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Emma M. Frans, MMedSc; Sven Sandin, MSc; Abraham Reichenberg, PhD; Paul Lichtenstein, PhD; Niklas Långström, MD, PhD; Christina M. Hultman, PhD

Arch Gen Psychiatry. 2008;65(9):1034-1040.

Context  Advancing paternal age has been reported as a risk factor for neurodevelopmental disorders.

Objectives  To determine whether advanced paternal age is associated with an increased risk of BPD in the offspring and to assess if there was any difference in risk when analyzing patients with early-onset BPD separately.

Design  A nationwide nested case-control study based on Swedish registers was performed. Risk for BPD in the offspring of older fathers was estimated using conditional logistic regression analysis controlling for potential confounding of parity, maternal age, socioeconomic status, and parental family history of psychotic disorders.

Setting  Identification of 7 328 100 individuals and their biological parents by linking the nationwide Multigeneration Register and the Hospital Discharge Register.

Participants  A total of 13 428 patients with a BPD diagnosis on at least 2 separate hospital admissions was identified. Five healthy control subjects matched for sex and year of birth were randomized to each case.

Main Outcome Measure  Bipolar disorder based on ICD codes at discharge from hospital treatment.

Results  An association between paternal age and risk for BPD in the offspring of older men was noted. The risk increased with advancing paternal age. After controlling for parity, maternal age, socioeconomic status, and family history of psychotic disorders, the offspring of men 55 years and older were 1.37 (95% confidence interval [CI], 1.02-1.84) times more likely to be diagnosed as having BPD than the offspring of men aged 20 to 24 years. The maternal age effect was less pronounced. For early-onset (<20 years) cases, the effect of paternal age was much stronger (odds ratio, 2.63; 95% CI, 1.19-5.81), whereas no statistically significant maternal age effect was found.

Conclusions  Advanced paternal age is a risk factor for BPD in the offspring. The results are consistent with the hypothesis that advancing paternal age increases the risk for de novo mutations in susceptibility genes for neurodevelopmental disorders.

Author Affiliations: Department of Medical Epidemiology and Biostatistics (Ms Frans, Mr Sandin, and Drs Lichtenstein and Hultman) and Center for Violence Prevention (Dr Långström), Karolinska Institutet, Stockholm, Sweden; and Institute of Psychiatry, King's College, London, England (Dr Reichenberg).

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