Genetic patterning for child psychopathology is distinct from that for adults and implicates fetal cerebellar
Dylan E Hughes1, Keiko Kunitoki2, Safia Elyounssi1
1Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
Insights
Genetic risk scores for neurodevelopmental disorders predict childhood psychiatric symptoms. These scores highlight the cerebellum’s prenatal development as crucial for enduring pediatric mental health.
Area of Science:
- Neurogenetics
- Developmental Neuroscience
- Psychiatry
Background:
- Childhood psychiatric symptoms are often nonspecific but can evolve into distinct mental illnesses.
- Understanding the genetic and neurodevelopmental underpinnings of these early symptoms is crucial for timely intervention.
Purpose of the Study:
- To utilize polygenic scores (PGSs) to analyze genomic risk for childhood psychiatric symptoms.
- To investigate associated neurodevelopmental mechanisms using transcriptomic and neuroimaging data.
Main Methods:
- Employed narrow and broad cross-disorder polygenic scores (PGSs) in independent adolescent cohorts (Adolescent Brain Cognitive Development, Generation R).
- Analyzed gene expression patterns and neuroimaging data (gray matter volume) in relation to PGSs and psychiatric symptoms.
- Examined gene expression in relation to prenatal development and cerebellar regions.
Main Results:
- A narrow cross-disorder neurodevelopmental PGS (ADHD, autism, depression, Tourette syndrome) showed higher sensitivity in predicting early adolescent psychiatric symptoms compared to broad PGSs or disorder-specific PGSs.
- Genes linked to the neurodevelopmental PGS were predominantly expressed in the cerebellum, with peak expression during prenatal development.
- Reduced cerebellar gray matter volume and altered functional connectivity in coupled cortical regions were associated with mid-childhood psychiatric symptoms.
Conclusions:
- The genetic basis of pediatric psychiatric symptoms differs from that of adult-onset illnesses.
- Prenatal developmental processes in the cerebellum play a significant role in psychiatric symptoms that persist through childhood.
Abstract:
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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