Advancing Paternal Age and the Risk of Schizophrenia
Abstract
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.
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Paternal age effects on psychological disease might be attributed to elevated sperm mutation rates, but other hypotheses are equally compatible, and maternal age effects operate in the opposite direction.
“Paternal age effects on psychological disease63 might be attributed to elevated mutation rates in sperm, but other hypotheses are equally compatible with the data, and maternal age effects operate in the opposite direction as younger mothers have higher likelihoods of having affected children64.”
From Rare and common variants: twenty arguments (2012) · cites this paper as [63]
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- Authors
- Malaspina, D., Harlap, S., Fennig, S., Heiman, D., Nahon, D., Feldman, D., & Susser, E. S.
- Affiliations
- New York State Psychiatric Institute (US)
- Venue
- Archives of General Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2001-04-01
- Volume
- 58
- Issue
- 4
- Pages
- 361
- ISSN
- 0003-990X (ISSN-L)
- OpenAlex
- W2137330216
- Cited by
- 562
- References
- 46
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 7 · 2023: 10 · 2022: 16 · 2021: 13 · 2020: 14 · 2019: 30 · 2018: 16 · 2017: 15 · 2016: 29 · 2015: 38 · 2014: 31 · 2013: 27 · 2012: 29
- FWCI
- 15.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of General Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (MH01699 K24, K24MH001699, R01MH059114)
- National Center for Research Resources (M01RR000096)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Keywords
- paternal age, schizophrenia, de novo mutations, male germline, psychiatric hospitalization, maternal age
- MeSH terms
- Adult, Age Factors, Female, Humans, Israel, Male, Marriage, Maternal Age, Middle Aged, Mutation, Paternal Age, Psychotic Disorders, Schizophrenia, Sex Factors, Cohort Studies, Incidence, Proportional Hazards Models
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