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Schizophrenia Risk and Paternal Age: A Potential Role for De Novo Mutations in Schizophrenia Vulnerability Genes

Published online by Cambridge University Press:  07 November 2014

Dolores Malaspina ,
Alan Brown ,
Deborah Goetz ,
Nelly Alia-Klein ,
Jill Harkavy-Friedman ,
Susan Harlap  and
Shmuel Fennig
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Abstract

How schizophrenia (SZ) is maintained at roughly 1% of the population despite diminished reproduction is one puzzle currently facing researchers. De novo mutations were first proposed over half a century ago as a source for new SZ genes. Current evidence linking advancing paternal age to SZ risk makes revisiting this hypothesis important. Advancing paternal age is the major source of new mutations in the human population. This article will examine potential mechanisms whereby parental age may impact new mutations, as well as review recent data supporting such a hypothesis.

Type
Feature Article
Information
CNS Spectrums , Volume 7 , Issue 1 , January 2002 , pp. 26 - 29
Copyright
Copyright © Cambridge University Press 2002

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References

REFERENCES

1.Book, JA. Schizophrenia as a gene mutation. Acta Genetica Stat Med. 1953;4:133–139.Google ScholarPubMed
2.Lewis, A. Fertility and mental illness. Eugen Rev. 1958;50:91–106.Google ScholarPubMed
3.Huxley, J, Mayr, E, Osmond, H. Schizophrenia as a genetic morphism. Nature. 1964;204:220–221.CrossRefGoogle ScholarPubMed
4.Rolf, C, Nieschlag, E. Reproductive functions, fertility and genetic risks of ageing men. Exp Clin Endocrinol Diabetes. 2001;109:68–74.CrossRefGoogle ScholarPubMed
5.Gottesman, I. Schizophrenia Genesis: The Origins of Madness. New York, NY: WH Freeman and Company; 1991.Google Scholar
6.Weinberg, W. Zur verebung des zwergwuchses. Arch Rass Ges Biol. 1912;9:710.Google Scholar
7.Penrose, LS. Parental age and mutation. Lancet. 1955;2:312.CrossRefGoogle Scholar
8.Drake, JW, Charlesworth, B, Charlesworth, D, et al.Rates of spontaneous mutation. Genetics. 1998;148:1667–1686.CrossRefGoogle ScholarPubMed
9.Crow, JF. Spontaneous mutation in man. Mutat Res. 1999;437:5–9.CrossRefGoogle ScholarPubMed
10.Cummins, JM, Jequier, AM, Kan, R. Molecular biology of human male infertility: links with aging, mitochondrial genetics, and oxidative stress? Mol Reprod Dev. 1994;37:345–362.CrossRefGoogle ScholarPubMed
11.Robbins, WA. Cytogenetic damage measured in human sperm following cancer chemotherapy. Mutat Res. 1996;355:235–252.CrossRefGoogle ScholarPubMed
12Cohen, FL. Paternal contributions to birth defects. Nurs Clin North Am. 1986;21:49–64.CrossRefGoogle ScholarPubMed
13.Ji, BT, Shu, XO, Linet, MS, et al.Paternal cigarette smoking and the risk of childhood cancer among offspring of nonsmoking mothers. J Natl Cancer Inst. 1997;89:238–244.CrossRefGoogle ScholarPubMed
14.Zenzes, MT. Smoking and reproduction: gene damage to human gametes and embryos. Hum Reprod Update. 2000;6:122–131.CrossRefGoogle ScholarPubMed
15.Rolf, C, Nieschlag, E. Reproductive functions, fertility and genetic risks of ageing men. Exp Clin Endocrinol Diabetes. 2001;109:68–74.CrossRefGoogle ScholarPubMed
16.Wilkin, DJ, Szabo, JK, Cameron, R, et al.CA Mutations in fibroblast growth-factor receptor 3 in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome. Am J Hum Genet. 1998;63:711–716.CrossRefGoogle Scholar
17.Tolarova, MM, Harris, JA, Ordway, DE, et al.Birth prevalence, mutation rate, sex ratio, parents' age, and ethnicity in Apert's syndrome. Am J Med Genet. 1997;72:394–398.3.0.CO;2-R>CrossRefGoogle Scholar
18.Jones, KL, Smith, DW, Harvey, MA, et al.Older paternal age and fresh gene mutation: data on additional disorders. J Pediatr. 1975;86:84–88.CrossRefGoogle ScholarPubMed
19.Zhang, Y, Kreger, BE, Dorgan, JF, et al.Parental age at child's birth and son's risk of prostate cancer. Am J Epidemiol. 1999;150:1208–1212.CrossRefGoogle ScholarPubMed
20.Hemminiki, K, Kyyronen, P. Parental age and risk of sporadic and familial cancer in offspring: implications for germ cell mutagenesis. Epidemiology. 1999;10:747–751.CrossRefGoogle Scholar
21.McIntosh, GC, Olshan, AF, Baird, PA. Paternal age and the risk of birth defects in offspring. Epidemiology. 1995;6:282–288.CrossRefGoogle ScholarPubMed
22.Malaspina, D, Harlap, S, Fennig, S, et al.Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry. 2001;58:361–367.CrossRefGoogle ScholarPubMed
23.Brown, A, Schaefer, CA, Wyatt, RJ, et al. Paternal age and risk of schizophrenia in adult offspring. In press.Google Scholar
24.El-Saadi, O, Cantor-Graae, ER, McGraph, JJ, et al.Maternal and paternal age and risk of schizophrenia or psychosis in data sets from Denmark, Sweden and Australia [abstract]. Schizophr Res. 2001;49(suppl):30.Google Scholar
25.Malaspina, D, Harlap, S, Susser, E, et al.Further data supporting new mutations in the etiology of sporadic schizophrenia. Neuropsychiatric Genetics. In press.Google Scholar
26.Yu, K, Herr, AB, Waksman, G, et al.Loss of fibroblast growth factor receptor 2 ligand-binding specificity in Apert's syndrome. Proc Natl Acad Sci U S A. 2000;97:14536–14541.CrossRefGoogle Scholar
27.Orioli, IM, Castilla, EE, Scarano, G, et al.Effect of paternal age in achondroplasia, thanatophoric dysplasia, and osteogenesis imperfecta. Am J Med Genet. 1995;59:209–217.CrossRefGoogle ScholarPubMed
28.Takano, H, Onodera, O, Takahashi, H, et al.Somatic mosaicism of expanded CAG repeats in brains of patients with dentatorubral-pallidoluysian atrophy: cellular population-dependent dynamics of mitotic instability. Am J Hum Genet. 1996;58:1212–1222.Google ScholarPubMed
29.Orr, HT. Unstable trinucleotide repeats and the diagnosis of neurodegenerative disease. Hum Pathol. 1994;25:598–601.CrossRefGoogle ScholarPubMed
30.Telenius, H, Kremer, HP, Theilmann, J, et al.Molecular analysis of juvenile Huntington's disease: the major influence on (CAG)n repeat length is the sex of the affected parent. Hum Mol Genet. 1993;2:1535–1540.CrossRefGoogle ScholarPubMed
31.Wellington, CL, Brinkman, RR, O'Kusky, JR, et al.Toward understanding the molecular pathology of Huntington's disease. Brain Pathol. 1997;7:979–1002.CrossRefGoogle ScholarPubMed
32.Ridley, RM, Frith, CD, Crow, TJ, et al.Anticipation in Huntington's disease is inherited through the male line but may originate in the female. J Med Genet. 1988;25:589–595.CrossRefGoogle ScholarPubMed
33.Petronis, A. The genes for major psychosis: aberrant sequence or regulation? Neuropsychopharmacology. 2000;23:1–12.CrossRefGoogle ScholarPubMed
34.Heiden, A, Willinger, U, Scharfetter, J, et al.Anticipation in schizophrenia. Schizophr Res. 1999;35:25–32.CrossRefGoogle ScholarPubMed
35.Gorwood, P, Leboyer, M, Falissard, B, et al.Further epidemiological evidence for anticipation in schizophrenia. Biomed Pharmacother. 1997;51:376–380.CrossRefGoogle ScholarPubMed
36.Johnson, JE, Cleary, J, Ahsan, H, et al.Anticipation in schizophrenia: biology or bias? Am J Med Genet. 1997;74:275–280.3.0.CO;2-P>CrossRefGoogle ScholarPubMed
37.Husted, J, Scutt, LE, Bassett, AS. Paternal transmission and anticipation in schizophrenia. Am J Med Genet. 1998;81:156–162.3.0.CO;2-U>CrossRefGoogle ScholarPubMed
38.Imamura, A, Honda, S, Nakane, Y, et al.Anticipation in Japanese families with schizophrenia. J Hum Genet. 1998;43:217–223.CrossRefGoogle ScholarPubMed
39.Jirtle, RL, Sander, M, Barrett, JC. Genomic imprinting and environmental disease susceptibility. Environ Health Perspect. 2000;108:271–278.CrossRefGoogle ScholarPubMed
40.Sapienza, C. Parental origin effects, genome imprinting, and sex-ratio distortion: double or nothing? [editorial]. Am J Hum Genet. 1994;55:1073–1075.Google ScholarPubMed
41.Freedman, R, Coon, H, Myles-Worsley, M, et al.Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci U S A. 1997;4:587–592.CrossRefGoogle Scholar
42.Mann, MR, Bartolomei, MS. Towards a molecular understanding of Prader-Willi and Angelman syndromes. Hum Mol Genet. 1999;8:1867–1873.CrossRefGoogle ScholarPubMed
43.Clarke, D. Prader-Willi syndrome and psychotic symptoms: a preliminary study of prevalence using the psychopathology assessment schedule for adults with developmental disability checklist. J Intellect Disabil Res. 1998;42(Pt 6):451–454.Google ScholarPubMed
44.Johanson, E. A study of schizophrenia in the male. Acta Psychiatr Scand. 1958;125(suppl):33.Google ScholarPubMed
45.Gregory, I. An analysis of family data on 1,000 patients admitted to a Canadian mental hospital. Acta Genetica Slat Med. 1959;9:54–96.Google Scholar
46.Bojanovsky, J, Gerylovova, A. The relation of schizophrenia to the age of parents of the patient. Nervenarzt. 1967;38:40–42.Google Scholar
47.Hare, EH, PAP, Moran. Raised paternal age in psychiatric patients: evidence for the constitutional hypothesis. Br J Psychiatry. 1979;134:169–177.CrossRefGoogle ScholarPubMed
48.Kinnell, HG. Parental age in schizophrenia. Br J Psychiatry. 1983;142:204.CrossRefGoogle ScholarPubMed