Parental Age Linked to Patterns of Mental Illness in Offspring

Further evidence has been found linking parental age to risk for various mental disorders among offspring.

In particular, the offspring of younger mothers (those aged 12 to 19) appear to have the highest risk for mental disorders compared with other parental age groups. And fathers’ age appears to present a J-shaped risk curve with offspring of teenage fathers and fathers over the age of 45 having increased risk for disorders.

Those were the findings of a large population-based Danish study published online in JAMA Psychiatry on January 22. The study adds to growing literature on parental age and mental disorders in offspring; in 2012 a widely publicized study in the journal Nature reported that older paternal age was linked with autism among offspring (Psychiatric News, October 19, 2012).

The Nature study, and much discussion that followed its publication, focused on the role of “de novo mutations” in the DNA of older fathers. But the JAMA Psychiatry study, using sophisticated epidemiologic genetics and drawing on a very large birth registry, suggests the role of social, environmental, and epigenetic variables associated with younger or older parents.

“This study really provides more information and greater detail about the genetic mechanisms that are associated with vulnerability to brain disorders affecting behavior and intellectual function,” APA President Jeffrey Lieberman, M.D., commented to Psychiatric News.

John McGrath, M.D., of the University of Queensland in Australia and colleagues used records from the Danish Psychiatric Central Research Register to follow 2,894,688 individuals born in Denmark from January 1, 1955, through December 31, 2006. Individuals within the study cohort and their parents and siblings were linked via their personal identification number to the Danish Psychiatric Central Research Register to obtain information about mental illness. The register was computerized in 1969 and contains data on all admissions to Danish psychiatric inpatient facilities and, from 1995, information on outpatient visits to psychiatric departments.

Maternal and paternal ages at the time of the child’s birth were categorized as 12 to 19, 20 to 24, 25 to 29, 30 to 34, 35 to 39, 40 to 44, and 45 or older. For each psychiatric disorder, individuals were observed from the earliest age at which they may possibly develop the specific disorder or January 1, 1995 (whichever came last), until onset of the outcome in question, death, emigration from Denmark, or December 31, 2011 (whichever came first).

The cohort was observed for 42.7 million person-years, during which 218,441 members of the cohort had their first psychiatric contact for any psychiatric disorder. Based on the overall risk of psychiatric disorders, the offspring of younger and older parents were at increased risk compared with those of parents aged 25 to 29. Considering the broadest category of “any psychiatric diagnosis” as the outcome of interest, the researchers found that the offspring of the youngest mothers were at the highest risk for any mental disorders: compared with the offspring of mothers aged 25 to 29, the offspring of mothers aged 12 to 19 had a 51 percent increased risk of having a mental disorder. No significantly increased risk for the offspring of older mothers was found.

Paternal age, however, showed a J-shaped relationship, with the offspring of teenaged fathers having a 28 percent increased risk for a psychiatric disorder, while the offspring of the fathers aged 45 or older had a 34 percent increased risk.

When the offspring were examined for particular disorders, the nature of the relationship changed. For example, the offspring of older fathers were at an increased risk of schizophrenia and related disorders, mental retardation, and autism spectrum disorder. In contrast, the offspring of young mothers (and to a lesser extent young fathers) were at an increased risk for substance use disorders, hyperkinetic disorders, and mental retardation.

“For many disorders, the risk for mental disorders in the offspring of young (especially teenaged) mothers is comparable to that seen in the offspring of older fathers,” the authors stated. “The offspring of teenaged fathers are also at risk for some disorders. For disorders such as schizophrenia and pervasive developmental disorder, the association between the variables of interest is J-shaped, with a higher risk found in the oldest group of fathers.”

McGrath and colleagues also noted that studies have generally suggested that early parenthood may contribute to a cascade of events related to socioeconomic exclusion. “Teenaged parenthood has been associated with a broad range of adverse health, educational, social, and crime-related outcomes in the mothers and their offspring,” they continued. “However, ascribing these outcomes directly to the ages of the parents versus a wide range of confounding factors is difficult, . . . further highlighting the complex and socially patterned web of causation that may link the variables of interest.”

Lieberman said that the wide array of disorders examined in the study and the patterns associated with parental age suggest a much more nuanced picture of risk than a simple linear relationship with de novo mutations. “The story that is emerging about medical genetics when it comes to psychiatric disorders is a far more complicated picture and a more complex set of mechanisms than we have anticipated in the past,” Lieberman said. “There are multiple ways in which the genome can express itself and in which the environment and social or cultural factors can influence gene expression leading to risk for mental illness.”

This study was supported by the John Cade Fellowship of the Australian National Health and Medical Research Council, the Stanley Medical Research Institute, and the Lundbeck Foundation. ■