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Advancing Paternal Age and the Risk of Schizophrenia
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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