Study suggests link between parental, grandparental age, increased ASD risk

Researchers have reported additional evidence suggesting an independent association between advanced parental age and increased risk for autism spectrum disorder among offspring.

The findings of a population-based, multigenerational cohort study, published in JAMA Network Open, also suggested that children with young maternal grandparents and children with young and old paternal grandparents had increased ASD risk.

“In light of worldwide increasing trends regarding postponed parenthood, the possible association of parental age on child health has generated considerable interest,” Yu Gao, PhD, of the department of environmental health at Shanghai Jiao Tong University School of Medicine, and colleagues wrote. “Research conducted in different study populations has suggested that advanced maternal and paternal age are independently associated with increased risk [for] ASD in children, for which different mechanisms have been proposed. Increased rates of de novo mutations and epigenetic alternations associated with increasing age are the most frequently cited mechanisms to explain the association between paternal age and ASD risk in children.”

A prior birth cohort study highlighted the emergence of epidemiological evidence of transgenerational exposure effects on risk for neurological diseases. Further, animal studies have suggested that intrauterine environmental exposures may lead to de novo and/or epigenetic alterations in the germline that could subsequently influence disease risk among future generations.

Gao and colleagues sought to estimate the associations between children’s ASD risk and parental and grandparental age. Using data from Danish national health registries, they constructed a parental age cohort to evaluate the relationship of parental age and ASD among 1,476,783 singleton children born from 1990 to 2013. They also constructed a multigenerational cohort that included 362,438 fathers and 458,234 mothers born from 1973 to 1990 for whom grandparental age data were available. Parental age at childbirth and grandparental age at the time of the birth of the parent served as exposures, and diagnoses of ASD in children obtained from the Danish Psychiatric Central Register between 1994 and 2017 served as main outcomes.

Among the children born from 1990 to 2013, 758,066 (51.3%) were male, and 27,616 (1.9%) had ASD. The researchers observed an monotonic association between advanced paternal or maternal age over 30 years and elevated ASD risk, with ORs of 1.56 (95% CI, 1.45-1.68) for mothers aged 40 years and older and 1.57 (95% CI, 1.39-1.78) for fathers aged 50 years and older, compared with parents aged 25 years to 29 years. Among the multigenerational cohort, 9,364 grandchildren (1.7%) had ASD. Gao and colleagues reported U-shaped associations, meaning ASD risk was higher among grandchildren of younger maternal grandmothers (OR = 1.68; 95% CI, 1.52-1.85), younger maternal grandfathers (OR = 1.5; 95% CI, 1.26-1.78) and younger paternal grandmothers (OR = 1.18; 95% CI, 1.04-1.34), as well as older paternal grandmothers (OR = 1.4; 95% CI, 1.03-1.9) compared with the grandchildren of grandparents who were 25 to 29 years old at the time of the birth of their own children.

“Our findings enrich the current understanding of the complex causes of ASD,” the researchers wrote. “Our findings also highlight the potential adverse association of very young age at pregnancy and neurodevelopmental risk that has often been overlooked, particularly for the risk for ASD. Further studies on the role of transgenerational age effects may be important in understanding the role of reproductive age–related mechanisms in ASD and other related neurodevelopmental disorders.” – by Joe Gramigna

Disclosures: The authors report no relevant financial disclosures.