Advancing paternal age (APA) at child-bearing is associated with increased risk of many psychiatric disorders in the offspring. Studies have shown that the number of de novo mutations in children depend on age of father at conception. Existing studies have many limitations. ( confounding factors,selection factors (e.g. personality traits associated with postponed parenthood), protective factors (maturity, social and cultural capital associated with late parenthood)). Sibling comparison studies provide the advantage of ruling out genetic and environmental factors shared by siblings. Sibling comparison studies to date show inconsistent findings.
Brian M. D’Onofrio and team of researchers at Indiana university and the Karolisnka institute carried out the largest ever study exploring the link between APA and psychiatric outcomes in offsprings.Association between APA and a range of offspring psychiatric and academic outcomes were studied among all offspring born in Sweden across 28 years. They used sibling comparison as well as numerous other quasi exp designs to calculate/test the hypotheses.
All individuals in the analysis cohort were born in Sweden between 1973 and 2001. 10 national registers/databases were used to extract information. Nearly 90% of swedish population was included in the cohort analysed. APA for each offspring was placed into 7 categories, ranging from 20 years or younger to 45 years or older in 5-year intervals with 20 to 24 years as the reference group.
When accounting for all factors shared by siblings and several measured covariates,parental age of 45 years and older was associated with a 3.5 times increased risk of an offspring having ASD, 13 times risk for ADHD, 2 times risk for psychosis and 25 times risk for bipolar disorder, compared with offspring born to fathers 20 to 24 years old. Multiple sensitivity analysis were carried out to check the robustness of these associations. Specific risks associated with APA follow a dose-response relationship .Unmeasured genetic and environmental selection factors shared by siblings, as well as the influence of several measured covariates, do not account for the associations between APA and offspring morbidity.
Limitations: Observational studies can not prove causality. The sibling comparisons could not rule out within-family confounders associated with APA and the outcomes.
Conclusions: APA represents a risk of numerous mental health outcomes. APA is a greater risk factor for psychiatric morbidity than has been previously reported. Genetic mutations during spermatogenesis associated with APA influence offspring morbidity across numerous indexes of morbidity.
Summary of the article:
Paternal Age at Childbearing and Offspring Psychiatric and Academic Morbidity. Brian M. D’Onofrio, PhD; Martin E. Rickert, PhD; Emma Frans, MSc; Ralf Kuja-Halkola, MSc; Catarina Almqvist, MD; Arvid Sjölander, PhD; Henrik Larsson, PhD; Paul Lichtenstein, PhD . Jama Psychiatry. Ahead of print. Feb 2014.