Alice Morgunova, BA; Irina Pokhvisneva, MSc; Saara Nolvi, PhD; Sonja Entringer, PhD; Pathik Wadhwa, MD, PhD; John Gilmore, MD; Martin Styner, MSc, PhD; Claudia Buss, PhD; Roberto Britto Sassi, MD; Geoffrey B.C. Hall, MSc, PhD; Kieran J. O’Donnell, PhD; Michael J. Meaney, PhD; Patricia P. Silveira, MD, MSc, PhD; Cecilia A. Flores, MSc, PhD
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.
Submitted Apr. 26, 2020; Revised Jul. 22, 2020; Accepted Aug. 14, 2020; Early-released Nov. 18, 2020
Affiliations: 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).
Funding: C. Flores is supported by the National Institute on Drug Abuse (R01DA037911) and the Canadian Institute for Health Research (MOP-74709; MOP-119543). P. Silveira is supported by the Ludmer Centre for Neuroinformatics and Mental Health, the Canadian Institutes of Health Research (PJT–173237, PI Silveira PP) and the JPB Foundation through a grant to the JPB Research Network on Toxic Stress: A Project of the Center on the Developing Child at Harvard University. Funders had no influence on study design, data collection, data analysis, interpretation or writing of the report.
Competing interests: No competing interests declared.
Contributors: A. Morgunova, P. Wadhwa, K. O’Donnell, M. Meaney, P. Silveira and C. Flores designed the study. A. Morgunova, S. Entringer, P. Wadhwa, C. Buss, R. Sassi, G. Hall, M. Meaney and P. Silveira acquired the data, which A. Morgunova, I. Pokhvisneva, S. Nolvi, P. Wadhwa, J. Gilmore, M. Styner, C. Buss, P. Silveira and C. Flores analyzed. A. Morgunova, S. Nolvi, C. Buss, P. Silveira and C. Flores wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.
Content licence: This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is non-commercial (i.e. research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/
Correspondence to: C. Flores, Department of Psychiatry, Douglas Mental Health University Institute, Perry Pavilion, Room 2111, 6875 LaSalle Boulevard, Montréal (Verdun), Quebec H4H 1R3, Canada; firstname.lastname@example.org; P. Silveira, MD Department of Psychiatry and Ludmer Centre for Neuroinformatics and Mental Health, Douglas Research Centre, McGill University, Montréal, Quebec, H4H 1R3, Canada; email@example.com