Prenatal Genetics: The Hidden Key to Childhood Mental Health Risk?

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Researchers from Massachusetts General Hospital have discovered a “neurodevelopmental gene set” that predicts risk for multiple developmental disorders such as autism, ADHD, Tourette syndrome, and depression. The expression of these genes, mainly in the cerebellum, begins even before birth, emphasizing the importance of early life interventions, including certain prenatal exposures like folic acid, for better brain health outcomes and resilience against psychiatric disorders in children.

The findings of the study further support the notion that the risk of mental illness in children originates during pregnancy.

A team of researchers, led by Massachusetts General Hospital (MGH), has found a number of genes whose pre-birth expression in the brain might influence the possibility of developing various mental illnesses during childhood. Their findings were recently published in the journal Nature Neuroscience.

The research group leveraged data from the Adolescent Brain and Cognitive Development (ABCD) Study. This federally funded study focuses on the brain development of children and adolescents, and has involved close to 12,000 participants aged 9-10 years. The researchers’ initial investigation explored if genetic patterns linked with psychiatric diseases in adults corresponded with psychiatric symptoms observed in children.

“We found those relationships to be more complex than we had imagined.  For example, genetic risk for ADHD and depression were associated with a range of symptoms in children, not just those related to attention or mood,” says co–senior author Joshua Roffman, MD, director of MGH’s Early Brain Development Initiative. “The genetic factors that shape mental illness symptoms in kids differ from the ones that shape mental illness symptoms in adults.”

The strongest genetic predictor for most mental health symptoms in ABCD participants was a new measure, developed by co–senior author and computational geneticist Phil H. Lee, Ph.D., and colleagues at the Mass General Center for Genomic Medicine, that indexes risk not for a single disorder, but rather for a constellation of developmental disorders. The scientists refer to this new genetic measure as a “neurodevelopmental gene set,” as it combines elements of genetic risk for several neurodevelopmental disorders, including autism, ADHD, Tourette syndrome, and depression.

Roffman, Lee, and their international collaborators found that this neurodevelopmental gene set also predicted childhood psychiatric symptoms in participants of the Generation R study, which included children of a similar age in the Netherlands.

Additional analyses of information from brain banks revealed that the genes in this set are expressed most strongly in the brain’s cerebellum (which is most known for its involvement in complex motor functions), and their expression in the cerebellum peaks before birth. Also, brain imaging data from the ABCD study indicated that children with psychiatric symptoms tended to have a slightly smaller cerebellum, perhaps a reflection of these genes’ effects on cerebellar development during prenatal life.

“That genetic risk factors for mental illness in kids begin to influence the brain so early on—even before birth—means that interventions that protect them from risk may also need to start earlier in life than previously expected,” says Roffman. “It is also important to note that while genes play an important part in risk for mental illness, the early life environment is also critical—and at this point, potentially easier to modify.”

Indeed, certain prenatal exposures—such as folic acid—show promise for better brain health outcomes in children.  “Our research team at Mass General is searching for other factors during pregnancy—whether in the realm of a healthy lifestyle (such as quality sleep, exercise, and diet), optimal prenatal care, or psychosocial support—that can confer resiliency in developing brains and protect against the risk of psychiatric disorders in young people.”

Reference: “Genetic patterning for child psychopathology is distinct from that for adults and implicates fetal cerebellar development” by Dylan E. Hughes, Keiko Kunitoki, Safia Elyounssi, Mannan Luo, Oren M. Bazer, Casey E. Hopkinson, Kevin F. Dowling, Alysa E. Doyle, Erin C. Dunn, Hamdi Eryilmaz, Jodi M. Gilman, Daphne J. Holt, Eve M. Valera, Jordan W. Smoller, Charlotte A. M. Cecil, Henning Tiemeier, Phil H. Lee and Joshua L. Roffman, 18 May 2023, Nature Neuroscience.
DOI: 10.1038/s41593-023-01321-8

One study, called Brain health Begins Before Birth (B4), is actively enrolling families at MGH during pregnancy and following brain development in children after birth.

The study was funded by the National Institute of Mental Health (NIMH) and the Mass General Early Brain Development Initiative.

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