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

  1. Worrawat Engchuan
  2. Omar Shanta
  3. Kuldeep Kumar
  4. Jeffrey R. MacDonald
  5. Bhooma Thiruvahindrapuram
  6. Omar Hamdan
  7. Marieke Klein
  8. Adam Maihofer
  9. James Guevara
  10. Oanh Hong
  11. Guillaume Huguet
  12. Molly Sacks
  13. Mohammad Ahangari
  14. Rayssa M.M.W. Feitosa
  15. Kara Han
  16. Marla Mendes
  17. Xiaopu Zhou
  18. Nelson X. Bautista
  19. Giovanna Pellecchia
  20. Zhouzhi Wang
  21. Daniele Merico
  22. Ryan K.C. Yuen
  23. Brett Trost
  24. Ida Sønderby
  25. Mark J. Adams
  26. Rolf Adolfsson
  27. Ingrid Agartz
  28. Allison E. Aiello
  29. Martin Alda
  30. Judith Allardyce
  31. Ananda B. Amstadter
  32. Till F.M. Andlauer
  33. Ole A. Andreassen
  34. María S. Artigas
  35. S. Bryn Austin
  36. Muhammad Ayub
  37. Dewleen G. Baker
  38. Nick Bass
  39. Bernhard T. Baune
  40. Maximilian Bayas
  41. Klaus Berger
  42. Joanna M. Biernacka
  43. Tim Bigdeli
  44. Jonathan I. Bisson
  45. Douglas Blackwood
  46. Marco Boks
  47. David Braff
  48. Elvira Bramon
  49. Gerome Breen
  50. Tanja Brueckl
  51. Richard A. Bryant
  52. Cynthia M. Bulik
  53. Joseph Buxbaum
  54. Murray J. Cairns
  55. Jose M. Caldas-de-Almeida
  56. Megan Campbell
  57. Dominique Campion
  58. Vaughan J. Carr
  59. Enrique Castelao
  60. Boris Chaumette
  61. Sven Cichon
  62. David Cohen
  63. Aiden Corvin
  64. Nicholas Craddock
  65. Jennifer Crosbie
  66. Darrina Czamara
  67. Udo Dannlowski
  68. Franziska Degenhardt
  69. Douglas L. Delahanty
  70. Astrid Dempfle
  71. Guillaume Desachy
  72. Arianna Di Florio
  73. Faith B. Dickerson
  74. Srdjan Djurovic
  75. Katharina Domschke
  76. Lisa Douglas
  77. Ole K. Drange
  78. Laramie E. Duncan
  79. Howard J. Edenberg
  80. Tonu Esko
  81. Steve Faraone
  82. Norah C. Feeny
  83. Andreas J. Forstner
  84. Barbara Franke
  85. Mark Frye
  86. Dong-jing Fu
  87. Janice M. Fullerton
  88. Anna Gareeva
  89. Linda Garvert
  90. Justine M. Gatt
  91. Pablo Gejman
  92. Daniel H. Geschwind
  93. Ina Giegling
  94. Stephen J. Glatt
  95. Joe Glessner
  96. Fernando S. Goes
  97. Katherine Gordon-Smith
  98. Hans Grabe
  99. Melissa J. Green
  100. Michael F. Green
  101. Tiffany Greenwood
  102. Maria Grigoroiu-Serbanescu
  103. Raquel E. Gur
  104. Ruben C. Gur
  105. Jose Guzman-Parra
  106. Jan Haavik
  107. Tim Hahn
  108. Hakon Hakonarson
  109. Joachim Hallmayer
  110. Marian L. Hamshere
  111. Annette M. Hartmann
  112. Arsalan Hassan
  113. Caroline Hayward
  114. Johannes Hebebrand
  115. Sian M.J. Hemmings
  116. Stefan Herms
  117. Marisol Herrera-Rivero
  118. Anke Hinney
  119. Georg Homuth
  120. Andrés Ingason
  121. Lucas T. Ito
  122. Nakao Iwata
  123. Ian Jones
  124. Lisa A. Jones
  125. Lina Jonsson
  126. Erik G. Jönsson
  127. René S. Kahn
  128. Robert Karlsson
  129. Milissa L. Kaufman
  130. John R. Kelsoe
  131. James L. Kennedy
  132. Anthony King
  133. Tilo Kircher
  134. George Kirov
  135. Per Knappskog
  136. James A. Knowles
  137. Nene Kobayashi
  138. Karestan C. Koenen
  139. Bettina Konte
  140. Mayuresh Korgaonkar
  141. Kaarina Kowalec
  142. Marie-Odile Krebs
  143. Mikael Landén
  144. Claudine Laurent-Levinson
  145. Lauren A. Lebois
  146. Doug Levinson
  147. Cathryn Lewis
  148. Qingqin Li
  149. Israel Liberzon
  150. Greg Light
  151. Sandra K. Loo
  152. Yi Lu
  153. Susanne Lucae
  154. Charles Marmar
  155. Nicholas G. Martin
  156. Fermin Mayoral
  157. Andrew M. McIntosh
  158. Katie A. McLaughlin
  159. Samuel A. McLean
  160. Andrew McQuillin
  161. Sarah E. Medland
  162. Andreas Meyer-Lindenberg
  163. Vihra Milanova
  164. Philip B. Mitchell
  165. Esther Molina
  166. Bryan Mowry
  167. Bertram Muller-Myhsok
  168. Niamh Mullins
  169. Robin Murray
  170. Markus M. Nöthen
  171. John I. Nurnberger
  172. Kevin S. O’Connell
  173. Roel A. Ophoff
  174. Holly K. Orcutt
  175. Michael J. Owen
  176. Aarno Palotie
  177. Carlos Pato
  178. Michele Pato
  179. Joanna Pawlak
  180. Triinu Peters
  181. Tracey L. Petryshen
  182. Giorgio Pistis
  183. James B. Potash
  184. John Powell
  185. Martin Preisig
  186. Digby Quested
  187. Josep A. Ramos-Quiroga
  188. Andreas Reif
  189. Kerry J. Ressler
  190. Marta Ribasés
  191. Marcella Rietschel
  192. Victoria B. Risbrough
  193. Margarita Rivera
  194. Alex O. Rothbaum
  195. Barbara O. Rothbaum
  196. Dan Rujescu
  197. Takeo Saito
  198. Alan R. Sanders
  199. Russell J. Schachar
  200. Peter R. Schofield
  201. Eva C. Schulte
  202. Thomas G. Schulze
  203. Laura J. Scott
  204. Soraya Seedat
  205. Christina Sheerin
  206. Jianxin Shi
  207. Pamela Sklar
  208. Susan Smalley
  209. Olav B. Smeland
  210. Jordan W. Smoller
  211. Edmund Sonuga-Barke
  212. David St. Clair
  213. Nils Eiel Steen
  214. Dan Stein
  215. Frederike Stein
  216. Murray B. Stein
  217. Fabian Streit
  218. Neal Swerdlow
  219. Florence Thibaut
  220. Johan H. Thygesen
  221. Ilgiz Timerbulatov
  222. Claudio Toma
  223. Edward Trapido
  224. Micheline Tremblay
  225. Ming T. Tsuang
  226. Monica Uddin
  227. Marquis P. Vawter
  228. John B. Vincent
  229. Henry Völzke
  230. James T. Walters
  231. Cynthia S. Weickert
  232. Lauren A. Weiss
  233. Myrna M. Weissman
  234. Thomas Werge
  235. Stephanie H. Witt
  236. Miguel Xavier
  237. Robert Yolken
  238. Ross M. Young
  239. Tetyana Zayats
  240. Lori A. Zoellner
  241. AGP Consortium
  242. PEIC Psychosis Endophenotypes International Consortium
  243. ADHD Working Group of the Psychiatric Genomics Consortium
  244. Autism Working Group of the Psychiatric Genomics Consortium
  245. Bipolar Disorder Working Group of the Psychiatric Genomics Consortium
  246. Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium
  247. PTSD Working Group of the Psychiatric Genomics Consortium
  248. Schizophrenia Working Group of the Psychiatric Genomics Consortium
  249. CNV Working Group of the Psychiatric Genomics Consortium
  250. Kimberley Kendall
  251. Brien Riley
  252. Naomi R. Wray
  253. Michael C. O’Donovan
  254. Patrick F. Sullivan
  255. Sandra Sanchez-Roige
  256. Caroline M. Nievergelt
  257. Sébastien Jacquemont
  258. Stephen W. Scherer
  259. Jonathan Sebat
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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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  1. Version published to 10.1101/2025.07.11.25331381 on medRxiv