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Transcriptome-based polygenic score links depression-related corticolimbic gene expression changes to sex-specific brain morphology and depression risk

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  • Amy E Miles, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, M6J 1H4, ON, Canada.
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  • Fernanda C Dos Santos, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, M6J 1H4, ON, Canada.
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  • Enda M Byrne, The University of Queensland
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  • Miguel E Renteria, QIMR Berghofer Medical Research Institute, The University of Queensland
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  • Andrew M McIntosh, University of Edinburgh
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  • Mark J Adams, University of Edinburgh
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  • Giorgio Pistis, Nephrology and Hypertension Service, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
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  • Enrique Castelao, Nephrology and Hypertension Service, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
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  • Martin Preisig, Nephrology and Hypertension Service, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
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  • Bernhard T Baune, University of Münster, Münster, Germany., University of Melbourne
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  • K Oliver Schubert, Univ Adelaide, University of Adelaide, Discipline Psychiat, Northern Adelaide Local Health Network, Mental Health Services, Adelaide, SA, Australia.
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  • Cathryn M Lewis, King's College London
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  • Lisa A Jones, Department of Psychological Medicine, University of Worcester, Worcester, United Kingdom.
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  • Ian Jones, Cardiff Metropolitan University
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  • Rudolf Uher, Dalhousie University
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  • Jordan W Smoller, Massachusetts General Hospital, Boston, Massachusetts, USA., Stanley Center for Psychiatric Research
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  • Roy H Perlis, Massachusetts General Hospital, Boston, Massachusetts, USA., Harvard University
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  • Douglas F Levinson, Stanford University
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  • James B Potash, Johns Hopkins University School of Medicine
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  • Myrna M Weissman, Columbia University, College of Physicians and Surgeons, New York State Psychiatric Institute
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  • Jianxin Shi, National Cancer Institute, Bethesda, MD
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  • Glyn Lewis, University College London
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  • Brenda W J H Penninx, Vrije Universiteit Medical Center and GGZ inGeest
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  • Dorret I Boomsma, Department of Biological Psychology and EMGO+ Institute for Health and Care Research, Vrije Universiteit Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
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  • Steven P Hamilton, Kaiser Permanente Northern California
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  • Etienne Sibille, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, M6J 1H4, ON, Canada., University of Toronto
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  • Ahmad R Hariri, Duke University
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  • Yuliya S Nikolova, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, M6J 1H4, ON, Canada., Duke University
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  • Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

Studies in post-mortem human brain tissue have associated major depressive disorder (MDD) with cortical transcriptomic changes, whose potential in vivo impact remains unexplored. To address this translational gap, we recently developed a transcriptome-based polygenic risk score (T-PRS) based on common functional variants capturing 'depression-like' shifts in cortical gene expression. Here, we used a non-clinical sample of young adults (n = 482, Duke Neurogenetics Study: 53% women; aged 19.8 ± 1.2 years) to map T-PRS onto brain morphology measures, including Freesurfer-derived subcortical volume, cortical thickness, surface area, and local gyrification index, as well as broad MDD risk, indexed by self-reported family history of depression. We conducted side-by-side comparisons with a PRS independently derived from a Psychiatric Genomics Consortium (PGC) MDD GWAS (PGC-PRS), and sought to link T-PRS with diagnosis and symptom severity directly in PGC-MDD participants (n = 29,340, 59% women; 12,923 MDD cases, 16,417 controls). T-PRS was associated with smaller amygdala volume in women (t = -3.478, p = 0.001) and lower prefrontal gyrification across sexes. In men, T-PRS was associated with hypergyrification in temporal and occipital regions. Prefrontal hypogyrification mediated a male-specific indirect link between T-PRS and familial depression (b = 0.005, p = 0.029). PGC-PRS was similarly associated with lower amygdala volume and cortical gyrification; however, both effects were male-specific and hypogyrification emerged in distinct parietal and temporo-occipital regions, unassociated with familial depression. In PGC-MDD, T-PRS did not predict diagnosis (OR = 1.007, 95% CI = [0.997-1.018]) but correlated with symptom severity in men (rho = 0.175, p = 7.957 × 10-4) in one cohort (N = 762, 48% men). Depression-like shifts in cortical gene expression have sex-specific effects on brain morphology and may contribute to broad depression vulnerability in men.

Original languageEnglish
JournalNeuropsychopharmacology
Volume46
Issue13
Pages (from-to)2304-2311
Number of pages8
ISSN0893-133X
DOIs
Publication statusPublished - Dec 2021

    Research areas

  • AMYGDALA, ASSOCIATION, DISORDERS, DSM-IV, ONSET, Genetic Predisposition to Disease, Humans, Transcriptome, Male, Multifactorial Inheritance, Depressive Disorder, Major/genetics, Young Adult, Brain/diagnostic imaging, Depression/genetics, Female

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