Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study

Johan H Thygesen^#¹, Amelia Presman^#¹, Jasmine Harju-Seppänen^#¹, Haritz Irizar¹, Rebecca Jones¹, Karoline Kuchenbaecker^{1

2}, Kuang Lin^{3

4}, Behrooz Z Alizadeh^{5

6}, Isabelle Austin-Zimmerman¹, Agna Bartels-Velthuis⁵, Anjali Bhat¹, Richard Bruggeman^{5

7}, Wiepke Cahn^{8

9}, Stella Calafato¹, Benedicto Crespo-Facorro^{10

11

12}, Liewe de Haan^{13

14}, Sonja M C de Zwarte⁸, Marta Di Forti³, Álvaro Díez-Revuelta^{1

15}, Jeremy Hall¹⁶, Mei-Hua Hall¹⁷, Conrad Iyegbe³, Assen Jablensky¹⁸, Rene Kahn^{8

19}, Luba Kalaydjieva²⁰, Eugenia Kravariti³, Stephen Lawrie²¹, Jurjen J Luykx^{8

22

23}, Igancio Mata^{10

24}, Colm McDonald²⁵, Andrew M McIntosh^{21

26}, Andrew McQuillin¹, Rebecca Muir¹, Roel Ophoff^{27

28

29}, Marco Picchioni³, Diana P Prata^{3

30

31}, Siri Ranlund^{1

3}, Dan Rujescu^{32

33}, Bart P F Rutten^{34

35}, Katja Schulze^{3

36}, Madiha Shaikh^{37

38}, Frederike Schirmbeck^{13

14}, Claudia J P Simons^{34

39}, Timothea Toulopoulou^{3

40}, Therese van Amelsvoort³⁴, Neeltje van Haren^{8

41}, Jim van Os^{3

34

42}, Ruud van Winkel⁴³, Evangelos Vassos³, Muriel Walshe¹, Matthias Weisbrod^{44

45}, Eirini Zartaloudi¹, Vaughan Bell¹, John Powell³, Cathryn M Lewis³, Robin M Murray^{3

36}, Elvira Bramon^{46

47

48}

Affiliations

¹ Division of Psychiatry, University College London, London, UK.
² UCL Genetics Institute, University College London, London, UK.
³ Institute of Psychiatry, Psychology & Neuroscience at King's College London, London, UK.
⁴ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁵ University of Groningen, University Medical Center Groningen, University Center for Psychiatry, Rob Giel Research Center, Groningen, The Netherlands.
⁶ Department of Epidemiology, University Medical Center Groningen, Groningen, The Netherlands.
⁷ Department of Clinical and Developmental Neuropsychology, University of Groningen, Groningen, The Netherlands.
⁸ University Medical Center Utrecht, Department of Psychiatry, Brain Centre Rudolf Magnus, Utrecht University, Utrecht, The Netherlands.
⁹ Altrecht, General Mental Health Care, Utrecht, The Netherlands.
¹⁰ CIBERSAM, Centro Investigación Biomédica en Red Salud Mental, Sevilla, Spain.
¹¹ University Hospital Marqués de Valdecilla, University of Cantabria-IDIVAL, Santander, Spain.
¹² Hospital Universitario Virgen del Rocío, IBiS, Department of Psychiatry, School of Medicine, University of Sevilla, Sevilla, Spain.
¹³ Amsterdam UMC, Department of Psychiatry, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.
¹⁴ Arkin, Institute for Mental Health, Amsterdam, The Netherlands.
¹⁵ Laboratory of Cognitive and Computational Neuroscience-Centre for Biomedical Technology (CTB), Complutense University and Technical University of Madrid, Madrid, Spain.
¹⁶ School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, UK.
¹⁷ Psychosis Neurobiology Laboratory, Harvard Medical School, McLean Hospital, Belmont, MA, USA.
¹⁸ Centre for Clinical Research in Neuropsychiatry, The University of Western Australia, Perth, WA, Australia.
¹⁹ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁰ Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Perth, WA, Australia.
²¹ Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, Scotland, UK.
²² Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
²³ Second opinion outpatient clinic, GGNet Mental Health, Warsnveld, The Netherlands.
²⁴ Fundación Argibide, Pamplona, Spain.
²⁵ The Centre for Neuroimaging & Cognitive Genomics (NICOG) and NCBES Galway Neuroscience Centre, National University of Ireland Galway, Galway, Ireland.
²⁶ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
²⁷ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
²⁸ Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
²⁹ Department of Psychiatry, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
³⁰ Instituto de Biofísica e Engenharia Biomédica, Faculdade de Ciencias da Universidade de Lisboa, Lisboa, Portugal.
³¹ Centre for Psychological Research and Social Intervention, ISCTE-IUL, Lisboa, Portugal.
³² Department of Psychiatry, Ludwig-Maximilians University of Munich, Munich, Germany.
³³ Department of Psychiatry, Psychotherapy and Psychosomatics, University of Halle Wittenberg, Halle, Germany.
³⁴ Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands.
³⁵ The Brain+Nerve Centre, Maastricht University Medical Centre+ (MUMC+), Maastricht, The Netherlands.
³⁶ South London and Maudsley NHS Foundation Trust, London, UK.
³⁷ North East London Foundation Trust, London, UK.
³⁸ Research Department of Clinical, Educational and Health Psychology, University College London, London, UK.
³⁹ GGzE Institute for Mental Health Care, Eindhoven, The Netherlands.
⁴⁰ Department of Psychology, Bilkent University, Main Campus, Bilkent, Ankara, Turkey.
⁴¹ Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center, Sophia's Children Hospital, Rotterdam, The Netherlands.
⁴² Department of Psychiatry, UMC Utrecht Brain Center, Utrecht, The Netherlands.
⁴³ KU Leuven, Department of Neuroscience, Research Group Psychiatry, Leuven, Belgium.
⁴⁴ Department of General Psychiatry, Center of Psychosocial Medicine, University of Heidelberg, Heidelberg, Germany.
⁴⁵ SRH Klinikum, Karlsbad-Langensteinbach, Germany.
⁴⁶ Division of Psychiatry, University College London, London, UK. e.bramon@ucl.ac.uk.
⁴⁷ Institute of Psychiatry, Psychology & Neuroscience at King's College London, London, UK. e.bramon@ucl.ac.uk.
⁴⁸ Institute of Cognitive Neuroscience, University College London, London, UK. e.bramon@ucl.ac.uk.

^# Contributed equally.

PMID: 32719466
PMCID: PMC8589646
DOI: 10.1038/s41380-020-0820-7

Meta-Analysis

Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study

Johan H Thygesen et al. Mol Psychiatry. 2021 Sep.

. 2021 Sep;26(9):5307-5319.

doi: 10.1038/s41380-020-0820-7. Epub 2020 Jul 27.

Authors

Affiliations

¹ Division of Psychiatry, University College London, London, UK.
² UCL Genetics Institute, University College London, London, UK.
³ Institute of Psychiatry, Psychology & Neuroscience at King's College London, London, UK.
⁴ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁵ University of Groningen, University Medical Center Groningen, University Center for Psychiatry, Rob Giel Research Center, Groningen, The Netherlands.
⁶ Department of Epidemiology, University Medical Center Groningen, Groningen, The Netherlands.
⁷ Department of Clinical and Developmental Neuropsychology, University of Groningen, Groningen, The Netherlands.
⁸ University Medical Center Utrecht, Department of Psychiatry, Brain Centre Rudolf Magnus, Utrecht University, Utrecht, The Netherlands.
⁹ Altrecht, General Mental Health Care, Utrecht, The Netherlands.
¹⁰ CIBERSAM, Centro Investigación Biomédica en Red Salud Mental, Sevilla, Spain.
¹¹ University Hospital Marqués de Valdecilla, University of Cantabria-IDIVAL, Santander, Spain.
¹² Hospital Universitario Virgen del Rocío, IBiS, Department of Psychiatry, School of Medicine, University of Sevilla, Sevilla, Spain.
¹³ Amsterdam UMC, Department of Psychiatry, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.
¹⁴ Arkin, Institute for Mental Health, Amsterdam, The Netherlands.
¹⁵ Laboratory of Cognitive and Computational Neuroscience-Centre for Biomedical Technology (CTB), Complutense University and Technical University of Madrid, Madrid, Spain.
¹⁶ School of Medicine, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, UK.
¹⁷ Psychosis Neurobiology Laboratory, Harvard Medical School, McLean Hospital, Belmont, MA, USA.
¹⁸ Centre for Clinical Research in Neuropsychiatry, The University of Western Australia, Perth, WA, Australia.
¹⁹ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁰ Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Perth, WA, Australia.
²¹ Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, Scotland, UK.
²² Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
²³ Second opinion outpatient clinic, GGNet Mental Health, Warsnveld, The Netherlands.
²⁴ Fundación Argibide, Pamplona, Spain.
²⁵ The Centre for Neuroimaging & Cognitive Genomics (NICOG) and NCBES Galway Neuroscience Centre, National University of Ireland Galway, Galway, Ireland.
²⁶ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
²⁷ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
²⁸ Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
²⁹ Department of Psychiatry, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
³⁰ Instituto de Biofísica e Engenharia Biomédica, Faculdade de Ciencias da Universidade de Lisboa, Lisboa, Portugal.
³¹ Centre for Psychological Research and Social Intervention, ISCTE-IUL, Lisboa, Portugal.
³² Department of Psychiatry, Ludwig-Maximilians University of Munich, Munich, Germany.
³³ Department of Psychiatry, Psychotherapy and Psychosomatics, University of Halle Wittenberg, Halle, Germany.
³⁴ Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands.
³⁵ The Brain+Nerve Centre, Maastricht University Medical Centre+ (MUMC+), Maastricht, The Netherlands.
³⁶ South London and Maudsley NHS Foundation Trust, London, UK.
³⁷ North East London Foundation Trust, London, UK.
³⁸ Research Department of Clinical, Educational and Health Psychology, University College London, London, UK.
³⁹ GGzE Institute for Mental Health Care, Eindhoven, The Netherlands.
⁴⁰ Department of Psychology, Bilkent University, Main Campus, Bilkent, Ankara, Turkey.
⁴¹ Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center, Sophia's Children Hospital, Rotterdam, The Netherlands.
⁴² Department of Psychiatry, UMC Utrecht Brain Center, Utrecht, The Netherlands.
⁴³ KU Leuven, Department of Neuroscience, Research Group Psychiatry, Leuven, Belgium.
⁴⁴ Department of General Psychiatry, Center of Psychosocial Medicine, University of Heidelberg, Heidelberg, Germany.
⁴⁵ SRH Klinikum, Karlsbad-Langensteinbach, Germany.
⁴⁶ Division of Psychiatry, University College London, London, UK. e.bramon@ucl.ac.uk.
⁴⁷ Institute of Psychiatry, Psychology & Neuroscience at King's College London, London, UK. e.bramon@ucl.ac.uk.
⁴⁸ Institute of Cognitive Neuroscience, University College London, London, UK. e.bramon@ucl.ac.uk.

^# Contributed equally.

PMID: 32719466
PMCID: PMC8589646
DOI: 10.1038/s41380-020-0820-7

Abstract

The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

**Fig. 1. Forest plots for the meta-analyses investigating length of deletions (N = 18,658) and length of duplications (N = 18,580).**
For additional plots see Supplementary Fig. 3.

See this image and copyright information in PMC

References

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1. Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, et al. Global variation in copy number in the human genome. Nature. 2006;444:444–54. - PMC - PubMed
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Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study

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Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study

Authors

Affiliations

Abstract

Conflict of interest statement

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