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Dolores Malaspina, MD; Susan Harlap, MBBS; Shmuel Fennig, MD; Dov Heiman, MPH; Daniella Nahon, BA; Dina Feldman, MA; Ezra S. Susser, MD, PhD

Arch Gen Psychiatry. 2001;58:361-367.

Background  A major source of new mutations in humans is the male germ line, with mutation rates monotonically increasing as father's age at conception advances, possibly because of accumulating replication errors in spermatogonial cell lines.

Method  We investigated whether the risk of schizophrenia was associated with advancing paternal age in a population-based birth cohort of 87 907 individuals born in Jerusalem from 1964 to 1976 by linking their records to the Israel Psychiatric Registry.

Results  Of 1337 offspring admitted to psychiatric units before 1998, 658 were diagnosed as having schizophrenia and related nonaffective psychoses. After controlling for maternal age and other confounding factors (sex, ethnicity, education [to reflect socioeconomic status], and duration of marriage) in proportional hazards regression, we found that paternal age was a strong and significant predictor of the schizophrenia diagnoses, but not of other psychiatric disorders. Compared with offspring of fathers younger than 25 years, the relative risk of schizophrenia increased monotonically in each 5-year age group, reaching 2.02 (95% confidence interval, 1.17-3.51) and 2.96 (95% confidence interval, 1.60-5.47) in offspring of men aged 45 to 49 and 50 years or more, respectively. Categories of mother's age showed no significant effects, after adjusting for paternal age.

Conclusions  These findings support the hypothesis that schizophrenia may be associated, in part, with de novo mutations arising in paternal germ cells. If confirmed, they would entail a need for novel approaches to the identification of genes involved in schizophrenia.

From the Department of Psychiatry/New York State Psychiatric Institute, Columbia University, New York (Drs Malaspina and Susser); Department of Obstetrics and Gynecology, New York University School of Medicine, New York (Dr Harlap); Shalvata Mental Health, Ministry of Mental Health, Even-Yehuda, Israel (Dr Fennig and Mr Heiman); and Mental Health Services Section, Israel Ministry of Health, Tel Aviv (Mss Nahon and Feldman).

Corresponding author: Dolores Malaspina, MD, New York State Psychiatric Institute, 1051 Riverside Dr, New York, NY 10032 (e-mail: dm9{at}Columbia.edu).

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