCrossref
45.
Keverne  EBMartel  FLNevison  CM Primate brain evolution: genetic and functional considerations.  Proc Biol Sci 1996;263 ((1371)) 689- 696PubMedGoogle ScholarCrossref
46.
Isles  ARWilkinson  LS Imprinted genes, cognition and behaviour.  Trends Cogn Sci 2000;4309- 318PubMedGoogle ScholarCrossref
47.
Skuse  DHJames  RSCoppin  BDalton  PAamodt-Leeper  GBacarese-Hamilton  MCreswell  CMcGurk  RJacobs  PA Evidence from Turner's syndrome of an imprinted X-linked locus affecting cognitive function.  Nature 1997;387705- 708Google ScholarCrossref
48.
Mann  MRBartolomei  MS Towards a molecular understanding of Prader-Willi and Angelman syndromes.  Hum Mol Genet 1999;81867- 1873PubMedGoogle ScholarCrossref
49.
Cook  EH  JrLindgern  VLeventhal  BLCourchesne  RLincoln  AShulman  CLord  CCourchesne  E Autism or atypical autism in maternally but not paternally derived proximal 15q duplication.  Am J Hum Genet 1997;60928- 934PubMedGoogle Scholar
50.
Schroer  RJPhelan  MCMichaelis  RCCrawford  ECSkinner  SACuccaro  MSimensen  RJBishop  JSkinner  CFender  DStevenson  RE Autism and maternally derived aberrations of chromosome 15q.  Am J Med Genet 1998;76327- 336PubMedGoogle ScholarCrossref
51.
Piven  JPalmer  PJacobi  DChildress  DArndt  S Broader autism phenotype: evidence from a family history study of multiple-incidence autism families.  Am J Psychiatry 1997;154185- 190PubMedGoogle Scholar
52.
Hare  EHMoran  PA Raised paternal age in psychiatric patients: evidence for the constitutional hypothesis.  Br J Psychiatry 1979;134169- 177PubMedGoogle ScholarCrossref
53.
Zammit  SAllebeck  PDalman  CLundberg  IHemmingson  TOwen  MJLewis  G Paternal age and risk for schizophrenia.  Br J Psychiatry 2003;183405- 408PubMedGoogle ScholarCrossref
54.
Juul-Dam  NTownsend  JCourchesne  E Prenatal, perinatal, and neonatal factors in autism, pervasive developmental disorder–not otherwise specified, and the general population.  Pediatrics 2001;107E63PubMedGoogle ScholarCrossref
55.
Chen  WLandau  SSham  PFombonne  E No evidence for links between autism, MMR and measles virus.  Psychol Med 2004;34543- 553PubMedGoogle ScholarCrossref
56.
Bolton  PFMurphy  MMacdonald  HWhitlock  BPickles  ARutter  M Obstetric complications in autism: consequences or causes of the condition?  J Am Acad Child Adolesc Psychiatry 1997;36272- 281PubMedGoogle ScholarCrossref
Original Article
September 2006

Advancing Paternal Age and Autism

Author Affiliations

Author Affiliations: Department of Psychiatry (Drs Reichenberg, Silverman, and Davidson) and Seaver Center for Autism Research (Dr Silverman), Mount Sinai School of Medicine; Department of Epidemiology, Mailman School of Public Health, Columbia University (Drs Gross, Bresnahan, Harlap, Malaspina, and Susser); New York State Psychiatric Institute (Drs Gross, Bresnahan, Malaspina, and Susser), New York; Institute of Psychiatry, King's College, London, England (Dr Reichenberg); and Department of Psychiatry, Chaim Sheba Medical Center, Tel Hashomer (Drs Weiser and Davidson); School of Social Work, Bar Ilan University, Ramat-Gan (Dr Rabinowitz); School of Social Work, Hebrew University, Jerusalem (Dr Shulman); and Medical Corps, Israel Defense Forces, Tel Aviv (Drs Lubin and Knobler), Israel.

Arch Gen Psychiatry. 2006;63(9):1026-1032. doi:10.1001/archpsyc.63.9.1026
Abstract

Context  Maternal and paternal ages are associated with neurodevelopmental disorders.

Objective  To examine the relationship between advancing paternal age at birth of offspring and their risk of autism spectrum disorder (ASD).

Design  Historical population-based cohort study.

Setting  Identification of ASD cases from the Israeli draft board medical registry.

Participants  We conducted a study of Jewish persons born in Israel during 6 consecutive years. Virtually all men and about three quarters of women in this cohort underwent draft board assessment at age 17 years. Paternal age at birth was obtained for most of the cohort; maternal age was obtained for a smaller subset. We used the smaller subset (n = 132 271) with data on both paternal and maternal age for the primary analysis and the larger subset (n = 318 506) with data on paternal but not maternal age for sensitivity analyses.

Main Outcome Measures  Information on persons coded as having International Classification of Diseases, 10th Revision ASD was obtained from the registry. The registry identified 110 cases of ASD (incidence, 8.3 cases per 10 000 persons), mainly autism, in the smaller subset with complete parental age data.

Results  There was a significant monotonic association between advancing paternal age and risk of ASD. Offspring of men 40 years or older were 5.75 times (95% confidence interval, 2.65-12.46; P<.001) more likely to have ASD compared with offspring of men younger than 30 years, after controlling for year of birth, socioeconomic status, and maternal age. Advancing maternal age showed no association with ASD after adjusting for paternal age. Sensitivity analyses indicated that these findings were not the result of bias due to missing data on maternal age.

Conclusions  Advanced paternal age was associated with increased risk of ASD. Possible biological mechanisms include de novo mutations associated with advancing age or alterations in genetic imprinting.

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