Paternal age at childbearing and offspring psychiatric and academic morbidity

Abstract

Importance: Advancing paternal age is associated with increased genetic mutations during spermatogenesis, which research suggests may cause psychiatric morbidity in the offspring. The effects of advancing paternal age at childbearing on offspring morbidity remain unclear, however, because of inconsistent epidemiologic findings and the inability of previous studies to rigorously rule out confounding factors.

Objective: To examine the associations between advancing paternal age at childbearing and numerous indexes of offspring morbidity.

Design, setting, and participants: We performed a population-based cohort study of all individuals born in Sweden in 1973-2001 (N = 2,615,081), with subsets of the data used to predict childhood or adolescent morbidity. We estimated the risk of psychiatric and academic morbidity associated with advancing paternal age using several quasi-experimental designs, including the comparison of differentially exposed siblings, cousins, and first-born cousins.

Exposure: Paternal age at childbearing.

Main outcomes and measures: Psychiatric (autism, attention-deficit/hyperactivity disorder, psychosis, bipolar disorder, suicide attempt, and substance use problem) and academic (failing grades and low educational attainment) morbidity.

Results: In the study population, advancing paternal age was associated with increased risk of some psychiatric disorders (eg, autism, psychosis, and bipolar disorders) but decreased risk of the other indexes of morbidity. In contrast, the sibling-comparison analyses indicated that advancing paternal age had a dose-response relationship with every index of morbidity, with the magnitude of the associations being as large or larger than the estimates in the entire population. Compared with offspring born to fathers 20 to 24 years old, offspring of fathers 45 years and older were at heightened risk of autism (hazard ratio [HR] = 3.45; 95% CI, 1.62-7.33), attention-deficit/hyperactivity disorder (HR = 13.13; 95% CI, 6.85-25.16), psychosis (HR = 2.07; 95% CI, 1.35-3.20), bipolar disorder (HR = 24.70; 95% CI, 12.12-50.31), suicide attempts (HR = 2.72; 95% CI, 2.08-3.56), substance use problems (HR = 2.44; 95% CI, 1.98-2.99), failing a grade (odds ratio [OR] = 1.59; 95% CI, 1.37-1.85), and low educational attainment (OR = 1.70; 95% CI, 1.50-1.93) in within-sibling comparisons. Additional analyses using several quasi-experimental designs obtained commensurate results, further strengthening the internal and external validity of the findings.

Conclusions and relevance: Advancing paternal age is associated with increased risk of psychiatric and academic morbidity, with the magnitude of the risks being as large or larger than previous estimates. These findings are consistent with the hypothesis that new genetic mutations that occur during spermatogenesis are causally related to offspring morbidity.

Figure 1. Baseline, Adjusted, and Fixed Effects Associations between Paternal Age at Childbearing and Offspring Psychiatric and Academic Morbidity

Panels A–G present the point estimates (with 95% Confidence Intervals presented with the error bars) of the association between the paternal age at childbearing and each index of offspring morbidity using paternal age 20–24 years old as the reference category. The x-axis presents the ordinal bins of paternal age at childbearing. The y-axis presents effect sizes, either Hazard Ratios or Odds Ratios, which quantify the magnitude of the associations. The effect size estimates are depicted at the median age within each bin of APA. The blue estimates provide the baseline relations, the associations in the population. The green estimates provide the adjusted relations, the associations when statistically controlling for statistical covariates, which is what is standard in ordinary epidemiological studies of APA. The red estimates present the fixed effects relations, the association when accounting for all factors shared by siblings and measured covariates. The final estimates, therefore, provide the estimates when comparing differentially exposed siblings and statistically controlling for measured covariates. Because these estimates account for both measured and unmeasured covariates, these results are thought to be closer to the potential true causal effect.

Figure 1. Baseline, Adjusted, and Fixed Effects Associations between Paternal Age at Childbearing and Offspring Psychiatric and Academic Morbidity

Panels A–G present the point estimates (with 95% Confidence Intervals presented with the error bars) of the association between the paternal age at childbearing and each index of offspring morbidity using paternal age 20–24 years old as the reference category. The x-axis presents the ordinal bins of paternal age at childbearing. The y-axis presents effect sizes, either Hazard Ratios or Odds Ratios, which quantify the magnitude of the associations. The effect size estimates are depicted at the median age within each bin of APA. The blue estimates provide the baseline relations, the associations in the population. The green estimates provide the adjusted relations, the associations when statistically controlling for statistical covariates, which is what is standard in ordinary epidemiological studies of APA. The red estimates present the fixed effects relations, the association when accounting for all factors shared by siblings and measured covariates. The final estimates, therefore, provide the estimates when comparing differentially exposed siblings and statistically controlling for measured covariates. Because these estimates account for both measured and unmeasured covariates, these results are thought to be closer to the potential true causal effect.