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Original Investigation |

Paternal Age at Childbearing and Offspring Psychiatric and Academic Morbidity

Brian M. D’Onofrio, PhD1; Martin E. Rickert, PhD1; Emma Frans, MSc2; Ralf Kuja-Halkola, MSc2; Catarina Almqvist, MD2,3; Arvid Sjölander, PhD2; Henrik Larsson, PhD2; Paul Lichtenstein, PhD2
[+] Author Affiliations
1Department of Psychological and Brain Sciences, Indiana University, Bloomington
2Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
3Lung and Allergy Unit, Astrid Lindgren Children’s Hospital, Stockholm, Sweden
JAMA Psychiatry. 2014;71(4):432-438. doi:10.1001/jamapsychiatry.2013.4525.
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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.

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Baseline, Adjusted, and Fixed-Effects Associations Between Paternal Age at Childbearing and Offspring Psychiatric and Academic Morbidity

The point estimates (with 95% CIs presented as error bars) of the association between the paternal age at childbearing and each index of offspring morbidity using paternal age of 20 to 24 years as the reference category: autism (A), attention-deficit/hyperactivity disorder (B), psychosis (C), bipolar disorder (D), suicide attempt (E), substance use problem (F), failing grades (G), and educational attainment of less than 10 years (H). 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 advancing paternal age (APA). The circle estimates provide the baseline relations, the associations in the population. The square estimates provide the adjusted relations, the associations when statistically controlling for statistical covariates, which is what is standard in ordinary epidemiologic studies of APA. The triangle estimates present the fixed-effects relations, the association when accounting for all factors shared by siblings and measured covariates.

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Submit a Comment
Questioning diagnostic data quality
Posted on February 26, 2014
Thomas Morgan
Vanderbilt University
Conflict of Interest: None Declared
As a clinical geneticist, I read with interest the study by D'Onofrio et al reporting an association between paternal age and psychiatric morbidity. However, I noted that only 2861 of 900,337 (0.32%) of individuals were diagnosed with attention deficit hyperactivity disorder (ADHD, see Table, \"Descriptive Statistics of the Study Population\"). This population prevalence of ADHD is far too low, even for Sweden, off by at least one order of magnitude. In addition, I noted in panel B of the Figure that there appeared to be an apparently protective association of advancing paternal age on risk of ADHD in the unadjusted data, essentially no association in the \"adjusted\" model, and a rocketing rise of ADHD risk to 13-fold hazard ratio in the \"fixed effects\" model. Such vastly different apparent effects lead me to question the validity of the models employed. Finally, I was stunned to see the claim by the authors to have previously established an association between advanced paternal age and \"criminality,\" particularly given their inference that \"genetic mutations during spermatogenesis associated with advanced paternal age influence offspring morbidity,\" as I'm unaware of convincing data establishing \"criminality\" as a genetically influenced trait.Looking back at the \"Advancing paternal age and offspring violent offending\" study cited by the authors (Dev Psychopathol. 2012; 24(3): 739-53), I found that the very lowest risk of \"violent offending\" was actually among those who had fathers 35-39 years old (who are far from the youngest dads), and that any apparent risk increase with advancing paternal age was due to a small number of highly unusual cases in which the violent offender's father was from 55-80 years old (extreme outliers). Given that their study is likely to garner extensive coverage in the lay press, I would like to provide the authors with an opportunity to comment further on the limitations of their data (particularly on ADHD) and to provide clarification about \"criminality\" in relation to paternal age. Such an extraordinary claim surely demands extraordinary evidence that has not been provided by the authors.
Questions to the statistical analysis
Posted on April 7, 2014
Odd O. Aalen
University of Oslo, norway
Conflict of Interest: None Declared
This is an intriguing paper. However, as a biostatistician I am surprised that the effects are so large, especially for bipolar disorder and ADHD. There is in both cases a large discrepancy between the baseline effects and those found in the fixed effect analysis. If the risk for bipolar disorder, say, is 25 times higher in the highest age group compared to the 20-24 age group, why do we see almost no age effect in the baseline curve? Clearly, the fixed effects analysis is a very complex one with several time scales involved; is it possible that biases can be hidden here? Some comments on methodological issues would have been of great interest.
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