Presented During:
Wednesday, June 25, 2025: 5:45 PM - 7:00 PM
Brisbane Convention & Exhibition Centre
Room:
M2 (Mezzanine Level)
Poster No:
694
Submission Type:
Abstract Submission
Authors:
Jack Dodson1, Sai Sruthi Amirtha Ganesh1, Kimiya Natan1, Michi Kumagai1, Leanna Hernandez1
Institutions:
1University of California, Los Angeles, Los Angeles, CA
First Author:
Jack Dodson
University of California, Los Angeles
Los Angeles, CA
Co-Author(s):
Kimiya Natan
University of California, Los Angeles
Los Angeles, CA
Michi Kumagai
University of California, Los Angeles
Los Angeles, CA
Introduction:
The strongest common genetic association with schizophrenia is linked to increased expression of the complement component 4A (C4A) gene. In the brain, C4A expression is thought to influence synaptic pruning and to act in a sex-specific manner, contributing to a higher risk of schizophrenia in males compared to females. We previously demonstrated in a cohort of ~7,500 youth from the ABCD Study that increased genetically predicted C4 gene expression is associated with reduced surface area of the entorhinal cortex at 9–10 years of age, which predicts greater number and severity of psychosis-like experiences 1–2 years later (Hernandez, 2023). However, the impact of C4A expression on the rate of change (ROC) in brain structure during childhood and adolescence remains unclear. To address this, we investigated the relationship between genetically predicted C4A expression and longitudinal changes in regional brain surface area, cortical thickness, and volume in 2,977 ABCD participants with structural MRI data collected at three timepoints (ages 9–10, 11–12, and 13–14 years). Additionally, we conducted a phenome-wide association study (PheWAS) to evaluate associations between brain regions influenced by C4A expression and 138 psychiatric and behavioral traits assessed at 13–14 years.
Methods:
Structural MRI (sMRI) and genetic data were obtained from the ABCD Study. C4 haplotypes were imputed for youth of European, African, and Latinx ancestry using Beagle and a multiethnic reference panel (Kamitaki, 2020). Genetically predicted C4A expression was calculated using established weights (Sekar, 2016). ROC in sMRI measures was estimated by calculating the slope of a linear regression model fitted to longitudinal data across the three timepoints. Linear mixed-effects models examined associations between genetically predicted C4A expression, ROC in MRI-derived brain metrics, and psychiatric symptoms. Results were corrected for multiple comparisons using the false discovery rate (FDR, p < 0.05).
Results:
ROC showed broad and significant sex-differences whereby female youth demonstrated faster (more negative) ROC relative to males. To account for this sex-specific effect, subsequent analyses were performed in male and female youth separately. In male youth, genetically predicted C4A expression was negatively associated with cortical thickness ROC in the banks of the superior temporal sulcus (bSTS) and posterior cingulate cortex (PCC), suggesting that increased C4A expression is related to faster age-related cortical thinning in these brain regions. PheWAS revealed that smaller bSTS size in males at 13–14 years of age was associated with reduced sensation-seeking behaviors as measured by the UPPS Impulsive Behavior Scale (Whiteside & Lynam, 2001). In contrast, no significant associations were observed between C4A expression and ROC in female youth, nor between ROC of the PCC and psychiatric or behavioral traits in males.
Conclusions:
These results suggest that genetically predicted C4A expression is associated with cortical thickness ROC in brain regions previously implicated in schizophrenia pathophysiology (i.e., bSTS, PCC), in adolescent male youth only. Our observation that reduced cortical thickness of the bSTS at 13–14 years is associated with fewer sensation-seeking behaviors further suggests that faster ROC (resulting in smaller bSTS size) may be linked to a reduced desire to pursue novel experiences-a pattern also observed in individuals with psychosis, who exhibit heightened sensory sensitivity. Together with prior research, these data indicate that the effects of C4A expression on brain morphology may be associated with broader developmental patterns of brain maturation whereby sensory areas mature more quickly relative to brain regions involved in higher-order cognition. Overall, these results provide novel insights into how C4A-driven effects on brain development contribute to psychosis risk by altering regions critical for social cognition and self-perception.
Disorders of the Nervous System:
Psychiatric (eg. Depression, Anxiety, Schizophrenia) 2
Genetics:
Genetics Other 1
Lifespan Development:
Normal Brain Development: Fetus to Adolescence
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Neuroanatomy Other
Keywords:
Development
Phenotype-Genotype
Psychiatric Disorders
Schizophrenia
STRUCTURAL MRI
1|2Indicates the priority used for review
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Structural MRI
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Provide references using APA citation style.
Hernandez, L. M., et al. (2023). Multi-ancestry phenome-wide association of complement component 4 variation with psychiatric and brain phenotypes in youth. Genome Biology, 24(1):42.
Kamitaki, N., et al. (2020). Complement genes contribute sex-biased vulnerability in diverse disorders. Nature, 582, 577–581.
Sekar, A., et al. (2016). Schizophrenia risk from complex variation of complement component 4. Nature, 530(7589), 177–183.
Whiteside, S. P., et al. (2003). Understanding the role of impulsivity and externalizing psychopathology in alcohol abuse: Application of the UPPS impulsive behavior scale. Experimental and Clinical Psychopharmacology, 11(3):210-7.
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