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Sexually divergent development of depression-related brain networks during healthy human adolescence

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Original languageEnglish
Article numbereabm7825
Pages (from-to)eabm7825
JournalScience Advances
Issue number21
Published27 May 2022

Bibliographical note

Funding Information: We appreciate V. Warrier’s advice on statistical methods for gene set enrichment analyses. We thank J. Spindel for sharing expertise on epigenetic data. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care, UK. Funding: This work was funded by the Wellcome Trust collaborative award for the Neuroscience in Psychiatry Network at University College London and the University of Cambridge Wellcome Trust collaborative award for the Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA) (grant number: 104025/Z/14/Z), which was also funded by Janssen, GlaxoSmithKline, Lundbeck, and Pfizer; NIH Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215-20014) Mental Health Theme (to E.T.B.); NIH Research Senior Investigator award (to E.T.B.); Gates Cambridge Trust (to L.D.) MQ: Transforming Mental Health grant MQF17_24 (to P.E.V.), Alan Turing Institute (to S.E.M.), and EPSRC grant EP/N510129/1 (to P.E.V.); British Academy Post-Doctoral fellowship (to R.A.B.); Autism Research Trust (to R.A.B.); Cambridge Philosophical Society Henslow Fellowship Lucy Cavendish College, University of Cambridge (to S.E.M.); UK Research and Innovation (UKRI) Data to Early Diagnosis and Precision Medicine Industrial Strategy Challenge Fund (to F.V.); and MRC Clinical Research Infra-structure award MR/M009041/1. Author contributions: Research design: L.D., P.E.V., and E.T.B. Data analysis: L.D., R.A.B., and J.S. Research performance: L.D., R.R.-G., F.V., M.G.K., and P.E.V. Contribution of analytical tools: J.S., R.A.B., S.E.M., M.G.K., and A.R.A. Advice on statistical methods: S.R.W. NSPN study design: E.T.B., P.B.J., R.J.D., I.M.G., and P.F. BIODEP study design: E.T.B. and N.A.H. Manuscript writing: E.T.B., L.D., and P.E.V. Competing interests: E.T.B. serves on the Scientific Advisory Board of Sosei Heptares and as a consultant for GlaxoSmithKline, Boehringer Ingelheim, and Monument Therapeutics. The other authors declare that they have no competing interests. Data and materials availability: External gene lists used for the gene enrichment analyses are available in the respective cited manuscripts. All other data needed to evaluate the conclusions in the manuscript are archived at 10.5281/zenodo.6390851. The code required to run the analyses can be found at 10.5281/zenodo.6390752. Publisher Copyright: Copyright © 2022 The Authors, some rights reserved.

King's Authors


Sexual differences in human brain development could be relevant to sex differences in the incidence of depression during adolescence. We tested for sex differences in parameters of normative brain network development using fMRI data on N = 298 healthy adolescents, aged 14 to 26 years, each scanned one to three times. Sexually divergent development of functional connectivity was located in the default mode network, limbic cortex, and subcortical nuclei. Females had a more "disruptive" pattern of development, where weak functional connectivity at age 14 became stronger during adolescence. This fMRI-derived map of sexually divergent brain network development was robustly colocated with i prior loci of reward-related brain activation ii a map of functional dysconnectivity in major depressive disorder (MDD), and iii an adult brain gene transcriptional pattern enriched for genes on the X chromosome, neurodevelopmental genes, and risk genes for MDD. We found normative sexual divergence in adolescent development of a cortico-subcortical brain functional network that is relevant to depression.

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