Pré-Publication, Document De Travail Année : 2025

Psychiatric disorders converge on common pathways but diverge in cellular context, spatial distribution, and directionality of genetic effects

Worrawat Engchuan (1) , Omar Shanta (2) , Kuldeep Kumar (3) , Jeffrey R Macdonald (1) , Bhooma Thiruvahindrapuram (1) , Omar Hamdan (1) , Marieke Klein (2, 4) , Adam Maihofer (2) , James Guevara (2) , Oanh Hong (2) , Guillaume Huguet (3) , Molly Sacks (2) , Mohammad Ahangari (2) , Rayssa M M W Feitosa (1) , Kara Han (1) , Marla Mendes (1) , Xiaopu Zhou (1) , Nelson X Bautista (1) , Giovanna Pellecchia (1) , Zhouzhi Wang (1) , Daniele Merico (1) , Ryan K C Yuen (1, 5) , Brett Trost (1, 5) , Ida Sønderby (6, 7) , Mark J Adams (8) , Rolf Adolfsson (9) , Ingrid Agartz (10, 6) , Allison E Aiello (11) , Martin Alda (12) , Judith Allardyce (8) , Ananda B Amstadter (13) , Till F M Andlauer (14, 15) , Ole A Andreassen (6) , María S Artigas (16, 17) , S Bryn Austin (18, 19) , Muhammad Ayub (20) , Dewleen G Baker (2) , Nick Bass (21, 22, 23) , Bernhard T Baune (21) , Maximilian Bayas (24, 25) , Klaus Berger (21) , Joanna M Biernacka (26, 27, 28) , Tim Bigdeli (29) , Jonathan I Bisson (30) , Douglas Blackwood (8) , Marco Boks (31) , David Braff (2) , Elvira Bramon (20) , Gerome Breen (32) , Tanja Brueckl (33) , Richard A Bryant (34) , Cynthia M Bulik (35, 36) , Joseph Buxbaum (37) , Murray J Cairns (38) , Jose M Caldas-De-Almeida (39) , Megan Campbell (40) , Dominique Campion (41, 42, 43, 44) , Vaughan J Carr (45, 34) , Enrique Castelao (46, 47) , Boris Chaumette (48, 49) , Sven Cichon (50) , David Cohen (51, 52) , Aiden Corvin (53) , Nicholas Craddock (54) , Jennifer Crosbie (5, 1) , Darrina Czamara (33) , Udo Dannlowski (21) , Franziska Degenhardt (55) , Douglas L Delahanty (56) , Astrid Dempfle (57) , Guillaume Desachy (58, 59) , Arianna Di Florio (54) , Faith B Dickerson (60) , Srdjan Djurovic (6, 7) , Katharina Domschke (61) , Lisa Douglas (62) , Ole K Drange (6, 7) , Laramie E Duncan (63) , Howard J Edenberg (64) , Tonu Esko (65) , Steve Faraone (66) , Norah C Feeny (67) , Andreas J Forstner (68, 55, 69) , Barbara Franke (70) , Mark Frye (26) , Dong-Jing Fu (71) , Janice M Fullerton (72, 34) , Anna Gareeva (73) , Linda Garvert (74) , Justine M Gatt (34) , Pablo Gejman (75) , Daniel H Geschwind (76, 77) , Ina Giegling (78) , Stephen J Glatt (66) , Joe Glessner (79) , Fernando S Goes (80) , Katherine Gordon-Smith (81) , Hans Grabe (74) , Melissa J Green (82) , Michael F Green (83) , Tiffany Greenwood (2) , Maria Grigoroiu-Serbanescu (84) , Raquel E Gur (85) , Ruben C Gur (85) , Jose Guzman-Parra (86) , Jan Haavik (87) , Tim Hahn (21) , Hakon Hakonarson (79) , Joachim Hallmayer (88) , Marian L Hamshere (54) , Annette M Hartmann (78) , Arsalan Hassan (89) , Caroline Hayward (8) , Johannes Hebebrand (90) , Sian M J Hemmings (91) , Stefan Herms (92, 93) , Marisol Herrera-Rivero (21) , Anke Hinney (94) , Georg Homuth (74) , Andrés Ingason (95) , Lucas T Ito (37) , Nakao Iwata (96) , Ian Jones (54) , Lisa A Jones (81) , Lina Jonsson (97) , Erik G Jönsson (98) , René S Kahn (37) , Robert Karlsson (10) , Milissa L Kaufman (19) , John R Kelsoe (2) , James L Kennedy (5) , Anthony King (99) , Tilo Kircher (100) , George Kirov (54) , Per Knappskog (87) , James A Knowles (101) , Nene Kobayashi (25) , Karestan C Koenen (102) , Bettina Konte (78) , Mayuresh Korgaonkar (103) , Kaarina Kowalec (10) , Marie-Odile Krebs (49, 48) , Mikael Landén (104) , Claudine Laurent-Levinson (51, 105) , Lauren A Lebois (19) , Doug Levinson (63) , Cathryn Lewis (106) , Qingqin Li (107) , Israel Liberzon (108) , Greg Light (2) , Sandra K Loo (77) , Yi Lu (10) , Susanne Lucae (33) , Charles Marmar (109) , Nicholas G Martin (110) , Fermin Mayoral (86) , Andrew M Mcintosh (8) , Katie A Mclaughlin (111) , Samuel A Mclean (35) , Andrew Mcquillin (20) , Sarah E Medland (110) , Andreas Meyer-Lindenberg (112) , Vihra Milanova (113) , Philip B Mitchell (34) , Esther Molina (114) , Bryan Mowry (115) , Bertram Muller-Myhsok (33, 116) , Niamh Mullins (37) , Robin Murray (106) , Markus M Nöthen (68) , John I Nurnberger (117) , Kevin O'Connell (7) , Roel A Ophoff (76) , Holly K Orcutt (118) , Michael J Owen (54) , Aarno Palotie (119, 120) , Carlos Pato (121) , Michele Pato (121) , Joanna Pawlak (122) , Triinu Peters (90, 94) , Tracey L Petryshen (119) , Giorgio Pistis (46, 47) , James B Potash (123) , John Powell (106) , Martin Preisig (46, 47) , Digby Quested (124) , Josep A Ramos-Quiroga (125) , Andreas Reif (24, 25) , Kerry J Ressler (126) , Marta Ribasés (127) , Marcella Rietschel (112) , Victoria B Risbrough (2) , Margarita Rivera (114) , Alex O Rothbaum (126) , Barbara O Rothbaum (128) , Dan Rujescu (78) , Takeo Saito (129) , Alan R Sanders (75) , Russell J Schachar (5) , Peter R Schofield (34) , Eva C Schulte (68, 130) , Thomas G Schulze (130) , Laura J Scott (131) , Soraya Seedat (91) , Christina Sheerin (132) , Jianxin Shi (133) , Pamela Sklar (37) , Susan Smalley (77) , Olav B Smeland (7, 6) , Jordan W Smoller (119) , Edmund Sonuga-Barke (106) , David St Clair (134) , Nils Eiel Steen (7, 6) , Dan Stein (40) , Frederike Stein (100) , Murray B Stein (2) , Fabian Streit (112) , Neal Swerdlow (2) , Florence Thibaut (49, 135, 136) , Johan H Thygesen (20) , Ilgiz Timerbulatov (137) , Claudio Toma (34) , Edward Trapido (138) , Micheline Tremblay (139) , Ming T Tsuang (2) , Monica Uddin (140) , Marquis P Vawter (141) , John B Vincent (5) , Henry Völzke (74) , James T Walters (54) , Cynthia S Weickert (34) , Lauren A Weiss (58) , Myrna M Weissman (142) , Thomas Werge (95) , Stephanie H Witt (143, 112) , Miguel Xavier (144, 145) , Robert Yolken (123) , Ross M Young (146) , Tetyana Zayats (87, 119, 19) , Lori A Zoellner (147) , Kimberley Kendall (54) , Brien Riley (132) , Naomi R Wray (148, 115) , Michael C O’donovan (54) , Patrick F. Sullivan (10, 149) , Sandra Sanchez-Roige (150, 2) , Caroline M. Nievergelt (2) , Sébastien Jacquemont (151, 152) , Stephen W. Scherer (1, 5) , Jonathan Sebat (2)
1 SickKids - The Hospital for sick children [Toronto]
2 UC San Diego - University of California [San Diego]
3 Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada]
4 RadboudUMC - Radboud University Medical Center [Nijmegen]
5 University of Toronto
6 UiO - University of Oslo
7 Oslo University Hospital [Oslo]
8 The University of Edinburgh
9 Umeå University = Umeå Universitet
10 Karolinska Institutet = Karolinska Institute [Stockholm]
11 Columbia Mailman School of Public Health
12 Dalhousie University [Halifax]
13 Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry
14 MRI TUM - Klinikum rechts der Isar
15 TUM - Technische Universität Munchen = Technical University Munich = Université Technique de Munich
16 CIBER-SAM - Centro de Investigación Biomédica en Red Salud Mental [Madrid]
17 Vall d'Hebron University Hospital [Barcelona]
18 Boston Children's Hospital
19 HMS - Harvard Medical School [Boston]
20 UCL - University College London [UCL]
21 WWU - Westfälische Wilhelms-Universität Münster = University of Münster = Université de Münster [Münster, Allemagne]
22 Melbourne Medical School [Melbourne]
23 The Florey Institute of Neuroscience and Mental Health [Parkville, VIC, Australie]
24 Frankfurt University Hospital
25 Goethe University Frankfurt = Goethe-Universität Frankfurt am Main
26 Mayo Clinic [Rochester]
27 Hôpital Lariboisière-Fernand-Widal [APHP]
28 OPTeN (UMR_S 1144 / U1144) - Optimisation thérapeutique en Neuropsychopharmacologie
29 New York State Department of Health [Albany]
30 GESVAB - Groupe d’Etudes des Substances Végétales à Activité Biologique
31 UMCU - University Medical Center [Utrecht]
32 SGDP - MRC Social, Genetic and Developmental Psychiatry Centre
33 Max Planck Institute of Psychiatry = Max-Planck-Institut für Psychiatrie
34 UNSW - University of New South Wales [Sydney]
35 UNC-Chapel Hill - Université de Caroline du Nord à Chapel Hill = University of North Carolina [Chapel Hill]
36 CCK - Cancer Center Karolinska [Karolinska Institutet]
37 MSSM - Icahn School of Medicine at Mount Sinai [New York]
38 UoN - University of Newcastle [Callaghan, Australia]
39 CEDOC - Centro de Estudos de Doenças Crónicas
40 University of Cape Town
41 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
42 Service de Génétique [CHU Rouen]
43 CNRMAJ - Centre national de référence pour les malades Alzheimer jeunes
44 Caractérisation structurale et fonctionnelle des mutations et des polymorphismes en cancérologie et neuro-psychiatrie
45 Monash university
46 CHUV - Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne]
47 UNIL - Université de Lausanne = University of Lausanne
48 GHU Paris Psychiatrie et Neurosciences - Groupe hospitalier universitaire Paris psychiatrie & neurosciences [Paris]
49 IPNP - U1266 Inserm - Institut de psychiatrie et neurosciences de Paris
50 Unibas - Université de Bâle = University of Basel = Basel Universität
51 CHU Pitié-Salpêtrière [AP-HP]
52 ISIR - Institut des Systèmes Intelligents et de Robotique
53 Trinity College Dublin
54 Cardiff University
55 University Hospital Bonn
56 Kent State University
57 UKSH - University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein
58 UC San Francisco - University of California [San Francisco]
59 PIERRE FABRE
60 Sheppard Pratt Health System
61 Albert-Ludwigs-Universität Freiburg = University of Freiburg
62 Mid Cheshire Hospitals NHS Foundation Trust, Crewe, England.
63 Stanford University
64 Indiana State University
65 Tartu Ülikool = University of Tartu [Estonie]
66 SUNY Upstate Medical University
67 Case Western Reserve University [Cleveland]
68 Universität Bonn = University of Bonn
69 INM-1 - Institute of Neuroscience and Medicine / Institut für Neurowissenschaften und Medizin [Jülich, Germany]
70 UNIBA - Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro
71 Janssen Research and Development
72 NeuRA - Neuroscience Research Australia
73 KemSU - Kemerovo State University
74 University of Medicine Greifswald
75 University of Chicago
76 David Geffen School of Medicine [Los Angeles]
77 UCLA - University of California [Los Angeles]
78 MedUni Vienna - Medical University of Vienna = Medizinische Universität Wien
79 CHOP - Children’s Hospital of Philadelphia
80 JHU - Johns Hopkins University [Baltimore]
81 UMASS - University of Massachusetts Medical School [Worcester]
82 MACS - Macquarie Centre for Cognitive Science
83 UMASS - University of Massachusetts System
84 ERA-LEARN - Prof. Dr. Alexandru Obregia Psychiatry Hospital
85 University of Pennsylvania [Philadelphia]
86 Hospital Regional Universitario de Málaga = Regional University Hospital of Malaga [Spain]
87 UiB - University of Bergen
88 Stanford School of Medicine [Stanford]
89 UOP - University of Peshawar
90 AöR - University Hospital Essen
91 SU - Stellenbosch University
92 Institut für Genetik - Universität Bonn / Institute of Genetics - University of Bonn
93 University Hospital Basel [Basel]
94 Universität Duisburg-Essen = University of Duisburg-Essen [Essen]
95 KUH - Copenhagen University Hospital [Denmark] = Københavns Universitetshospital [Danmark]
96 Fujita Health University School of Medicine
97 GU - Göteborgs Universitet = University of Gothenburg
98 SGU - Geological Survey of Sweden = Sveriges Geologiska Undersökning
99 OSU - The Ohio State University [Columbus]
100 Philipps Universität Marburg = Philipps University of Marburg
101 Rutgers University [Camden]
102 Harvard T.H. Chan School of Public Health
103 The University of Sydney
104 Sahlgrenska Academy at University of Gothenburg [Göteborg]
105 U933 - Maladies génétiques d'expression pédiatrique
106 King‘s College London
107 Janssen Research & Development
108 Texas A&M University Health Science Center
109 NYU Grossman School of Medicine - New York University School of Medicine
110 QIMR Berghofer Medical Research Institute
111 Harvard University
112 Universität Heidelberg [Heidelberg] = Heidelberg University
113 Medical University of Sofia [Bulgarie]
114 UGR - Universidad de Granada = University of Granada
115 UQ [All campuses : Brisbane, Dutton Park Gatton, Herston, St Lucia and other locations] - The University of Queensland
116 Institute of Translational Medicine, University of Liverpool
117 Indiana University School of Medicine
118 Northern Illinois University
119 Massachusetts General Hospital [Boston]
120 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
121 Rutgers University [Newark]
122 PUMS - Poznan University of Medical Sciences [Poland]
123 Johns Hopkins University School of Medicine [Baltimore]
124 Oxford Health NHS Foundation Trust
125 VHRI - Vall d'Hebron Research Institute - Institut de Recerca Vall d’Hebron
126 Emory University [Atlanta, GA]
127 UB - Universitat de Barcelona
128 Emory University School of Medicine
129 Fujita Health University
130 University Hospital LMU Munich
131 University of Michigan [Dearborn]
132 VCU - Virginia Commonwealth University
133 National Cancer Institute Frederick
134 University of Aberdeen
135 U894 - Centre de Psychiatrie et Neurosciences
136 Hôpital Cochin [AP-HP]
137 Russian Medical Academy for Continuous Medical Education [Moscow]
138 LSU - Louisiana State University [BatonRouge]
139 NHS Foundation Trust
140 USF - University of South Florida [Tampa]
141 UC Irvine - University of California [Irvine]
142 CUMC - Columbia University Medical Center
143 University Hospital Mannheim | Universitätsmedizin Mannheim
144 NOVA - Universidade Nova de Lisboa = NOVA University Lisbon
145 NMS - NOVA Medical School - Faculdade de Ciências Médicas
146 QUT - Queensland University of Technology [Brisbane]
147 University of Washington [Seattle]
148 University of Oxford
149 UNC - University of North Carolina System
150 Vanderbilt University [Nashville]
151 Centre Hospitalier Universitaire Sainte-Justine, Montréal, QC H3T 1C5
152 UdeM - Université de Montréal
Mark J Adams
Rolf Adolfsson
Martin Alda
Judith Allardyce
Ole A Andreassen
Muhammad Ayub
Douglas Blackwood
Marco Boks
Elvira Bramon
Megan Campbell
Aiden Corvin
Nicholas Craddock
Franziska Degenhardt
Douglas L Delahanty
Arianna Di Florio
Faith B Dickerson
Laramie E Duncan
Howard J Edenberg
Steve Faraone
Linda Garvert
Pablo Gejman
Stephen J Glatt
Hans Grabe
Ruben C Gur
Jan Haavik
Marian L Hamshere
Arsalan Hassan
Caroline Hayward
Johannes Hebebrand
Sian M J Hemmings
Georg Homuth
Ian Jones
James L Kennedy
George Kirov
Per Knappskog
Mayuresh Korgaonkar
Lauren A Lebois
Cathryn Lewis
Qingqin Li
Andrew M Mcintosh
Katie A Mclaughlin
Vihra Milanova
Robin Murray
Holly K Orcutt
Michael J Owen
Carlos Pato
Michele Pato
John Powell
Digby Quested
Kerry J Ressler
Marta Ribasés
Alex O Rothbaum
Takeo Saito
Alan R Sanders
Russell J Schachar
Thomas G Schulze
Soraya Seedat
Edmund Sonuga-Barke
Dan Stein
Micheline Tremblay
John B Vincent
Henry Völzke
James T Walters
Lori A Zoellner
Kimberley Kendall
Brien Riley
Michael C O’donovan

Résumé

Abstract Psychiatric conditions share common genes, but mechanisms that differentiate diagnoses remain unclear. We present a multidimensional framework for functional analysis of rare copy number variants (CNVs) across 6 diagnostic categories, including schizophrenia (SCZ), autism (ASD), bipolar disorder (BD), depression (MDD), PTSD, and ADHD (N = 574,965). Using gene-set burden analysis (GSBA), we tested duplication (DUP) and deletion (DEL) burden across 2,645 functional gene sets defined by the intersections of pathways, cell types, and cortical regions. While diagnoses converge on shared pathways, mixed-effects modeling revealed divergence of pathway effects by cell type, brain region, and gene dosage. Factor analysis identified latent dimensions aligned with clinical axes. A primary factor (F1) captured reciprocal dose-dependent effects of DUP and DEL in SCZ reflecting positive and negative effects in excitatory versus inhibitory neurons and association versus sensory cortex. SCZ and ASD were both strongly aligned with F1 but with opposing directionalities. Orthogonal factors highlighted neuronal versus non-neuronal effects in mood disorders (F2) and differential spatial distributions of DEL effects in ADHD and MDD (F3). High-impact CNVs at 16p11.2 and 22q11.2 were enriched for combinations of cell-type-specific genes involved in pathways consistent with our broader findings. These results reveal molecular and cellular mechanisms that are broadly shared across psychiatric traits but differ between diagnostic categories in context and directionality.

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Dates et versions

inserm-05294360 , version 1 (02-10-2025)

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Worrawat Engchuan, Omar Shanta, Kuldeep Kumar, Jeffrey R Macdonald, Bhooma Thiruvahindrapuram, et al.. Psychiatric disorders converge on common pathways but diverge in cellular context, spatial distribution, and directionality of genetic effects. 2025. ⟨inserm-05294360⟩
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