Advancing paternal age and the risk of schizophrenia

Background: A major source of new mutations in humans is the male germ line , with mutation rates monotonically increasing as father's age at conceptio n advances, possibly because of accumulating replication errors in spermato gonial cell lines. Methods We investigated whether the risk of schizophrenia was associated wi th advancing paternal age in a population-based birth cohort of 87907 indiv iduals 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 w ere diagnosed as having schizophrenia and related nonaffective psychoses. A fter controlling for maternal age and other confounding factors (sex, ethni city, education [to reflect socioeconomic status], and duration of marriage ) in proportional hazards regression, we found that paternal age was a stro ng and significant predictor of the schizophrenia diagnoses, but not of oth er psychiatric disorders. Compared with offspring of fathers younger than 2 5 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 acid 50 years or more, respectively. Categories of mother's age showed no s ignificant effects, after adjusting for paternal age. Conclusions: These findings support the hypothesis that schizophrenia may b e associated, in part, with de novo mutations arising in paternal germ cell s. If confirmed, they would entail a need for novel approaches to the ident ification of genes involved in schizophrenia.