An Indirect Test of the New Mutation Hypothesis Associating Advanced Paternal Age with the Etiology of Schizophrenia

Two studies by Malaspina et al. [2001: Arch Gen Psychiatr 58:361-367]; [2002: Am J Med Genet 114:299-303] have put forward the hypothesis that advanced paternal age with concomitant mutations in the male germ line is associated with sporadic schizophrenia in offspring. The hypothesis was supported by an observation of a monotonic increase in the risk for schizophrenia with increased paternal age, and a second observation in a separate sample of greater paternal mean age at birth among cases of apparent sporadic schizophrenia. The present study did not test the association of the risk of schizophrenia with advanced paternal age, but repeated the test of paternal age at birth among sporadic versus familial schizophrenic probands. We also examined the risk of schizophrenia, psychosis, and broad psychosis among paternal 1st and 2nd degree relatives of schizophrenic probands as a function of paternal age at birth of the proband, reasoning that if probands born to older fathers are more likely to be sporadic cases, the risk of schizophrenia (or psychosis) should be lower on the paternal side of the family. Results indicate a lack of support for the previous finding that sporadic probands tend to have older fathers at birth than familial probands. Results also failed to support the related hypothesis that increased paternal age is associated with the lower risk of schizophrenia (or psychosis) in the relatives of schizophrenic probands. The failure to support the paternal age hypothesis may be a function of heterogeneous samples, but calls for further research in the context of family studies.