Letters to the Editor
Paternal Age as a Risk Factor
Recent research reports have focused attention on the association between advanced paternal age and increased risk of schizophrenia in offspring (1,2). In addition to schizophrenia, numerous genetic illnesses are reported to have the same association with increased paternal age (3). An increased mutation rate related to increased paternal age has been documented in the male gametogenesis (4). Most of these illnesses are autosomal-dominant disorders (5). Two x-linked recessive illnesses—hemophilia A and Lesch-Nyhan disease—have been frequently found with increased maternal grandpaternal age (6–8). It is proposed that the origin of schizophrenia can in some cases be related to a mutation in the gametogenesis of the father that is related to aging. It is further proposed that, as with hemophilia A and Lesch-Nyhan disease, the mutated gene or genes in some cases of schizophrenia and other genetic illnesses can be transmitted to future generations. In such cases, the illness could be expressed in a distant relative far removed in time from the original mutational event. Further genetic research on germline mutations related to paternal age is needed to establish the significance of paternal age as a risk factor.
1. Malaspina D, Harlap S, Fennig S, Heiman D, Nahon D, Feldman D, and others. Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry 2001;58:361–7.
2. Raschka LB. Parental age and schizophrenia. Magyar Andrologia [Hungarian Andrology] 1998;111:47–50.
3. Tarin JJ, Brines J, Cano A. Long-term effects of delayed parenthood. Hum Reprod 1998;13:2371–6.
4. Crow JF. How much do we know about spontaneious human mutation rates? Environ Mol Mutagen 1993;21:122–9.
5. Carothers AD, McAllion SJ, Paterson CR. Risk of dominant mutation in older fathers: evidence from osteogenesis imperfecta. J Med Genet 1986;23:227–30.
6. Rimoin DL. Mutation in man. In: Emery AEH, Rimoin DA, editors. Principles and practice of medical genetics. Edinburgh (UK): Churchill Livingstone; 1983. p 32–3.
7. Crow JF. The high spontaneious mutation rate: is it a risk? Proc Natl Acad Sic USA 1997;94:8380–6.
8. Prevention of avoidable mutational disease: memorandum from a WHO meeting. Bull World Health Organ 1986;64:205–16.
Leslie B Raschka, MD, FRCPC