Advancing paternal age and bipolar disorder

Arch Gen Psychiatry. 2008 Sep;65(9):1034-40. doi: 10.1001/archpsyc.65.9.1034.


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.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aging / physiology*
  • Bipolar Disorder / diagnosis*
  • Bipolar Disorder / epidemiology*
  • Fathers*
  • Female
  • Humans
  • Male
  • Maternal Age
  • Middle Aged
  • Paternal Age*
  • Point Mutation / genetics
  • Prevalence
  • Registries
  • Socioeconomic Factors
  • Sweden / epidemiology