Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders Yash Patel, Nadine Parker, Jean Shin, Derek Howard, Leon French, Sophia Thomopoulos, Elena Pozzi, Yoshinari Abe, Christoph Abé, Alan Anticevic, et al. To cite this version: Yash Patel, Nadine Parker, Jean Shin, Derek Howard, Leon French, et al.. Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders. JAMA Psychiatry, Chicago, IL : American Medical Association, [2013]-, 2020, 10.1001/jamapsychiatry.2020.2694. hal-03026968 HAL Id: hal-03026968 https://hal.archives-ouvertes.fr/hal-03026968 Submitted on 8 Dec 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Research JAMA Psychiatry | Original Investigation Virtual Histology of Cortical Thickness and Shared Neurobiology Underlying Six Psychiatric Disorders Writing Committee for the Attention Deficit Hyperactivity Disorder, Autism Spectrum Disorder, Bipolar Disorder, Major Depressive Disorder, Obsessive Compulsive Disorder and Supplemental content IMPORTANCE Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood. OBJECTIVE To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia (SCZ). DESIGN, SETTING, AND PARTICIPANTS Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The number of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and SCZ: 2688 and 3244. MAIN OUTCOMES AND MEASURES Interregional profiles of group difference in cortical thickness between cases and controls. RESULTS A total of 12 721 cases and more than 15 000 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD). Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression. Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders. CONCLUSIONS AND RELEVANCE There are shared neurobiologic processes underlying differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders. The Writing Committee for the Attention Deficit Hyperactivity Disorder, Autism Spectrum Disorder, Bipolar Disorder, Major Depressive Disorder, Obsessive Compulsive Disorder and Schizophrenia ENIGMA Working Group members are listed at the end of this article. Corresponding Author: Tomas Paus, MD, PhD, Bloorview Research Institute, 150 Kilgour Rd, East York, JAMA Psychiatry. doi:10.1001/jamapsychiatry.2020.2694 ON M4G 1R8, Canada (tpaus@ Published online August 26, 2020. hollandbloorview.ca). (Reprinted) E1 © 2020 American Medical Association. All rights reserved. jamanetwork/2020/psy/08_26_2020/yoi200052pap PAGE: right 1 SESS: 12 OUTPUT: Jul 24 12:39 2020 Research Original Investigation Virtual Histology of Cortical Thickness and Shared Neurobiology Underlying Six Psychiatric Disorders he advancement of large-scale magnetic resonance imaging (MRI) studies has enabled systematic investi- Key Points gations of cortical morphology, such as cortical thick- T Question What are the neurobiologic underpinnings of group ness and surface area, across a variety of psychiatric disor- differences in cortical thickness in various psychiatric disorders? ders. In particular, the Enhanced Neuroimaging Genetics Findings In this consortium analysis, regions of the cerebral Through Meta-Analysis (ENIGMA) Consortium has con- cortex with greater expression of genes specific to pyramidal (CA1) ducted some of the largest MRI studies characterizing group cells were also regions with greater case-control group differences differences between patients (cases) and control individuals in cortical thickness in all 6 studied disorders, namely in the cerebral cortex for a number of disorders, including at- attention-deficit/hyperactivity disorder, autism spectrum disorder, tention-deficit/hyperactivity disorder (ADHD),1 autism spec- bipolar disorder, major depressive disorder, obsessive-compulsive trum disorder (ASD),2 bipolar disorder (BD),3 major depres- disorder, and schizophrenia. There is a common profile of the sive disorder (MDD),4 obsessive-compulsive disorder (OCD),5 group difference in cortical thickness shared among all these disorders (48% of the variance explained). A bioinformatics and schizophrenia (SCZ).6 Nonetheless, the neurobiology un- analysis of co-expression of genes associated with this shared derlying these MRI-derived macroscopic features is not well profile suggests that these genes are involved in understood. neurodevelopmental processes (prenatally), and processes As identified in postmortem studies, there are subtle dif- underlying synaptic activity & plasticity (postnatally). ferences in the cellular composition of the cerebral cortex of Meaning There are shared neurobiologic and cellular mechanisms patients diagnosed as having various psychiatric disorders (vs underlying differences in cortical thickness across multiple controls) such as the density of neurons and/or glial cells and psychiatric disorders, implicating a common role of prenatal the extent of dendritic arborization.7 Mostly lower neuronal development and postnatal functioning of the cerebral cortex. density and/or neuronal size have been documented in ASD,8 BD,9 MDD,10,11OCD,12 and SCZ.13-15 Similar alterations in the den- sity of glial cells (astrocytes, microglia, or oligodendrocytes) have been observed in ASD,8 BD,9 MDD,10,11 and SCZ.16 Methods Several MRI studies have demonstrated distinct interre- gional profiles of group differences in cortical thickness across Group Differences in Cortical Thickness the 34 regions of the Desikan-Killiany atlas.17 We use the word T1-weighted MRI scans were acquired in 145 cohorts partici- “profile” to refer to interregional (spatial) variations in a mea- pating in the ENIGMA Consortium with varying MRI field sure, such as cortical thickness, across the cerebral cortex. strength and vendors. Details regarding MRI acquisition and Lower cortical thickness in temporal regions in cases (vs con- sample demographics are found in eTable 1 and eTable 2 in the trols) is a common feature across ADHD, ASD, BD, MDD, OCD, Supplement. FreeSurfer cortical reconstruction (several ver- and SCZ1-6,18; a 2019 report of the ENIGMA cohorts19 showed sions) was used to derive measures of cortical thickness in 34 cross-disorder correlations among disorders. Likewise, large regions (per hemisphere), as segmented using the Desikan- scale genome-wide association studies (GWAS) identify shared Killiany atlas.17,21 Quality control was conducted by contrib- genetic architecture among these psychiatric disorders.20 uting cohorts, following standardized ENIGMA protocols To our knowledge, no studies have investigated system- (http://enigma.ini.usc.edu/protocols/imaging-protocols/). atically the association between microscopic ex vivo histol- Individual ENIGMA groups performed multiple linear- ogy and macroscopic in vivo differences in cortical thickness regression analyses on their respective cohorts, which modeled across psychiatric disorders. This is required to facilitate our cortical thickness of each region, separately, as a function of understanding of MRI-derived measures in a neurobiologic diagnosis (eg, ADHD), age, age squared,