Sensitive period-regulating genetic pathways and exposure to adversity shape risk for depression

Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

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Animal and human studies have documented the existence of developmental windows (or sensitive periods) when experience can have lasting effects on brain structure or function, behavior, and disease. Although sensitive periods for depression likely arise through a complex interplay of genes and experience, this possibility has not yet been explored in humans. We examined the effect of genetic pathways regulating sensitive periods, alone and in interaction with common childhood adversities, on depression risk. Guided by a translational approach, we: (1) performed association analyses of three gene sets (60 genes) shown in animal studies to regulate sensitive periods using summary data from a genome-wide association study of depression (n = 807,553); (2) evaluated the developmental expression patterns of these genes using data from BrainSpan (n = 31), a transcriptional atlas of postmortem brain samples; and (3) tested gene-by-development interplay (dGxE) by analyzing the combined effect of common variants in sensitive period genes and time-varying exposure to two types of childhood adversity within a population-based birth cohort (n = 6254). The gene set regulating sensitive period opening associated with increased depression risk. Notably, 6 of the 15 genes in this set showed developmentally regulated gene-level expression. We also identified a statistical interaction between caregiver physical or emotional abuse during ages 1–5 years and genetic risk for depression conferred by the opening genes. Genes involved in regulating sensitive periods are differentially expressed across the life course and may be implicated in depression vulnerability. Our findings about gene-by-development interplay motivate further research in large, more diverse samples to further unravel the complexity of depression etiology through a sensitive period lens.

Original languageEnglish
Pages (from-to)497-506
Number of pages10
Issue number2
Early online date23 Oct 2021
Publication statusPublished - Jan 2022

Bibliographical note

Funding Information:
Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health under Award Numbers K01MH102403 and R01MH113930 (ECD) and K24MH094614 (JWS). It was also supported in part by a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (ECD) and an award from the Jacobs Foundation (ECD and AET). The Psychiatric Genomics Consortium (PGC) has received major funding from the US National Institute of Mental Health and the US National Institute of Drug Abuse (U01 MH109528 and U01 MH1095320). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website ( external/documents/grant-acknowledgements.pdf). GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe, Inc. This publication is the work of the authors and all authors will serve as guarantors for the contents of this paper. JWS is an unpaid member of the Bipolar/ Depression Research Community Advisory Panel of 23andMe, Inc., a member of the Leon Levy Foundation Neuroscience Advisory Board, and has received an honorarium for an internal seminar at Biogen, Inc. He is the Principal Investigator of a collaborative study of the genetics of depression and bipolar disorder sponsored by 23andMe, Inc., for which 23andMe, Inc. provides analysis time as in-kind support but no payments. The remaining authors (including the contributing Consortium members) have nothing to disclose.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to American College of Neuropsychopharmacology.


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