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Abraham Reichenberg, PhD; Raz Gross, MD, MPH; Mark Weiser, MD; Michealine Bresnahan, PhD; Jeremy Silverman, PhD; Susan Harlap, MBBS; Jonathan Rabinowitz, PhD; Cory Shulman, PhD; Dolores Malaspina, MD; Gad Lubin, MD; Haim Y. Knobler, MD; Michael Davidson, MD; Ezra Susser, MD, DrPH

Arch Gen Psychiatry. 2006;63:1026-1032.

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.

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.

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