Advanced paternal age has been suggested as a risk factor for autism, but empirical evidence is mixed. This study examines whether the association between paternal age and autism in the offspring (1) persists controlling for documented autism risk factors, including family psychiatric history, perinatal conditions, infant characteristics and demographic variables; (2) may be explained by familial traits associated with the autism phenotype, or confounding by parity; and (3) is consistent across epidemiological studies. Multiple study methods were adopted. First, a Swedish 10-year birth cohort (N=1 075 588) was established. Linkage to the National Patient Register ascertained all autism cases (N=883). Second, 660 families identified within the birth cohort had siblings discordant for autism. Finally, meta-analysis included population-based epidemiological studies. In the birth cohort, autism risk increased monotonically with increasing paternal age. Offspring of men aged ⩾50 years were 2.2 times (95% confidence interval: 1.26–3.88: P=0.006) more likely to have autism than offspring of men aged ⩽29 years, after controlling for maternal age and documented risk factors for autism. Within-family analysis of discordant siblings showed that affected siblings had older paternal age, adjusting for maternal age and parity (P<0.0001). Meta-analysis demonstrated advancing paternal age association with increased risk of autism across studies. These findings provide the strongest evidence to date that advanced paternal age is a risk factor for autism in the offspring. Possible biological mechanisms include de novo aberration and mutations or epigenetic alterations associated with aging.
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This work was supported by a grant from the Swedish Council for Working Life and Social Research (guest research fellowship to A Reichenberg). The Swedish Council for Working Life and Social Research was not involved in the design and conduct of the study; collection, management, analysis and interpretation of the data; or in the preparation, review or approval of the manuscript. Approval to access the registries was given by the Swedish National Board of Health and Welfare, and the study was approved by a local human subjects committee at the Karolinska Institutet (Stockholm, Sweden).
Author Contributions: Drs Hultman, Reichenberg and Sandin had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Reichenberg, Sandin, Hultman and Lichtenstein.
Acquisition of data: Hultman and Sandin.
Analysis and interpretation of data: Hultman, Reichenberg, Sandin, Lichtenstein and Levine.
Drafting of the manuscript: Hultman and Reichenberg.
Critical revision of the manuscript for important intellectual content: Hultman, Reichenberg, Sandin, Lichtenstein and Levine.
Statistical analysis: Sandin, Levine and Reichenberg.
Obtained funding: Hultman.
Administrative, technical, or material support: Hultman, Lichtenstein.
Study supervision: Hultman and Reichenberg.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
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Hultman, C., Sandin, S., Levine, S. et al. Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies. Mol Psychiatry 16, 1203–1212 (2011). https://doi.org/10.1038/mp.2010.121
- paternal age
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