. 2020 Apr 1;77(4):420-430.

doi: 10.1001/jamapsychiatry.2019.3779.

Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition

Writing Committee for the ENIGMA-CNV Working Group; Dennis van der Meer^{1

2}, Ida E Sønderby¹, Tobias Kaufmann¹, G Bragi Walters^{3

4}, Abdel Abdellaoui^{5

6}, David Ames^{7

8}, Katrin Amunts^{9

10

11}, Micael Andersson^{12

13}, Nicola J Armstrong¹⁴, Manon Bernard¹⁵, Nicholas B Blackburn¹⁶, John Blangero¹⁶, Dorret I Boomsma^{6

17

18}, Henry Brodaty^{19

20}, Rachel M Brouwer²¹, Robin Bülow²², Wiepke Cahn^{21

23}, Vince D Calhoun^{24

25}, Svenja Caspers^{9

11

26}, Gianpiero L Cavalleri^{27

28}, Christopher R K Ching^{29

30}, Sven Cichon^{9

31

32}, Simone Ciufolini³³, Aiden Corvin³⁴, Benedicto Crespo-Facorro^{35

36}, Joanne E Curran¹⁶, Shareefa Dalvie³⁷, Paola Dazzan³³, Eco J C de Geus^{6

17

18}, Greig I de Zubicaray³⁸, Sonja M C de Zwarte²¹, Norman Delanty^{28

39}, Anouk den Braber^{6

17

40}, Sylvane Desrivieres⁴¹, Marta Di Forti⁴¹, Joanne L Doherty^{42

43}, Gary Donohoe⁴⁴, Stefan Ehrlich⁴⁵, Else Eising⁴⁶, Thomas Espeseth⁴⁷, Simon E Fisher^{46

48}, Tormod Fladby^{49

50}, Oleksandr Frei¹, Vincent Frouin⁵¹, Masaki Fukunaga^{52

53}, Thomas Gareau⁵¹, David C Glahn^{54

55

56}, Hans J Grabe^{57

58}, Nynke A Groenewold³⁷, Ómar Gústafsson³, Jan Haavik^{59

60}, Asta K Haberg^{61

62}, Ryota Hashimoto^{63

64}, Jayne Y Hehir-Kwa⁶⁵, Derrek P Hibar⁶⁶, Manon H J Hillegers⁶⁷, Per Hoffmann^{68

32}, Laurena Holleran⁴⁴, Jouke-Jan Hottenga^{6

17

18}, Hilleke E Hulshoff Pol²¹, Masashi Ikeda⁶⁹, Sébastien Jacquemont^{70

71}, Neda Jahanshad³⁰, Christiane Jockwitz^{9

72}, Stefan Johansson^{73

74}, Erik G Jönsson^{1

75}, Masataka Kikuchi⁷⁶, Emma E M Knowles^{54

56}, John B Kwok^{77

78}, Stephanie Le Hellard^{79

80}, David E J Linden^{2

42}, Jingyu Liu²⁴, Arvid Lundervold^{59

81}, Astri J Lundervold⁸², Nicholas G Martin⁸³, Karen A Mather^{19

84}, Samuel R Mathias^{54

56}, Katie L McMahon⁸⁵, Allan F McRae^{86

87}, Sarah E Medland⁸⁸, Torgeir Moberget¹, Clara Moreau^{70

89}, Derek W Morris⁴⁴, Thomas W Mühleisen^{9

10

31}, Robin M Murray⁴¹, Jan E Nordvik⁹⁰, Lars Nyberg^{12

13

91}, Loes M Olde Loohuis⁹², Roel A Ophoff⁹², Michael J Owen⁴², Tomas Paus^{93

94}, Zdenka Pausova^{15

94}, Juan M Peralta¹⁶, Bruce Pike⁹⁵, Carlos Prieto⁹⁶, Erin Burke Quinlan⁹⁷, Céline S Reinbold^{31

32

47}, Tiago Reis Marques^{33

98}, James J H Rucker⁴¹, Perminder S Sachdev^{19

99}, Sigrid B Sando^{61

100}, Peter R Schofield^{78

101}, Andrew J Schork¹⁰², Gunter Schumann⁹⁷, Jean Shin^{15

94}, Elena Shumskaya^{48

103}, Ana I Silva^{43

104}, Sanjay M Sisodiya¹⁰⁵, Vidar M Steen^{79

80}, Dan J Stein^{37

106}, Lachlan T Strike⁸⁷, Christian K Tamnes^{1

107

108}, Alexander Teumer¹⁰⁹, Anbupalam Thalamuthu¹⁹, Diana Tordesillas-Gutiérrez¹¹⁰, Anne Uhlmann³⁷, Magnús Ö Úlfarsson^{3

111}, Dennis van 't Ent^{6

17}, Marianne B M van den Bree^{42

112}, Evangelos Vassos^{41

113}, Wei Wen¹⁹, Katharina Wittfeld^{57

58}, Margaret J Wright⁸⁷, Tetyana Zayats^{59

114

115}, Anders M Dale¹¹⁶, Srdjan Djurovic^{79

117}, Ingrid Agartz^{1

74

108}, Lars T Westlye^{1

47}, Hreinn Stefánsson³, Kári Stefánsson^{3

4}, Paul M Thompson³⁰, Ole A Andreassen¹

Affiliations

¹ Norwegian Centre for Mental Disorders Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
² School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands.
³ deCODE Genetics, Reykjavík, Iceland.
⁴ Faculty of Medicine, University of Iceland, Reykjavík, Iceland.
⁵ Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
⁶ Department of Biological Psychology and Netherlands Twin Register, VU University Amsterdam, Amsterdam, the Netherlands.
⁷ University of Melbourne Academic Unit for Psychiatry of Old Age, Kew, Australia.
⁸ National Ageing Research Institute, Parkville, Australia.
⁹ Institute of Neuroscience and Medicine, Research Centre Juelich, Juelich, Germany.
¹⁰ C. and O. Vogt Institute for Brain Research, Medical Faculty, Heinrich Heine University Duesseldorf, Duesseldorf, Germany.
¹¹ JARA-BRAIN, Juelich-Aachen Research Alliance, Juelich, Germany.
¹² Umeå Centre for Functional Brain Imaging, Umeå University, Umeå, Sweden.
¹³ Department of Integrative Medical Biology, Umeå University, Umeå, Sweden.
¹⁴ Mathematics and Statistics, Murdoch University, Perth, Australia.
¹⁵ Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁶ South Texas Diabetes and Obesity Institute, Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Brownsville.
¹⁷ Amsterdam Neuroscience, Amsterdam, the Netherlands.
¹⁸ Amsterdam Public Health Research Institute, VU Medical Center, Amsterdam, the Netherlands.
¹⁹ Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia.
²⁰ Dementia Centre for Research Collaboration, School of Psychiatry, University of New South Wales, Sydney, Australia.
²¹ Department of Psychiatry, UMC Brain Center, University Medical Center Utrecht, Utrecht, the Netherlands.
²² Department of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
²³ Altrecht Science, Utrecht, the Netherlands.
²⁴ Tri-institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS), Georgia State University, Georgia Institute of Technology, Emory University, Atlanta.
²⁵ The Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque.
²⁶ Institute for Anatomy I, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
²⁷ The School of Pharmacy and Biomolecular Sciences, The Royal College of Surgeons in Ireland, Dublin, Ireland.
²⁸ The SFI FutureNeuro Research Centre, Dublin, Ireland.
²⁹ Interdepartmental Neuroscience Program, University of California, Los Angeles.
³⁰ Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging and Informatics, University of Southern California, Los Angeles.
³¹ Department of Biomedicine, University of Basel, Basel, Switzerland.
³² Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
³³ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
³⁴ Department of Psychiatry and Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.
³⁵ University Hospital Marqués de Valdecilla, IdahoIVAL, Centre de Investigación Biomédica en Red Salud Mental (CIBERSAM), Santander, Spain.
³⁶ University Hospital Virgen del Rocío, IBiS, Centre de Investigación Biomédica en Red Salud Mental (CIBERSAM), Sevilla, Spain.
³⁷ Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, Western Cape, South Africa.
³⁸ Faculty of Health and Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.
³⁹ Beaumont Hospital, Dublin, Ireland.
⁴⁰ Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, VU Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
⁴¹ Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
⁴² MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom.
⁴³ Cardiff University Brain Research Imaging Centre School of Psychology, Cardiff University, Cardiff, United Kingdom.
⁴⁴ Centre for Neuroimaging and Cognitive Genomics, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland.
⁴⁵ Psychological and Social Medicine, Faculty of Medicine, Dresden University of Technology, Dresden, Germany.
⁴⁶ Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands.
⁴⁷ Department of Psychology, University of Oslo, Oslo, Norway.
⁴⁸ Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands.
⁴⁹ Akershus University Hospital, Lorenskog, Norway.
⁵⁰ University of Oslo, Lorenskog, Norway.
⁵¹ Neurospin, Le Commissariat à l'énergie atomique et aux énergies alternatives, Université Paris-Saclay, Gif-sur-Yvette, France.
⁵² Division of Cerebral Integration, National Institute for Physiological Sciences, Okazaki, Japan.
⁵³ Department of Life Science, Sokendai, Hayama, Japan.
⁵⁴ Boston Children's Hospital, Boston, Massachusetts.
⁵⁵ Institute of Living, Hartford, Connecticut.
⁵⁶ Harvard Medical School, Boston, Massachusetts.
⁵⁷ Department of Psychiatry and Psychotherapy, Greifswald, Germany.
⁵⁸ German Center of Neurodegenerative Diseases (DZNE), Rostock/Greifswald, Greifswald, Germany.
⁵⁹ Department of Biomedicine, University of Bergen, Bergen, Norway.
⁶⁰ Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.
⁶¹ Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.
⁶² St Olav's Hospital, Department of Radiology and Nuclear Medicine, Trondheim, Norway.
⁶³ Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Japan.
⁶⁴ Osaka University, Osaka, Japan.
⁶⁵ Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
⁶⁶ Genentech, San Francisco, California.
⁶⁷ Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC-Sophia's Children's Hospital, Rotterdam, the Netherlands.
⁶⁸ Institute of Human Genetics, University of Bonn Medical School, Bonn, Germany.
⁶⁹ Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan.
⁷⁰ Sainte Justine Hospital Research Center, Montreal, Quebec, Canada.
⁷¹ Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada.
⁷² Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Medical Faculty, Aachen, Germany.
⁷³ Department of Clinical Science, University of Bergen, Bergen, Norway.
⁷⁴ Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
⁷⁵ Centre for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁷⁶ Department of Genome Informatics, Graduate School of Medicine, Osaka University, Osaka, Japan.
⁷⁷ The University of Sydney Central Clinical School, Sydney, Australia.
⁷⁸ School of Medical Sciences, University of New South Wales, Sydney, Australia.
⁷⁹ Norwegian Centre for Mental Disorders Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
⁸⁰ Dr Einar Martens Research Group for Biological Psychiatry, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
⁸¹ Mohn Medical Imaging and Visualization Centre, Department of Radiology, Haukeland University Hospital, Bergen, Norway.
⁸² Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway.
⁸³ Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁸⁴ Neuroscience Research Australia, Randwick, Australia.
⁸⁵ Herston Imaging Research Facility and School of Clinical Sciences, Queensland University of Technology, Brisbane, Australia.
⁸⁶ Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
⁸⁷ Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
⁸⁸ Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁸⁹ Centre de recherche de l'Institut universitaire de gériatrie de Montréal, Montreal, Quebec, Canada.
⁹⁰ The CatoSenteret Rehabilitation Center, Son, Norway.
⁹¹ Department of Radiation Sciences, Umeå University, Umeå, Sweden.
⁹² Center for Neurobehavioral Genetics, University of California, Los Angeles.
⁹³ Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada.
⁹⁴ Physiology and Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada.
⁹⁵ Department of Radiology, University of Calgary, Calgary, Alberta, Canada.
⁹⁶ Bioinformatics Service, Nucleus, University of Salamanca, Salamanca, Spain.
⁹⁷ Centre for Population Neuroscience and Precision Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
⁹⁸ Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Imperial College London, London, United Kingdom.
⁹⁹ Neuropsychiatric Institute, The Prince of Wales Hospital, Sydney, Australia.
¹⁰⁰ Department of Neurology, University Hospital of Trondheim, Trondheim, Norway.
¹⁰¹ Neuroscience Research Australia, Sydney, Australia.
¹⁰² Institute for Biological Psychiatry, Roskilde, Denmark.
¹⁰³ Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
¹⁰⁴ Neuroscience and Mental Health Research Institute, Cardiff, United Kingdom.
¹⁰⁵ Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology and Chalfont Centre for Epilepsy, London, United Kingdom.
¹⁰⁶ South African Medical Research Council Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
¹⁰⁷ PROMENTA Research Center, Department of Psychology, University of Oslo, Oslo, Norway.
¹⁰⁸ Department of Psychiatry, Diakonhjemmet Hospital, Oslo, Norway.
¹⁰⁹ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
¹¹⁰ Neuroimaging Unit, Technological Facilities, Valdecilla Biomedical Research Institute, IdahoIVAL, Santander, Spain.
¹¹¹ Faculty of Electrical and Computer Engineering, University of Iceland, Reykjavík, Iceland.
¹¹² School of Medicine, Cardiff University, Cardiff, United Kingdom.
¹¹³ National Institute for Health Research, Mental Health Biomedical Research Centre, South London and Maudsley National Health Service Foundation Trust and King's College London, London, United Kingdom.
¹¹⁴ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston.
¹¹⁵ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Boston, Massachusetts.
¹¹⁶ Center for Multimodal Imaging and Genetics, University of California, San Diego.
¹¹⁷ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.

PMID: 31665216
PMCID: PMC6822096
DOI: 10.1001/jamapsychiatry.2019.3779

Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition

Writing Committee for the ENIGMA-CNV Working Group et al. JAMA Psychiatry. 2020.

. 2020 Apr 1;77(4):420-430.

doi: 10.1001/jamapsychiatry.2019.3779.

Authors

Affiliations

¹ Norwegian Centre for Mental Disorders Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
² School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands.
³ deCODE Genetics, Reykjavík, Iceland.
⁴ Faculty of Medicine, University of Iceland, Reykjavík, Iceland.
⁵ Department of Psychiatry, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
⁶ Department of Biological Psychology and Netherlands Twin Register, VU University Amsterdam, Amsterdam, the Netherlands.
⁷ University of Melbourne Academic Unit for Psychiatry of Old Age, Kew, Australia.
⁸ National Ageing Research Institute, Parkville, Australia.
⁹ Institute of Neuroscience and Medicine, Research Centre Juelich, Juelich, Germany.
¹⁰ C. and O. Vogt Institute for Brain Research, Medical Faculty, Heinrich Heine University Duesseldorf, Duesseldorf, Germany.
¹¹ JARA-BRAIN, Juelich-Aachen Research Alliance, Juelich, Germany.
¹² Umeå Centre for Functional Brain Imaging, Umeå University, Umeå, Sweden.
¹³ Department of Integrative Medical Biology, Umeå University, Umeå, Sweden.
¹⁴ Mathematics and Statistics, Murdoch University, Perth, Australia.
¹⁵ Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁶ South Texas Diabetes and Obesity Institute, Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, Brownsville.
¹⁷ Amsterdam Neuroscience, Amsterdam, the Netherlands.
¹⁸ Amsterdam Public Health Research Institute, VU Medical Center, Amsterdam, the Netherlands.
¹⁹ Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia.
²⁰ Dementia Centre for Research Collaboration, School of Psychiatry, University of New South Wales, Sydney, Australia.
²¹ Department of Psychiatry, UMC Brain Center, University Medical Center Utrecht, Utrecht, the Netherlands.
²² Department of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
²³ Altrecht Science, Utrecht, the Netherlands.
²⁴ Tri-institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS), Georgia State University, Georgia Institute of Technology, Emory University, Atlanta.
²⁵ The Department of Electrical and Computer Engineering, University of New Mexico, Albuquerque.
²⁶ Institute for Anatomy I, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
²⁷ The School of Pharmacy and Biomolecular Sciences, The Royal College of Surgeons in Ireland, Dublin, Ireland.
²⁸ The SFI FutureNeuro Research Centre, Dublin, Ireland.
²⁹ Interdepartmental Neuroscience Program, University of California, Los Angeles.
³⁰ Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging and Informatics, University of Southern California, Los Angeles.
³¹ Department of Biomedicine, University of Basel, Basel, Switzerland.
³² Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
³³ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
³⁴ Department of Psychiatry and Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.
³⁵ University Hospital Marqués de Valdecilla, IdahoIVAL, Centre de Investigación Biomédica en Red Salud Mental (CIBERSAM), Santander, Spain.
³⁶ University Hospital Virgen del Rocío, IBiS, Centre de Investigación Biomédica en Red Salud Mental (CIBERSAM), Sevilla, Spain.
³⁷ Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, Western Cape, South Africa.
³⁸ Faculty of Health and Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.
³⁹ Beaumont Hospital, Dublin, Ireland.
⁴⁰ Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, VU Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.
⁴¹ Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
⁴² MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom.
⁴³ Cardiff University Brain Research Imaging Centre School of Psychology, Cardiff University, Cardiff, United Kingdom.
⁴⁴ Centre for Neuroimaging and Cognitive Genomics, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland.
⁴⁵ Psychological and Social Medicine, Faculty of Medicine, Dresden University of Technology, Dresden, Germany.
⁴⁶ Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, the Netherlands.
⁴⁷ Department of Psychology, University of Oslo, Oslo, Norway.
⁴⁸ Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands.
⁴⁹ Akershus University Hospital, Lorenskog, Norway.
⁵⁰ University of Oslo, Lorenskog, Norway.
⁵¹ Neurospin, Le Commissariat à l'énergie atomique et aux énergies alternatives, Université Paris-Saclay, Gif-sur-Yvette, France.
⁵² Division of Cerebral Integration, National Institute for Physiological Sciences, Okazaki, Japan.
⁵³ Department of Life Science, Sokendai, Hayama, Japan.
⁵⁴ Boston Children's Hospital, Boston, Massachusetts.
⁵⁵ Institute of Living, Hartford, Connecticut.
⁵⁶ Harvard Medical School, Boston, Massachusetts.
⁵⁷ Department of Psychiatry and Psychotherapy, Greifswald, Germany.
⁵⁸ German Center of Neurodegenerative Diseases (DZNE), Rostock/Greifswald, Greifswald, Germany.
⁵⁹ Department of Biomedicine, University of Bergen, Bergen, Norway.
⁶⁰ Division of Psychiatry, Haukeland University Hospital, Bergen, Norway.
⁶¹ Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.
⁶² St Olav's Hospital, Department of Radiology and Nuclear Medicine, Trondheim, Norway.
⁶³ Department of Pathology of Mental Diseases, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Japan.
⁶⁴ Osaka University, Osaka, Japan.
⁶⁵ Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
⁶⁶ Genentech, San Francisco, California.
⁶⁷ Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC-Sophia's Children's Hospital, Rotterdam, the Netherlands.
⁶⁸ Institute of Human Genetics, University of Bonn Medical School, Bonn, Germany.
⁶⁹ Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan.
⁷⁰ Sainte Justine Hospital Research Center, Montreal, Quebec, Canada.
⁷¹ Department of Pediatrics, University of Montreal, Montreal, Quebec, Canada.
⁷² Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Medical Faculty, Aachen, Germany.
⁷³ Department of Clinical Science, University of Bergen, Bergen, Norway.
⁷⁴ Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
⁷⁵ Centre for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁷⁶ Department of Genome Informatics, Graduate School of Medicine, Osaka University, Osaka, Japan.
⁷⁷ The University of Sydney Central Clinical School, Sydney, Australia.
⁷⁸ School of Medical Sciences, University of New South Wales, Sydney, Australia.
⁷⁹ Norwegian Centre for Mental Disorders Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
⁸⁰ Dr Einar Martens Research Group for Biological Psychiatry, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
⁸¹ Mohn Medical Imaging and Visualization Centre, Department of Radiology, Haukeland University Hospital, Bergen, Norway.
⁸² Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway.
⁸³ Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁸⁴ Neuroscience Research Australia, Randwick, Australia.
⁸⁵ Herston Imaging Research Facility and School of Clinical Sciences, Queensland University of Technology, Brisbane, Australia.
⁸⁶ Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
⁸⁷ Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
⁸⁸ Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁸⁹ Centre de recherche de l'Institut universitaire de gériatrie de Montréal, Montreal, Quebec, Canada.
⁹⁰ The CatoSenteret Rehabilitation Center, Son, Norway.
⁹¹ Department of Radiation Sciences, Umeå University, Umeå, Sweden.
⁹² Center for Neurobehavioral Genetics, University of California, Los Angeles.
⁹³ Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada.
⁹⁴ Physiology and Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada.
⁹⁵ Department of Radiology, University of Calgary, Calgary, Alberta, Canada.
⁹⁶ Bioinformatics Service, Nucleus, University of Salamanca, Salamanca, Spain.
⁹⁷ Centre for Population Neuroscience and Precision Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.
⁹⁸ Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Imperial College London, London, United Kingdom.
⁹⁹ Neuropsychiatric Institute, The Prince of Wales Hospital, Sydney, Australia.
¹⁰⁰ Department of Neurology, University Hospital of Trondheim, Trondheim, Norway.
¹⁰¹ Neuroscience Research Australia, Sydney, Australia.
¹⁰² Institute for Biological Psychiatry, Roskilde, Denmark.
¹⁰³ Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
¹⁰⁴ Neuroscience and Mental Health Research Institute, Cardiff, United Kingdom.
¹⁰⁵ Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology and Chalfont Centre for Epilepsy, London, United Kingdom.
¹⁰⁶ South African Medical Research Council Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
¹⁰⁷ PROMENTA Research Center, Department of Psychology, University of Oslo, Oslo, Norway.
¹⁰⁸ Department of Psychiatry, Diakonhjemmet Hospital, Oslo, Norway.
¹⁰⁹ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
¹¹⁰ Neuroimaging Unit, Technological Facilities, Valdecilla Biomedical Research Institute, IdahoIVAL, Santander, Spain.
¹¹¹ Faculty of Electrical and Computer Engineering, University of Iceland, Reykjavík, Iceland.
¹¹² School of Medicine, Cardiff University, Cardiff, United Kingdom.
¹¹³ National Institute for Health Research, Mental Health Biomedical Research Centre, South London and Maudsley National Health Service Foundation Trust and King's College London, London, United Kingdom.
¹¹⁴ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston.
¹¹⁵ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Boston, Massachusetts.
¹¹⁶ Center for Multimodal Imaging and Genetics, University of California, San Diego.
¹¹⁷ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.

PMID: 31665216
PMCID: PMC6822096
DOI: 10.1001/jamapsychiatry.2019.3779

Abstract

Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities.

Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance.

Design, setting, and participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019.

Main outcomes and measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort.

Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (β = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks.

Conclusions and relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Brodaty is an advisory board member for Nutricia Australia and has received research funding from the European Union Joint Programme Neurodegenerative Disorders and the National Health and Medical Research Council of Australia. Dr Brouwer has received grants from the Netherlands Organization for Scientific Research (MagW and Brain and Cognition) and Utrecht University. Dr Caspers has received grants from the Initiative and Networking Fund of the Helmholtz Association and the European Union Horizon 2020 Research and Innovation Program under Grant Agreement 785907. Dr Ching has received research support from Biogen. Dr Crespo-Facorro has received personal fees from Janssen-Cilag, Otsuka Pharmaceutical, and Lundbeck. Dr Desrivieres has received grants from the Medical Research Council, Medical Research Foundation, NIHR Biomedical Research Centre, and National Institutes of Health. Dr Di Forti has received personal fees from Janssen Pharmaceutica. Dr Doherty has received grants from the Wellcome Trust. Dr Fladby has received grants from the Norwegian Research Council and the European Union Joint Programme Neurodegenerative Disorders. Dr Fukunaga has received grants from the Japan Society for the Promotion of Science and Japan Agency for Medical Research and Development. Dr Grabe has received grants from the German Research Foundation (DFG), German Ministry of Education and Research (BMBF), the DAMP Foundation, the European Union Joint Programme Neurodegenerative Disorders, and the European Social Fund as well as grants and personal fees from Fresenius Medical Care; personal fees from Neuraxpharm and Janssen-Cilag. Dr Haavik has received grants from Stiftelsen Kristian Gerhard Jebsen and personal fees from Eli Lilly and Co, Shire, and Biocodex. Dr Hehir-Kwa has received grants from the Netherlands Organization for Scientific Research. Dr Hillegers has received grants from the National Alliance for Research on Schizophrenia and Depression Brain and Behavior Foundation and Netherlands Organisation for Health Research and Development. Dr Jacquemont has received grants from Brain Canada, Canada Research Chair, and Canadian Institutes of Health Research. Dr Jahanshad has received grants from the National Institutes of Health and Biogen. Dr Linden has received grants from the Wellcome Trust and book royalties from the Oxford University Press and Palgrave Macmillan. Dr Liu has received grants from the National Institutes of Health. Dr Astri Lundervold has received personal fees from Shire. Dr Mather has received grants from the National Health and Medical Research Council of Australia and Australian Research Council. Dr Moberget has received grants from the Southern and Eastern Norway Regional Health Authority. Dr Owen has received grants from the Medical Research Council, Wellcome Trust, and Takeda Pharmaceuticals. Dr Reis Marques has received personal fees from Lundbeck, Janssen Pharmaceutica, Astellas Pharma, and Angelini. Dr Rucker has received grants from the Wellcome Trust and NIHR Biomedical Research Centre. Dr Sachdev has received grants from the National Health and Medical Research Council of Australia, Australian Research Council, National Institute of Aging, Holden Foundation, Wicking Trust, Vincent Fairfax Family Foundation, and Yulgilbar Foundation as well as personal fees from Biogen. Dr Schofield has received grants from the National Health and Medical Research Council of Australia paid to Neuroscience Research Australia. Dr Steen has received grants from the Research Council of Norway. Dr Stein has received personal fees from Lundbeck and Sun Pharmaceutical Industries. Dr Thalamuthu has received grants from the National Health and Medical Research Council of Australia. Dr van den Bree has received grants from Takeda Pharmaceuticals. Dr Dale is a founder of, holds equity in, and serves on the scientific advisory board of CorTechs Lab; is a member of the scientific advisory board of Human Longevity; has received grants from GE Healthcare; and is a member of the Alzheimer’s Disease Genetics Consortium (ADGC), Enhancing Imaging Genetics through Meta-Analysis (ENIGMA), Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL), and Psychiatric Genomics Consortium (PGC) groups. Dr Westlye has received grants from the Research Council of Norway, Southern and Eastern Norway Regional Health Authority, and European Research Council. Dr Thompson has received grants from Biogen. Dr Andreassen has received grants from the Research Council of Norway, Stiftelsen Kristian Gerhard Jebsen, Southern and Eastern Norway Regional Health Authority, and National Institutes of Health; personal fees from Lundbeck; and serves as a consultant for HealthLytix. No other disclosures were reported.

Figures

**Figure 1.. Association of the 15q11.2 BP1-BP2 Copy Number Variation With Global and Subcortical Brain Morphology**
Bar plot visualizing Cohen d values for the difference in brain morphology measures between carriers and noncarriers of the 15q11.2 BP1-BP2 copy number variation, from the meta-analysis t tests. Error bars indicate standard errors. ^aP < 4.7 × 10⁻⁴. ^bP < 4.7 × 10⁻⁶.

**Figure 2.. Association of the 15q11.2 BP1-BP2 Copy Number Variation With Regional Cortical Brain Morphology**
Results from t tests and linear regression of 15q11.2 BP1-BP2 copy number variation on regional surface area (A) and cortical thickness (B). The effect sizes in the deletion carriers vs noncarriers and duplication carriers vs noncarriers columns are Cohen d values, and the effect sizes in the dosage columns are β coefficients. Black demarcations around a brain region indicates it passes the multiple comparisons–corrected significance threshold of P < 4.7 × 10⁻⁴, with thicker lines indicating more significant findings.

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Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition

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Association of Copy Number Variation of the 15q11.2 BP1-BP2 Region With Cortical and Subcortical Morphology and Cognition

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