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Cleynen I, Engchuan W, Hestand MS, et al. Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion. Mol Psychiatry. 2020;26(8):4496-4510doi: 10.1038/s41380-020-0654-3.
Cleynen, I., Engchuan, W., Hestand, M. S., Heung, T., Holleman, A. M., Johnston, H. R., Monfeuga, T., McDonald-McGinn, D. M., Gur, R. E., Morrow, B. E., Swillen, A., Vorstman, J. A. S., Bearden, C. E., Chow, E. W. C., van den Bree, M., Emanuel, B. S., Vermeesch, J. R., Warren, S. T., Owen, M. J., Chopra, P., Cutler, D. J., Duncan, R., Kotlar, A. V., Mulle, J. G., Voss, A. J., Zwick, M. E., Diacou, A., Golden, A., Guo, T., Lin, J. R., Wang, T., Zhang, Z., Zhao, Y., Marshall, C., Merico, D., Jin, A., Lilley, B., Salmons, H. I., Tran, O., Holmans, P., Pardinas, A., Walters, J. T. R., Demaerel, W., Boot, E., Butcher, N. J., Costain, G. A., Lowther, C., Evers, R., van Amelsvoort, T. A. M. J., van Duin, E., Vingerhoets, C., Breckpot, J., Devriendt, K., Vergaelen, E., Vogels, A., Crowley, T. B., McGinn, D. E., Moss, E. M., Sharkus, R. J., Unolt, M., Zackai, E. H., Calkins, M. E., Gallagher, R. S., Gur, R. C., Tang, S. X., Fritsch, R., Ornstein, C., Repetto, G. M., Breetvelt, E., Duijff, S. N., Fiksinski, A., Moss, H., Niarchou, M., Murphy, K. C., Prasad, S. E., Daly, E. M., Gudbrandsen, M., Murphy, C. M., Murphy, D. G., Buzzanca, A., Fabio, F. D., Digilio, M. C., Pontillo, M., Marino, B., Vicari, S., Coleman, K., Cubells, J. F., Ousley, O. Y., Carmel, M., Gothelf, D., Mekori-Domachevsky, E., Michaelovsky, E., Weinberger, R., Weizman, A., Kushan, L., Jalbrzikowski, M., Armando, M., Eliez, S., Sandini, C., Schneider, M., Béna, F. S., Antshel, K. M., Fremont, W., Kates, W. R., Belzeaux, R., Busa, T., Philip, N., Campbell, L. E., McCabe, K. L., Hooper, S. R., Schoch, K., Shashi, V., Simon, T. J., Tassone, F., Arango, C., Fraguas, D., García-Miñaúr, S., Morey-Canyelles, J., Rosell, J., Suñer, D. H., Raventos-Simic, J., Epstein, M. P., Williams, N. M., & Bassett, A. S. (2021). Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion. Molecular psychiatry, 26(8), 4496-4510. https://doi.org/10.1038/s41380-020-0654-3
Cleynen, Isabelle, et al. "Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion." Molecular psychiatry vol. 26,8 (2021): 4496-4510. doi: https://doi.org/10.1038/s41380-020-0654-3
Cleynen I, Engchuan W, Hestand MS, Heung T, Holleman AM, Johnston HR, Monfeuga T, McDonald-McGinn DM, Gur RE, Morrow BE, Swillen A, Vorstman JAS, Bearden CE, Chow EWC, van den Bree M, Emanuel BS, Vermeesch JR, Warren ST, Owen MJ, Chopra P, Cutler DJ, Duncan R, Kotlar AV, Mulle JG, Voss AJ, Zwick ME, Diacou A, Golden A, Guo T, Lin JR, Wang T, Zhang Z, Zhao Y, Marshall C, Merico D, Jin A, Lilley B, Salmons HI, Tran O, Holmans P, Pardinas A, Walters JTR, Demaerel W, Boot E, Butcher NJ, Costain GA, Lowther C, Evers R, van Amelsvoort TAMJ, van Duin E, Vingerhoets C, Breckpot J, Devriendt K, Vergaelen E, Vogels A, Crowley TB, McGinn DE, Moss EM, Sharkus RJ, Unolt M, Zackai EH, Calkins ME, Gallagher RS, Gur RC, Tang SX, Fritsch R, Ornstein C, Repetto GM, Breetvelt E, Duijff SN, Fiksinski A, Moss H, Niarchou M, Murphy KC, Prasad SE, Daly EM, Gudbrandsen M, Murphy CM, Murphy DG, Buzzanca A, Fabio FD, Digilio MC, Pontillo M, Marino B, Vicari S, Coleman K, Cubells JF, Ousley OY, Carmel M, Gothelf D, Mekori-Domachevsky E, Michaelovsky E, Weinberger R, Weizman A, Kushan L, Jalbrzikowski M, Armando M, Eliez S, Sandini C, Schneider M, Béna FS, Antshel KM, Fremont W, Kates WR, Belzeaux R, Busa T, Philip N, Campbell LE, McCabe KL, Hooper SR, Schoch K, Shashi V, Simon TJ, Tassone F, Arango C, Fraguas D, García-Miñaúr S, Morey-Canyelles J, Rosell J, Suñer DH, Raventos-Simic J, Epstein MP, Williams NM, Bassett AS. Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion. Mol Psychiatry. 2021 Aug;26(8):4496-4510. doi: 10.1038/s41380-020-0654-3. Epub 2020 Feb 03. PMID: 32015465; PMCID: PMC7396297.
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Mol Psychiatry. 2021 Aug;26(8):4496-4510. doi: 10.1038/s41380-020-0654-3. Epub 2020 Feb 03.

Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion.

Molecular psychiatry

Isabelle Cleynen, Worrawat Engchuan, Matthew S Hestand, Tracy Heung, Aaron M Holleman, H Richard Johnston, Thomas Monfeuga, Donna M McDonald-McGinn, Raquel E Gur, Bernice E Morrow, Ann Swillen, Jacob A S Vorstman, Carrie E Bearden, Eva W C Chow, Marianne van den Bree, Beverly S Emanuel, Joris R Vermeesch, Stephen T Warren, Michael J Owen, Pankaj Chopra, David J Cutler, Richard Duncan, Alex V Kotlar, Jennifer G Mulle, Anna J Voss, Michael E Zwick, Alexander Diacou, Aaron Golden, Tingwei Guo, Jhih-Rong Lin, Tao Wang, Zhengdong Zhang, Yingjie Zhao, Christian Marshall, Daniele Merico, Andrea Jin, Brenna Lilley, Harold I Salmons, Oanh Tran, Peter Holmans, Antonio Pardinas, James T R Walters, Wolfram Demaerel, Erik Boot, Nancy J Butcher, Gregory A Costain, Chelsea Lowther, Rens Evers, Therese A M J van Amelsvoort, Esther van Duin, Claudia Vingerhoets, Jeroen Breckpot, Koen Devriendt, Elfi Vergaelen, Annick Vogels, T Blaine Crowley, Daniel E McGinn, Edward M Moss, Robert J Sharkus, Marta Unolt, Elaine H Zackai, Monica E Calkins, Robert S Gallagher, Ruben C Gur, Sunny X Tang, Rosemarie Fritsch, Claudia Ornstein, Gabriela M Repetto, Elemi Breetvelt, Sasja N Duijff, Ania Fiksinski, Hayley Moss, Maria Niarchou, Kieran C Murphy, Sarah E Prasad, Eileen M Daly, Maria Gudbrandsen, Clodagh M Murphy, Declan G Murphy, Antonio Buzzanca, Fabio Di Fabio, Maria C Digilio, Maria Pontillo, Bruno Marino, Stefano Vicari, Karlene Coleman, Joseph F Cubells, Opal Y Ousley, Miri Carmel, Doron Gothelf, Ehud Mekori-Domachevsky, Elena Michaelovsky, Ronnie Weinberger, Abraham Weizman, Leila Kushan, Maria Jalbrzikowski, Marco Armando, Stéphan Eliez, Corrado Sandini, Maude Schneider, Frédérique Sloan Béna, Kevin M Antshel, Wanda Fremont, Wendy R Kates, Raoul Belzeaux, Tiffany Busa, Nicole Philip, Linda E Campbell, Kathryn L McCabe, Stephen R Hooper, Kelly Schoch, Vandana Shashi, Tony J Simon, Flora Tassone, Celso Arango, David Fraguas, Sixto García-Miñaúr, Jaume Morey-Canyelles, Jordi Rosell, Damià H Suñer, Jasna Raventos-Simic, Michael P Epstein, Nigel M Williams, Anne S Bassett

Affiliations

  1. Department of Human Genetics, KU Leuven, Leuven, Belgium.
  2. The Centre for Applied Genomics (TCAG), The Hospital for Sick Children, Toronto, ON, Canada.
  3. Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.
  4. Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  5. Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, ON, Canada.
  6. Dalglish Family 22q Clinic, Toronto General Hospital, University Health Network, Toronto, ON, Canada.
  7. Department of Epidemiology, Emory University, Atlanta, GA, USA.
  8. Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
  9. MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
  10. Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA.
  11. Division of Human Genetics and 22q and You Center, the Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  12. Department of Psychiatry and Lifespan Brain Institute, Penn Medicine-CHOP, University of Pennsylvania, Philadelphia, PA, USA.
  13. Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
  14. Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.
  15. Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  16. Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.
  17. Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
  18. Departments of Psychiatry and Biobehavioral Sciences and Psychology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
  19. Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
  20. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
  21. Division of Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
  22. Deep Genomics Inc., Toronto, ON, Canada.
  23. Hospital for Sick Children, Toronto, ON, Canada.
  24. School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
  25. Universidad de Chile, Santiago, Chile.
  26. Clinica Alemana Universidad del Desarrollo, Santiago, Chile.
  27. Department of Psychiatry, Hospital for Sick Children, Toronto, ON, Canada.
  28. Department of Pediatrics, University Medical Center Utrecht, Utrecht, Netherlands.
  29. Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
  30. Royal College of Surgeons in Ireland, Dublin, Ireland.
  31. Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's College London, London, UK.
  32. Department of Human Neurosciences, University Sapienza of Rome, Rome, Italy.
  33. Ospedale Bambino Gesu Pediatric Hospital, Rome, Italy.
  34. Child and Adolescence Neuropsychiatry Unit, Department of Neuroscience, IRCSS Bambino Gesù Children's Hospital of Rome, Rome, Italy.
  35. Sapienza University, Rome, Italy.
  36. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
  37. Felsenstein Medical Research Center, Petach Tikva, Israel.
  38. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  39. The Child Psychiatry Division, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel.
  40. Geha Mental Health Center, Petach Tikva, Israel.
  41. Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  42. Developmental Imaging and Psychopathology, Department of Psychiatry, University of Geneva, Geneva, Switzerland.
  43. Department of Medical Genetics, Geneva University Hospitals, Geneva, Switzerland.
  44. Department of Psychology, Syracuse University, Syracuse, NY, USA.
  45. Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA.
  46. Pôle de psychiatrie, Hopital Sainte Marguerite, Batiment Solaris, APHM, Marseille, France.
  47. Departement de Genetique Medicale Hôpital d'Enfants de la Timone, APHM, Marseille, France.
  48. Departement de Genetique Medicale Aix Marseille Univ, INSERM, GMGF, APHM, Marseille, France.
  49. University of Newcastle, Callaghan, Australia.
  50. University of California Davis, Davis, CA, USA.
  51. Department of Allied Health Sciences, School of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA.
  52. Department of Pediatrics, Division of Medical Genetics, Duke University School of Medicine, Durham, NC, USA.
  53. MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis, Davis, CA, USA.
  54. Department of Microbiology and Molecular Medicine, University of California Davis, Davis, CA, USA.
  55. Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón, IiSGM, CIBERSAM, School of Medicine, Universidad Complutense, Madrid, Spain.
  56. Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Madrid, Spain.
  57. Hospital Universitari Son Espases, Palma, Spain.
  58. Laboratorio Unidad de Diagnóstico Molecular y Genética Clínica, Hospital Universitari Son Espases, Palma de Mallorca, Spain.
  59. Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA. [email protected].
  60. MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK. [email protected].
  61. Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, ON, Canada. [email protected].
  62. Dalglish Family 22q Clinic, Toronto General Hospital, University Health Network, Toronto, ON, Canada. [email protected].
  63. Department of Psychiatry, University of Toronto, Toronto, ON, Canada. [email protected].

PMID: 32015465 PMCID: PMC7396297 DOI: 10.1038/s41380-020-0654-3

Abstract

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (p

© 2020. The Author(s), under exclusive licence to Springer Nature Limited.

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