Prenatal Brain Genes Tied to Childhood Mental Illness Risk

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05/31/2023

Summary: The expression of certain genes in the brain before birth could influence the risk of developing various mental illnesses during childhood. Researchers found genetic patterns linked with adult psychiatric illnesses also correspond with psychiatric symptoms in children.

Their strongest predictor was a “neurodevelopmental gene set,” which combines genetic risk elements for numerous developmental disorders, such as ADHD, autism, and depression. It seems that these genes, largely expressed in the cerebellum, begin impacting the brain before birth, suggesting the need for earlier interventions.

Key Facts:

  1. The study identified a “neurodevelopmental gene set,” a combined measure of genetic risk for various developmental disorders, as the strongest genetic predictor for childhood mental health symptoms.
  2. The genes in this set were found to be most active in the cerebellum and peak in their expression before birth.
  3. The discovery implies that interventions to mitigate the risk of mental illnesses may need to start earlier in life than previously anticipated.

Source: Mass General

Researchers have identified various genes whose expression in the brain before birth may affect the risk of developing a range of mental illnesses during childhood.

The team, which was led by investigators at Massachusetts General Hospital (MGH), a founding member of Mass General Brigham (MGB), published their findings recently in Nature Neuroscience.

Using data from the Adolescent Brain and Cognitive Development (ABCD) Study, a federally funded study of child and adolescent brain development that has enrolled nearly 12,000 individuals at age 9–10 years, the group first assessed whether genetic patterns that have been associated with psychiatric illnesses in adults also tracked with psychiatric symptoms 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 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. Credit: Neuroscience News

“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, PhD, 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 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 risk of psychiatric disorders in young people.”

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. 

Additional co-authors include Dylan E. Hughes, Keiko Kunitoki, Safia Elyounssi1, 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, and Henning Tiemeier.

Funding: This work was supported by the National Institute of Mental Health (NIMH) and the Mass General Early Brain Development Initiative.

About this genetics and mental health research news

Author: McKenzie Ridings
Source: Mass General
Contact: McKenzie Ridings – Mass General
Image: The image is credited to Neuroscience News

Original Research: Open access.
Genetic patterning for child psychopathology is distinct from that for adults and implicates fetal cerebellar development” by Joshua Roffman et al. Nature Neuroscience


Abstract

Genetic patterning for child psychopathology is distinct from that for adults and implicates fetal cerebellar development

Childhood psychiatric symptoms are often diffuse but can coalesce into discrete mental illnesses during late adolescence.

We leveraged polygenic scores (PGSs) to parse genomic risk for childhood symptoms and to uncover related neurodevelopmental mechanisms with transcriptomic and neuroimaging data.

In independent samples (Adolescent Brain Cognitive Development, Generation R) a narrow cross-disorder neurodevelopmental PGS, reflecting risk for attention deficit hyperactivity disorder, autism, depression and Tourette syndrome, predicted psychiatric symptoms through early adolescence with greater sensitivity than broad cross-disorder PGSs reflecting shared risk across eight psychiatric disorders, the disorder-specific PGS individually or two other narrow cross-disorder (Compulsive, Mood-Psychotic) scores.

Neurodevelopmental PGS-associated genes were preferentially expressed in the cerebellum, where their expression peaked prenatally. Further, lower gray matter volumes in cerebellum and functionally coupled cortical regions associated with psychiatric symptoms in mid-childhood.

These findings demonstrate that the genetic underpinnings of pediatric psychiatric symptoms differ from those of adult illness, and implicate fetal cerebellar developmental processes that endure through childhood.

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