DCC gene network in the prefrontal cortex is associated with total brain volume in childhood

Abstract

Background: Genetic variation in the guidance cue DCC gene is linked to psychopathologies involving dysfunction in the prefrontal cortex. We created an expression-based polygenic risk score (ePRS) based on the DCC coexpression gene network in the prefrontal cortex, hypothesizing that it would be associated with individual differences in total brain volume. Methods: We filtered single nucleotide polymorphisms (SNPs) from genes coexpressed with DCC in the prefrontal cortex obtained from an adult postmortem donors database (BrainEAC) for genes enriched in children 1.5 to 11 years old (BrainSpan). The SNPs were weighted by their effect size in predicting gene expression in the prefrontal cortex, multiplied by their allele number based on an individual’s genotype data, and then summarized into an ePRS. We evaluated associations between the DCC ePRS and total brain volume in children in 2 community-based cohorts: the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) and University of California, Irvine (UCI) projects. For comparison, we calculated a conventional PRS based on a genome-wide association study of total brain volume. Results: Higher ePRS was associated with higher total brain volume in children 8 to 10 years old (β = 0.212, p = 0.043; n = 88). The conventional PRS at several different thresholds did not predict total brain volume in this cohort. A replication analysis in an independent cohort of newborns from the UCI study showed an association between the ePRS and newborn total brain volume (β = 0.101, p = 0.048; n = 80). The genes included in the ePRS demonstrated high levels of coexpression throughout the lifespan and are primarily involved in regulating cellular function. Limitations: The relatively small sample size and age differences between the main and replication cohorts were limitations. Conclusion: Our findings suggest that the DCC coexpression network in the prefrontal cortex is critically involved in whole brain development during the first decade of life. Genes comprising the ePRS are involved in gene translation control and cell adhesion, and their expression in the prefrontal cortex at different stages of life provides a snapshot of their dynamic recruitment.

Corticolimbic DCC gene co-expression networks as predictors of impulsivity in children

“…S3 ), our ePRS predicts a larger number of outcomes, across all three cohorts. This is consistent with other studies that have observed a higher prediction accuracy of their ePRS compared to conventional PRSs [ 34 , 42 ]. Since the ePRS methodology relies on identifying tissue-specific gene networks and their function, instead of identifying scattered genetic variants across the genome, we are able to create a more biologically meaningful score compared to conventional PRSs.…”

“…Individual genes do not operate in isolation and cannot explain the entire spectrum of mental disorders, as it has been well established by a wealth of data from recent GWAS studies showing massive polygenicity among neuropsychiatric disorders. Therefore, DCC receptors act as a master organizer of specific synaptic circuits, as a part of a gene network, and we have shown that a PFC gene network for DCC is associated with overall brain structure [ 34 ]. Our functional analyses of the corticolimbic DCC gene networks suggest their implication in the development of the neural substrates underlying inhibitory control behaviors.…”

“…These disorders are characterized by PFC and NAcc dysfunction and deficits in impulse control [ 30 – 33 ]. Early postnatal expression of the DCC gene network in the PFC associates with total brain volume in children [ 34 ], emphasizing that the Netrin-1/ DCC guidance cue system is tightly linked to overall early neurodevelopment. In adolescent rodents, DCC-mediated Netrin-1 signaling organizes the maturation of dopamine networks by promoting mesolimbic dopamine axon targeting in the NAcc and controlling the growth of dopamine axons to the PFC [ 12 , 17 ].…”

MicroRNA regulation of prefrontal cortex development and psychiatric risk in adolescence

“…A rapidly increasing number of studies show that changes in DCC are linked to vulnerability to psychopathologies of adolescent onset and involving PFC dysfunction, most prominently MDD (reviews from [83,84]). Furthermore, we have shown that variation in the DCC gene co-expression network within the PFC is associated with total brain volume across childhood, highlighting the role of this system in broad postnatal neurodevelopment [85]. Whether genetic variants (single nucleotide polymorphisms) within DCC (see Ref.…”

Genetic Influences on the Developing Young Brain and Risk for Neuropsychiatric Disorders

“…Morgunova et al. ( 74 ) used this approach to investigate relationships between a coexpression network of the DCC gene, which is robustly associated with multiple psychiatric conditions, and total brain volume in both neonates and older children. Higher ePRSs for the DCC coexpression network were associated with larger brain volumes.…”