A cross-disorder analysis of CNVs finds novel loci and dose-dependent relationships of genes to psychiatric traits

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

Rare copy number variants (CNVs) are a key component of the genetic basis of psychiatric conditions, but have not been well characterized for most. We conducted a genome-wide CNV analysis across six diagnostic categories (N = 574,965): autism (ASD), ADHD, bipolar disorder (BD), major depressive disorder (MDD), PTSD, and schizophrenia (SCZ). We identified 35 genome-wide significant associations at 18 loci, including novel associations in SCZ ( SMYD3, USP7 - HAPSTR1 ) and in the combined cross-disorder analysis ( ASTN2 ). Rare CNVs accounted for 1–3% of heritability across diagnoses. In ASD, associations were uniformly positive, consistent with autism having diverse etiologies and clinical presentations. By contrast, CNVs showed a dose-dependent relationship for other diagnoses, including SCZ and PTSD, with reciprocal deletions and duplications having inversely correlated effects and distinct genotype-phenotype relationships. Our findings suggest that genes have effects that are both dose-dependent and pleiotropic, such that a positive influence on one dimension of psychopathology may be accompanied by positive or negative effects on others.

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  1. Version published to 10.1101/2025.07.11.25331310v2 on medRxiv
  2. Version published to 10.1101/2025.07.11.25331310v1 on medRxiv