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

Alice Morgunova; Irina Pokhvisneva; Saara Nolvi; Sonja Entringer; Pathik Wadhwa; John Gilmore; Martin Styner; Claudia Buss; Roberto Britto Sassi; Geoffrey B C Hall; Kieran J O'Donnell; Michael J Meaney; Patricia P Silveira; Cecilia A Flores

doi:10.1503/jpn.200081

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

J Psychiatry Neurosci. 2020 Nov 18;46(1):E154-E163. doi: 10.1503/jpn.200081.

Affiliation

¹ From the Integrated Program in Neuroscience (IPN), McGill University, Montréal, Que., Canada (Morgunova); the Department of Psychiatry, Faculty of Medicine, McGill University, Montréal, Que., Canada (O'Donnell, Meaney, Silveira, Flores); the Department of Neurology and Neurosurgery, McGill University, Montréal, Que., Canada (Flores); the Douglas Research Centre, Montréal, Que., Canada (Morgunova, Flores, Silveira); the Ludmer Centre for Neuroinformatics and Mental Health, Douglas Research Centre, McGill University, Montréal, Que., Canada (Pokhvisneva, O'Donnell, Meaney, Silveira); the Child and Brain Development Program, Canadian Institute for Advanced Research (CIFAR), Toronto, Ont., Canada (O'Donnell, Meaney); the Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR; Meaney); the Department of Medical Psychology Charité Universitätsmedizin, Berlin, Germany (Nolvi, Buss); the FinnBrain Birth Cohort Study, Department of Clinical Medicine, University of Turku, Turku, Finland (Nolvi); the Development, Health and Disease Research Program, School of Medicine, University of California, Irvine, Irvine, CA, USA (Entringer, Wadhwa); the Department of Pediatrics, School of Medicine, University of California, Irvine, Irvine, CA, USA (Entringer, Wadhwa); the Institute of Medical Psychology, Charité-Universitätsmedizin Berlin, Berlin, Germany (Entringer); the Department of Psychiatry and Human Behavior, School of Medicine, University of California, Irvine, CA, USA (Wadhwa); the Department of Obstetrics and Gynecology, School of Medicine, University of California, Irvine, CA, USA (Wadhwa); the Department of Epidemiology, School of Medicine, University of California, Irvine, CA, USA (Wadhwa); the Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA (Gilmore, Styner); the Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA (Styner); the Mood Disorders Program, Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ont., Canada (Sassi); and the Department of Psychology, Neuroscience and Behaviour, McMaster University, Hamilton, Ont., Canada (Hall).

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Brain* / anatomy & histology
Brain* / growth & development
Brain* / metabolism
Child
Child, Preschool
Cohort Studies
DCC Receptor / genetics*
Female
Gene Regulatory Networks / genetics*
Genome-Wide Association Study
Humans
Infant
Infant, Newborn
Male
Multifactorial Inheritance
Polymorphism, Single Nucleotide
Prefrontal Cortex* / anatomy & histology
Prefrontal Cortex* / growth & development
Prefrontal Cortex* / metabolism

Substances

DCC Receptor
DCC protein, human

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

Authors

Affiliation

Abstract

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MeSH terms

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