Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia

Ida E Sønderby¹, Ómar Gústafsson², Nhat Trung Doan¹, Derrek P Hibar^{3

4}, Sandra Martin-Brevet⁵, Abdel Abdellaoui^{6

7}, David Ames^{8

9}, Katrin Amunts^{10

11

12}, Michael Andersson¹³, Nicola J Armstrong¹⁴, Manon Bernard¹⁵, Nicholas Blackburn¹⁶, John Blangero¹⁶, Dorret I Boomsma¹⁷, Janita Bralten¹⁸, Hans-Richard Brattbak^{19

20}, Henry Brodaty²¹, Rachel M Brouwer²², Robin Bülow²³, Vince Calhoun²⁴, Svenja Caspers^{10

11

12}, Gianpiero Cavalleri²⁵, Chi-Hua Chen^{26

27}, Sven Cichon^{28

29

30}, Simone Ciufolini³¹, Aiden Corvin³², Benedicto Crespo-Facorro^{33

34}, Joanne E Curran¹⁶, Anders M Dale²⁷, Shareefa Dalvie³⁵, Paola Dazzan^{36

37}, Eco J C de Geus^{38

39}, Greig I de Zubicaray⁴⁰, Sonja M C de Zwarte²², Norman Delanty^{25

41}, Anouk den Braber^{38

42}, Sylvane Desrivières⁴³, Gary Donohoe^{44

45}, Bogdan Draganski^{46

47}, Stefan Ehrlich^{48

49

50}, Thomas Espeseth^{1

51}, Simon E Fisher^{52

53}, Barbara Franke^{18

53

54}, Vincent Frouin⁵⁵, Masaki Fukunaga⁵⁶, Thomas Gareau⁵⁵, David C Glahn^{57

58}, Hans Grabe⁵⁹, Nynke A Groenewold³⁵, Jan Haavik⁶⁰, Asta Håberg⁶¹, Ryota Hashimoto⁶², Jayne Y Hehir-Kwa⁶³, Andreas Heinz⁶⁴, Manon H J Hillegers^{22

65}, Per Hoffmann^{29

30

66}, Laurena Holleran⁶⁷, Jouke-Jan Hottenga⁶, Hilleke E Hulshoff²², Masashi Ikeda⁶⁸, Neda Jahanshad³, Terry Jernigan⁶⁹, Christiane Jockwitz^{10

12

70}, Stefan Johansson^{20

60}, Gudrun A Jonsdottir², Erik G Jönsson^{1

71}, Rene Kahn²², Tobias Kaufmann¹, Sinead Kelly⁶⁷, Masataka Kikuchi⁷², Emma E M Knowles⁷³, Knut K Kolskår^{1

51

74}, John B Kwok⁷⁵, Stephanie Le Hellard^{76

77}, Costin Leu^{78

79}, Jingyu Liu^{80

81}, Astri J Lundervold^{60

82}, Arvid Lundervold⁸³, Nicholas G Martin⁸⁴, Karen Mather⁸⁵, Samuel R Mathias⁷³, Mark McCormack^{86

87}, Katie L McMahon⁸⁸, Allan McRae⁸⁹, Yuri Milaneschi⁹⁰, Clara Moreau⁹¹, Derek Morris^{44

45}, David Mothersill⁶⁷, Thomas W Mühleisen^{28

29}, Robin Murray⁹², Jan E Nordvik⁷⁴, Lars Nyberg¹³, Loes M Olde Loohuis⁹³, Roel Ophoff^{22

93}, Tomas Paus^{94

95

96

97}, Zdenka Pausova¹⁵, Brenda Penninx⁹⁸, Juan M Peralta¹⁶, Bruce Pike⁹⁹, Carlos Prieto¹⁰⁰, Sara Pudas^{13

101}, Erin Quinlan¹⁰², Daniel S Quintana^{1

51}, Céline S Reinbold^{29

30}, Tiago Reis Marques^{36

103}, Alexandre Reymond¹⁰⁴, Genevieve Richard^{1

51

74}, Borja Rodriguez-Herreros^{5

91}, Roberto Roiz-Santiañez^{33

34}, Jarek Rokicki¹, James Rucker^{37

43}, Perminder Sachdev⁸⁵, Anne-Marthe Sanders^{1

51

75}, Sigrid B Sando^{61

105}, Lianne Schmaal^{106

107

108}, Peter R Schofield^{109

110}, Andrew J Schork²⁷, Gunter Schumann⁴³, Jean Shin^{15

93}, Elena Shumskaya^{18

53}, Sanjay Sisodiya^{111

112}, Vidar M Steen^{76

77}, Dan J Stein^{113

114}, Stacy Steinberg², Lachlan Strike¹¹⁵, Alexander Teumer¹¹⁶, Anbu Thalamuthu⁸⁵, Diana Tordesillas-Gutierrez^{34

117}, Jessica Turner¹¹⁸, Torill Ueland¹, Anne Uhlmann^{35

119

120}, Magnus O Ulfarsson^{2

121}, Dennis van 't Ent⁶, Dennis van der Meer¹, Neeltje E M van Haren²², Anja Vaskinn¹, Evangelos Vassos¹²², G Bragi Walters^{2

123}, Yunpeng Wang¹, Wei Wen⁸⁵, Christopher D Whelan⁸⁶, Katharina Wittfeld¹²⁴, Margie Wright^{84

125}, Hidenaga Yamamori¹²⁶, Tetyana Zayats^{60

83}, Ingrid Agartz¹, Lars T Westlye^{1

51}, Sébastien Jacquemont^{91

127}, Srdjan Djurovic^{76

128}, Hreinn Stefánsson², Kári Stefánsson^{2

123}, Paul Thompson³, Ole A Andreassen¹²⁹; 16p11.2 European Consortium, for the ENIGMA-CNV working group

Affiliations

¹ NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
² deCODE Genetics/Amgen, Reykjavik, Iceland.
³ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of the University of Southern California, Marina del Rey, USA.
⁴ Janssen Research and Development, La Jolla, CA, USA.
⁵ Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland.
⁶ Biological Psychology, Vrije Universiteit Amsterdam, van Boechorststraat 1, 1081 BT, Amsterdam, The Netherlands.
⁷ Department of Psychiatry, Academic Medical Center, Amsterdam, The Netherlands.
⁸ National Ageing Research Institute, Melbourne, Australia.
⁹ Academic Unit for Psychiatry of Old Age, University of Melbourne, Melbourne, Australia.
¹⁰ Institute of Neuroscience and Medicine (INM-1), Research Centre Juelich, Wilhelm-Johnen-Str., 52425, Juelich, Germany.
¹¹ C. and O. Vogt Institute for Brain Research, Medical Faculty, University of Dusseldorf, Merowingerplatz 1A, 40225, Dusseldorf, Germany.
¹² JARA-BRAIN, Juelich-Aachen Research Alliance, Wilhelm-Johnen-Str., 52425, Juelich, Germany.
¹³ Umeå Center for Functional Brain Imaging (UFBI), Umeå University, 90187, Umeå, Sweden.
¹⁴ Mathematics and Statistics, Murdoch University, Perth, Australia.
¹⁵ The Hospital for Sick Children, University of Toronto, Toronto, M5G 1X8, Canada.
¹⁶ South Texas Diabetes and Obesity Institute, Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, One West University Blvd., 78520, Brownsville, TX, USA.
¹⁷ Netherlands Twin Register, Vrije Universiteit, van der Boechorststraat 1, 1081BT, Amsterdam, Netherlands.
¹⁸ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁹ Department of Clinical Science, University of Bergen, Bergen, Norway.
²⁰ Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
²¹ Centre for Healthy Brain Ageing and Dementia Collaborative Research Centre, UNSW, Sydney, Australia.
²² Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
²³ Department of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
²⁴ The Mind Research Network, The University of New Mexico, Albuquerque, NM, Mexico.
²⁵ The Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland.
²⁶ Department of Radiology, University of California San Diego, La Jolla, USA.
²⁷ Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, USA.
²⁸ Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organisation of the Brain, Genomic Imaging, Research Centre Juelich, Leo-Brandt-Strasse 5, 52425, Jülich, Germany.
²⁹ Human Genomics Research Group, Department of Biomedicine, University of Basel, Hebelstrasse 20, 4031, Basel, Switzerland.
³⁰ Institute of Medical Genetics and Pathology, University Hospital Basel, Schönbeinstrasse 40, 4031, Basel, Switzerland.
³¹ Psychosis Studies, Insitute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespingy Park, SE5 8AF, London, United Kingdom.
³² Neuropsychiatric Genetics Research Group, Discipline of Psychiatry, School of Medicine, Trinity College Dublin, Dublin 2, Ireland.
³³ Department of Medicine and Psychiatry, University Hospital Marqués de Valdecilla, School of Medicine, University of Cantabria-IDIVAL, 39008, Santander, Spain.
³⁴ CIBERSAM (Centro Investigación Biomédica en Red Salud Mental), Santander, 39011, Spain.
³⁵ Department of Psychiatry and Mental Health, Anzio Road, 7925, Cape Town, South Africa.
³⁶ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, SE5 8AF, London, United Kingdom.
³⁷ National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, United Kingdom.
³⁸ Department of Biological Psychology, Behavioral and Movement Sciences, Vrije Universiteit, van der Boechorststraat 1, 1081 BT, Amsterdam, Netherlands.
³⁹ Amsterdam Neuroscience, VU University medical center, van der Boechorststraat 1, 1081 BT, Amsterdam, NH, Netherlands.
⁴⁰ Faculty of Health and Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
⁴¹ Imaging of Dementia and Aging (IDeA) Laboratory, Department of Neurology and Center for Neuroscience, University of California at Davis, 4860 Y Street, Suite 3700, Sacramento, California, 95817, USA.
⁴² Alzheimer Center and Department of Neurology, VU University Medical Center, De Boelelaan 1105, 1081HV, Amsterdam, Netherlands.
⁴³ Medical Research Council - Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.
⁴⁴ Cognitive Genetics and Cognitive Therapy Group, Neuroimaging, Cognition & Genomics Centre (NICOG) & NCBES Galway Neuroscience Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, H91 TK33, Galway, Ireland.
⁴⁵ Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Psychiatry, Trinity College Dublin, Dublin 8, Ireland.
⁴⁶ LREN - Département des neurosciences cliniques, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
⁴⁷ Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
⁴⁸ Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, TU Dresden, 01307, Dresden, Germany.
⁴⁹ Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, 02114, USA.
⁵⁰ Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts, 02129, USA.
⁵¹ Department of Psychology, University of Oslo, Oslo, Norway.
⁵² Language and Genetics Department, Max Planck Institute for Psycholinguistics, Wundtlaan 1, 6525 XD, Nijmegen, Netherlands.
⁵³ Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands.
⁵⁴ Department of Psychiatry, Radboud University Medical Center, Nijmegen, The Netherlands.
⁵⁵ NeuroSpin, CEA, Université Paris-Saclay, F-91191, Gif-sur-Yvette, France.
⁵⁶ Division of Cerebral Integration, National Institute for Physiological Sciences, Aichi, Japan.
⁵⁷ Yale University School of Medicine, 40 Temple Street, Suite 6E, 6511, New Haven, Vaud, USA.
⁵⁸ Olin Neuropsychiatric Research Center, Institute of Living, Hartford Hospital, 300 George Street, 6106, Hartford, CT, USA.
⁵⁹ Department of Psychiatry und Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
⁶⁰ K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
⁶¹ Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
⁶² Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Suita, Osaka, Japan.
⁶³ Princess Máxima Center for Pediatric Oncology, Lundlaan 6, 3584 EA, Utrecht, The Netherlands.
⁶⁴ Dept. of Psychiatry and Psychotherapie, Charite, Humboldt University, Chariteplatz 1, 10017, Berlin, Germany.
⁶⁵ Child and adolescent Psychiatry / Psychology, Erasmus medical center-Sophia's Childerens hospitaal, Rotterdam, Wytemaweg 8, 3000 CB, Rotterdam, The Netherlands.
⁶⁶ Institute of Human Genetics, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.
⁶⁷ The Centre for Neuroimaging & Cognitive Genomics (NICOG) and NCBES Galway Neuroscience Centre, National University of Ireland Galway, Galway, Ireland.
⁶⁸ Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan.
⁶⁹ Center for Human Development, University of California San Diego, San Diego, CA, USA.
⁷⁰ Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Medical Faculty, Pauwelsstraße 30, 52074, Aachen, Germany.
⁷¹ Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital Solna, R5:00, SE-17176, Stockholm, Sweden.
⁷² Department of Genome Informatics, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
⁷³ Department of Psychiatry, Yale University, 40 Temple Street, 6515, New Haven, CT, USA.
⁷⁴ Sunnaas Rehabilitation Hospital HT, Nesodden, Norway.
⁷⁵ Brain and Mind Centre, University of Sydney, Sydney, Australia.
⁷⁶ NORMENT - KG Jebsen Centre, Department of Clinical Science, University of Bergen, Jonas Lies veg 87, 5021, Bergen, Norway.
⁷⁷ Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Jonas Lies veg 87, 5021, Bergen, Norway.
⁷⁸ Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
⁷⁹ Institute of Neurology, University College London, London, United Kingdom.
⁸⁰ The Mind Research Network, 1101 Yale Blvd., 87106, Albuquerque, CT, USA.
⁸¹ Dept. of Electrical and Computer Engineering, University of New Mexico, 87131, Albuquerque, New Mexico, USA.
⁸² Department of Biological and Medical Psychology, Jonas Lies vei 91, N-5009, Bergen, Norway.
⁸³ Department of Biomedicine, University of Bergen, 5009, Bergen, Norway.
⁸⁴ QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁸⁵ Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, New South Wales, 2052, Australia.
⁸⁶ Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St. Stephens Green, D02 YN77, Dublin, Ireland.
⁸⁷ Centre for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, Netherlands.
⁸⁸ Centre for Advanced Imaging, University of Queensland, Brisbane, Queensland, Australia.
⁸⁹ Program in Complex Trait Genomics, Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia.
⁹⁰ Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands, Oldenaller 1, 1081 HJ, Amsterdam, The Netherlands.
⁹¹ CHU Sainte-Justine Research Center, Université de Montréal, Montréal, QC, Canada.
⁹² Departments of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.
⁹³ Center for Neurobehavioral Genetics, University of California, Los Angeles, California, 90095, USA.
⁹⁴ Rotman Research Institute, University of Toronto, Toronto, M6A 2E1, Canada.
⁹⁵ Department of Psychiatry, University of Toronto, Toronto, M5S 1A1, Canada.
⁹⁶ Center for Developing Brain, Child Mind Institute, New York, NY, 10022, USA.
⁹⁷ Department of Psychology, University of Toronto, Toronto, M5S 1A1, Canada.
⁹⁸ Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, VU University Medical, Amsterdam, Netherlands.
⁹⁹ Departments of Radiology & Clinical Neuroscience, University of Calgary, Calgary, T2N 1N4, Canada.
¹⁰⁰ Bioinformatics Service, Nucleus, University of Salamanca (USAL), 37007, Salamanca, Spain.
¹⁰¹ Department of Integrative Medical Biology, Linnéus väg 9, 901 87, Umeå, Sweden.
¹⁰² Centre for Population Neuroscience and Stratified Medicine, Social, Genetic and Development Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, SE5 8AF, London, UK.
¹⁰³ Psychiatry Imaging Group, MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, W12 0NN, London, UK.
¹⁰⁴ Center for Integrative Genomics, University of Lausanne, Genopode building, CH-1015, Lausanne, Switzerland.
¹⁰⁵ Department of Neurology, University Hospital of Trondheim, Edvard Griegs gate 8, N-7006, Trondheim, Norway.
¹⁰⁶ Orygen, The National Centre of Excellence in Youth Mental Health, 35 Poplar Road, 3502, Parkville, New Mexico, Australia.
¹⁰⁷ Centre for Youth Mental Health, The University of Melbourne, 35 Poplar Road, 3502, Parkville, Victoria, Australia.
¹⁰⁸ Department of Psychiatry, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands.
¹⁰⁹ Neuroscience Research Australia, Randwick, Australia.
¹¹⁰ School of Medical Sciences, University of New South Wales, Sydney, Australia.
¹¹¹ Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.
¹¹² Chalfont Centre for Epilepsy, London, UK.
¹¹³ Dept of Psychiatry, University of Cape Town, Groote Schuur Hospital, Anzio Rd, 7925, Cape Town, South Africa.
¹¹⁴ MRC Unit on Risk & Resilience in Mental Disorders, Stellenbosch, South Africa.
¹¹⁵ Queensland Brain Institute, University of Queensland, St Lucia, Queensland, Australia.
¹¹⁶ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
¹¹⁷ Neuroimaging Unit, Technological Facilities. Valdecilla Biomedical Research Institute IDIVAL, Santander, Cantabria, 39011, Spain.
¹¹⁸ Department of Psychology, Georgia State University, Atlanta, GA, USA.
¹¹⁹ Department of Psychiatry, Stellenbosch University, TBH Francie van Zijl Avenue, 7500, Cape Town, South Africa.
¹²⁰ Department of Psychiatry, 1 South Prospect Street, 5401, Burlington, Vermont, USA.
¹²¹ Faculty of Electrical and Computer Engineering, University of Iceland, Reykjavik, Iceland.
¹²² MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, SE5 8AF, London, UK.
¹²³ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹²⁴ German Center for Neurodegenerative Diseases (DZNE), Rostock, Greifswald, Greifswald, Germany.
¹²⁵ Centre for Advanced Imaging, University of Queensland, St Lucia, Queensland, Australia.
¹²⁶ Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
¹²⁷ Department of Pediatrics, University of Montreal, Montreal, H3C 3J7, Canada.
¹²⁸ Department of Medical Genetics, Oslo University Hospital, Kirkeveien 166, 424, Oslo, Norway.
¹²⁹ NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. andreassen@medisin.uio.no.

PMID: 30283035
PMCID: PMC7042770
DOI: 10.1038/s41380-018-0118-1

Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia

Ida E Sønderby et al. Mol Psychiatry. 2020 Mar.

. 2020 Mar;25(3):584-602.

doi: 10.1038/s41380-018-0118-1. Epub 2018 Oct 3.

Authors

Affiliations

¹ NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
² deCODE Genetics/Amgen, Reykjavik, Iceland.
³ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of the University of Southern California, Marina del Rey, USA.
⁴ Janssen Research and Development, La Jolla, CA, USA.
⁵ Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland.
⁶ Biological Psychology, Vrije Universiteit Amsterdam, van Boechorststraat 1, 1081 BT, Amsterdam, The Netherlands.
⁷ Department of Psychiatry, Academic Medical Center, Amsterdam, The Netherlands.
⁸ National Ageing Research Institute, Melbourne, Australia.
⁹ Academic Unit for Psychiatry of Old Age, University of Melbourne, Melbourne, Australia.
¹⁰ Institute of Neuroscience and Medicine (INM-1), Research Centre Juelich, Wilhelm-Johnen-Str., 52425, Juelich, Germany.
¹¹ C. and O. Vogt Institute for Brain Research, Medical Faculty, University of Dusseldorf, Merowingerplatz 1A, 40225, Dusseldorf, Germany.
¹² JARA-BRAIN, Juelich-Aachen Research Alliance, Wilhelm-Johnen-Str., 52425, Juelich, Germany.
¹³ Umeå Center for Functional Brain Imaging (UFBI), Umeå University, 90187, Umeå, Sweden.
¹⁴ Mathematics and Statistics, Murdoch University, Perth, Australia.
¹⁵ The Hospital for Sick Children, University of Toronto, Toronto, M5G 1X8, Canada.
¹⁶ South Texas Diabetes and Obesity Institute, Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, One West University Blvd., 78520, Brownsville, TX, USA.
¹⁷ Netherlands Twin Register, Vrije Universiteit, van der Boechorststraat 1, 1081BT, Amsterdam, Netherlands.
¹⁸ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁹ Department of Clinical Science, University of Bergen, Bergen, Norway.
²⁰ Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
²¹ Centre for Healthy Brain Ageing and Dementia Collaborative Research Centre, UNSW, Sydney, Australia.
²² Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
²³ Department of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
²⁴ The Mind Research Network, The University of New Mexico, Albuquerque, NM, Mexico.
²⁵ The Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland.
²⁶ Department of Radiology, University of California San Diego, La Jolla, USA.
²⁷ Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, USA.
²⁸ Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organisation of the Brain, Genomic Imaging, Research Centre Juelich, Leo-Brandt-Strasse 5, 52425, Jülich, Germany.
²⁹ Human Genomics Research Group, Department of Biomedicine, University of Basel, Hebelstrasse 20, 4031, Basel, Switzerland.
³⁰ Institute of Medical Genetics and Pathology, University Hospital Basel, Schönbeinstrasse 40, 4031, Basel, Switzerland.
³¹ Psychosis Studies, Insitute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespingy Park, SE5 8AF, London, United Kingdom.
³² Neuropsychiatric Genetics Research Group, Discipline of Psychiatry, School of Medicine, Trinity College Dublin, Dublin 2, Ireland.
³³ Department of Medicine and Psychiatry, University Hospital Marqués de Valdecilla, School of Medicine, University of Cantabria-IDIVAL, 39008, Santander, Spain.
³⁴ CIBERSAM (Centro Investigación Biomédica en Red Salud Mental), Santander, 39011, Spain.
³⁵ Department of Psychiatry and Mental Health, Anzio Road, 7925, Cape Town, South Africa.
³⁶ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, SE5 8AF, London, United Kingdom.
³⁷ National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, United Kingdom.
³⁸ Department of Biological Psychology, Behavioral and Movement Sciences, Vrije Universiteit, van der Boechorststraat 1, 1081 BT, Amsterdam, Netherlands.
³⁹ Amsterdam Neuroscience, VU University medical center, van der Boechorststraat 1, 1081 BT, Amsterdam, NH, Netherlands.
⁴⁰ Faculty of Health and Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
⁴¹ Imaging of Dementia and Aging (IDeA) Laboratory, Department of Neurology and Center for Neuroscience, University of California at Davis, 4860 Y Street, Suite 3700, Sacramento, California, 95817, USA.
⁴² Alzheimer Center and Department of Neurology, VU University Medical Center, De Boelelaan 1105, 1081HV, Amsterdam, Netherlands.
⁴³ Medical Research Council - Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.
⁴⁴ Cognitive Genetics and Cognitive Therapy Group, Neuroimaging, Cognition & Genomics Centre (NICOG) & NCBES Galway Neuroscience Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, H91 TK33, Galway, Ireland.
⁴⁵ Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Psychiatry, Trinity College Dublin, Dublin 8, Ireland.
⁴⁶ LREN - Département des neurosciences cliniques, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
⁴⁷ Max-Planck-Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
⁴⁸ Division of Psychological and Social Medicine and Developmental Neurosciences, Faculty of Medicine, TU Dresden, 01307, Dresden, Germany.
⁴⁹ Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, 02114, USA.
⁵⁰ Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts, 02129, USA.
⁵¹ Department of Psychology, University of Oslo, Oslo, Norway.
⁵² Language and Genetics Department, Max Planck Institute for Psycholinguistics, Wundtlaan 1, 6525 XD, Nijmegen, Netherlands.
⁵³ Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands.
⁵⁴ Department of Psychiatry, Radboud University Medical Center, Nijmegen, The Netherlands.
⁵⁵ NeuroSpin, CEA, Université Paris-Saclay, F-91191, Gif-sur-Yvette, France.
⁵⁶ Division of Cerebral Integration, National Institute for Physiological Sciences, Aichi, Japan.
⁵⁷ Yale University School of Medicine, 40 Temple Street, Suite 6E, 6511, New Haven, Vaud, USA.
⁵⁸ Olin Neuropsychiatric Research Center, Institute of Living, Hartford Hospital, 300 George Street, 6106, Hartford, CT, USA.
⁵⁹ Department of Psychiatry und Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
⁶⁰ K.G. Jebsen Centre for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.
⁶¹ Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
⁶² Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Suita, Osaka, Japan.
⁶³ Princess Máxima Center for Pediatric Oncology, Lundlaan 6, 3584 EA, Utrecht, The Netherlands.
⁶⁴ Dept. of Psychiatry and Psychotherapie, Charite, Humboldt University, Chariteplatz 1, 10017, Berlin, Germany.
⁶⁵ Child and adolescent Psychiatry / Psychology, Erasmus medical center-Sophia's Childerens hospitaal, Rotterdam, Wytemaweg 8, 3000 CB, Rotterdam, The Netherlands.
⁶⁶ Institute of Human Genetics, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.
⁶⁷ The Centre for Neuroimaging & Cognitive Genomics (NICOG) and NCBES Galway Neuroscience Centre, National University of Ireland Galway, Galway, Ireland.
⁶⁸ Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan.
⁶⁹ Center for Human Development, University of California San Diego, San Diego, CA, USA.
⁷⁰ Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Medical Faculty, Pauwelsstraße 30, 52074, Aachen, Germany.
⁷¹ Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska Institutet, Karolinska University Hospital Solna, R5:00, SE-17176, Stockholm, Sweden.
⁷² Department of Genome Informatics, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
⁷³ Department of Psychiatry, Yale University, 40 Temple Street, 6515, New Haven, CT, USA.
⁷⁴ Sunnaas Rehabilitation Hospital HT, Nesodden, Norway.
⁷⁵ Brain and Mind Centre, University of Sydney, Sydney, Australia.
⁷⁶ NORMENT - KG Jebsen Centre, Department of Clinical Science, University of Bergen, Jonas Lies veg 87, 5021, Bergen, Norway.
⁷⁷ Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Jonas Lies veg 87, 5021, Bergen, Norway.
⁷⁸ Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
⁷⁹ Institute of Neurology, University College London, London, United Kingdom.
⁸⁰ The Mind Research Network, 1101 Yale Blvd., 87106, Albuquerque, CT, USA.
⁸¹ Dept. of Electrical and Computer Engineering, University of New Mexico, 87131, Albuquerque, New Mexico, USA.
⁸² Department of Biological and Medical Psychology, Jonas Lies vei 91, N-5009, Bergen, Norway.
⁸³ Department of Biomedicine, University of Bergen, 5009, Bergen, Norway.
⁸⁴ QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁸⁵ Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, New South Wales, 2052, Australia.
⁸⁶ Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St. Stephens Green, D02 YN77, Dublin, Ireland.
⁸⁷ Centre for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, Netherlands.
⁸⁸ Centre for Advanced Imaging, University of Queensland, Brisbane, Queensland, Australia.
⁸⁹ Program in Complex Trait Genomics, Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia.
⁹⁰ Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands, Oldenaller 1, 1081 HJ, Amsterdam, The Netherlands.
⁹¹ CHU Sainte-Justine Research Center, Université de Montréal, Montréal, QC, Canada.
⁹² Departments of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.
⁹³ Center for Neurobehavioral Genetics, University of California, Los Angeles, California, 90095, USA.
⁹⁴ Rotman Research Institute, University of Toronto, Toronto, M6A 2E1, Canada.
⁹⁵ Department of Psychiatry, University of Toronto, Toronto, M5S 1A1, Canada.
⁹⁶ Center for Developing Brain, Child Mind Institute, New York, NY, 10022, USA.
⁹⁷ Department of Psychology, University of Toronto, Toronto, M5S 1A1, Canada.
⁹⁸ Department of Psychiatry, Amsterdam Public Health and Amsterdam Neuroscience, VU University Medical, Amsterdam, Netherlands.
⁹⁹ Departments of Radiology & Clinical Neuroscience, University of Calgary, Calgary, T2N 1N4, Canada.
¹⁰⁰ Bioinformatics Service, Nucleus, University of Salamanca (USAL), 37007, Salamanca, Spain.
¹⁰¹ Department of Integrative Medical Biology, Linnéus väg 9, 901 87, Umeå, Sweden.
¹⁰² Centre for Population Neuroscience and Stratified Medicine, Social, Genetic and Development Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, SE5 8AF, London, UK.
¹⁰³ Psychiatry Imaging Group, MRC London Institute of Medical Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, W12 0NN, London, UK.
¹⁰⁴ Center for Integrative Genomics, University of Lausanne, Genopode building, CH-1015, Lausanne, Switzerland.
¹⁰⁵ Department of Neurology, University Hospital of Trondheim, Edvard Griegs gate 8, N-7006, Trondheim, Norway.
¹⁰⁶ Orygen, The National Centre of Excellence in Youth Mental Health, 35 Poplar Road, 3502, Parkville, New Mexico, Australia.
¹⁰⁷ Centre for Youth Mental Health, The University of Melbourne, 35 Poplar Road, 3502, Parkville, Victoria, Australia.
¹⁰⁸ Department of Psychiatry, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands.
¹⁰⁹ Neuroscience Research Australia, Randwick, Australia.
¹¹⁰ School of Medical Sciences, University of New South Wales, Sydney, Australia.
¹¹¹ Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.
¹¹² Chalfont Centre for Epilepsy, London, UK.
¹¹³ Dept of Psychiatry, University of Cape Town, Groote Schuur Hospital, Anzio Rd, 7925, Cape Town, South Africa.
¹¹⁴ MRC Unit on Risk & Resilience in Mental Disorders, Stellenbosch, South Africa.
¹¹⁵ Queensland Brain Institute, University of Queensland, St Lucia, Queensland, Australia.
¹¹⁶ Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
¹¹⁷ Neuroimaging Unit, Technological Facilities. Valdecilla Biomedical Research Institute IDIVAL, Santander, Cantabria, 39011, Spain.
¹¹⁸ Department of Psychology, Georgia State University, Atlanta, GA, USA.
¹¹⁹ Department of Psychiatry, Stellenbosch University, TBH Francie van Zijl Avenue, 7500, Cape Town, South Africa.
¹²⁰ Department of Psychiatry, 1 South Prospect Street, 5401, Burlington, Vermont, USA.
¹²¹ Faculty of Electrical and Computer Engineering, University of Iceland, Reykjavik, Iceland.
¹²² MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, SE5 8AF, London, UK.
¹²³ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹²⁴ German Center for Neurodegenerative Diseases (DZNE), Rostock, Greifswald, Greifswald, Germany.
¹²⁵ Centre for Advanced Imaging, University of Queensland, St Lucia, Queensland, Australia.
¹²⁶ Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
¹²⁷ Department of Pediatrics, University of Montreal, Montreal, H3C 3J7, Canada.
¹²⁸ Department of Medical Genetics, Oslo University Hospital, Kirkeveien 166, 424, Oslo, Norway.
¹²⁹ NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. andreassen@medisin.uio.no.

PMID: 30283035
PMCID: PMC7042770
DOI: 10.1038/s41380-018-0118-1

Erratum in

Correction: Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.
Sønderby IE, Gústafsson Ó, Doan NT, Hibar DP, Martin-Brevet S, Abdellaoui A, Ames D, Amunts K, Andersson M, Armstrong NJ, Bernard M, Blackburn N, Blangero J, Boomsma DI, Bralten J, Brattbak HR, Brodaty H, Brouwer RM, Bülow R, Calhoun V, Caspers S, Cavalleri G, Chen CH, Cichon S, Ciufolini S, Corvin A, Crespo-Facorro B, Curran JE, Dale AM, Dalvie S, Dazzan P, de Geus EJC, de Zubicaray GI, de Zwarte SMC, Delanty N, den Braber A, Desrivières S, Donohoe G, Draganski B, Ehrlich S, Espeseth T, Fisher SE, Franke B, Frouin V, Fukunaga M, Gareau T, Glahn DC, Grabe H, Groenewold NA, Haavik J, Håberg A, Hashimoto R, Hehir-Kwa JY, Heinz A, Hillegers MHJ, Hoffmann P, Holleran L, Hottenga JJ, Hulshoff HE, Ikeda M, Jahanshad N, Jernigan T, Jockwitz C, Johansson S, Jonsdottir GA, Jönsson EG, Kahn R, Kaufmann T, Kelly S, Kikuchi M, Knowles EEM, Kolskår KK, Kwok JB, Hellard SL, Leu C, Liu J, Lundervold AJ, Lundervold A, Martin NG, Mather K, Mathias SR, McCormack M, McMahon KL, McRae A, Milaneschi Y, Moreau C, Morris D, Mothersill D, Mühleisen TW, Murray R, Nordvik JE, Nyberg L, Olde Loohuis LM, Ophoff R, Paus T, Pausova Z, Penninx B, Peralta JM, Pike B, Prieto C, Pudas S, Quinlan E, Quintana DS, Re… See abstract for full author list ➔ Sønderby IE, et al. Mol Psychiatry. 2020 Mar;25(3):692-695. doi: 10.1038/s41380-019-0358-8. Mol Psychiatry. 2020. PMID: 30705424 Free PMC article.

Abstract

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10^-6, 1.7 × 10^-⁹, 3.5 × 10^-12 and 1.0 × 10^-4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.

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Conflict of interest statement

D.P.H. is a full-time employee of Janssen R&D. Decode: O.G., GB Walters, Gudrun A Jonsdottir, Stacy Steinberg, Magnus O Ulfarsson, Hreinn Stefansson and Kari Stefansson are employees of deCODE genetics/Amgen.

Figures

**Fig. 1**
Recurrent CNVs in the 16p11.2 region. CNVs are indicated with reddish lines. All coordinates (in MB) are from the human genome build hg18/NCBI 36. This study includes CNVs overlapping the core 16p11.2 distal region (BP2–BP3) of 220 kb (blue box). These CNVs include the 16p11.2 distal BP2–BP3 (~220 kb), the 16p11.2 distal BP1–BP3 (~550 kb), the 16p11.2 distal BP1–BP4 (~800 kb) and the 16p11.2 distal-proximal BP1–BP5 (~1.7 MB) CNVs

**Fig. 2**
Measures of caudate, pallidum, putamen and ICV show a dose response to differences in copy number in the 16p11.2 distal region. All analyses were corrected for age, age squared, sex, scanner site and ICV (except for ICV). Deletion carriers (del) in red, non-carriers (con) in grey and duplication carriers (dup) in blue, respectively. a Boxplots of subcortical volumes, surface area and thickness and ICV. The normalized brain values are presented. Boxplots represent the mean. Significant differences after Bonferroni correction between groups are noted as *P < 0.005, **P < 0.0005. Centre line represents median, box limits are the upper and lower 25% quartiles, whiskers the 1.5 interquartile range and the points are the outliers. b Bivariate plot of age versus uncorrected ICV

**Fig. 3**
Forest plots on the dose response of copy number on subcortical volumes, surface area, thickness and ICV. The effect size (β of the linear regression) at each site for each measure is shown by the position on the x-axis. Standard error is shown by the horizontal line. A summary polygon shows the results when fitting a random-effects model to the two groups: ENIGMA-CNV discovery and deCODE replication samples. del, con and dup denote the number of individuals in each analysis. *P < 0.005, **P < 0.0005. Effect size and confidence intervals are to the right

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References

1. Kirov G, Rees E, Walters J. What a psychiatrist needs to know about copy number variants. Br J Psych Adv. 2015;21:157–63.
1. Stefansson H, Meyer-Lindenberg A, Steinberg S, Magnusdottir B, Morgen K, Arnarsdottir S, et al. CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature. 2014;505:361–6. - PubMed
1. Bijlsma EK, Gijsbers AC, Schuurs-Hoeijmakers JH, van Haeringen A, Fransen van de Putte DE, Anderlid BM, et al. Extending the phenotype of recurrent rearrangements of 16p11.2: deletions in mentally retarded patients without autism and in normal individuals. Eur J Med Genet. 2009;52:77–87. - PubMed
1. Shen Y, Chen X, Wang L, Guo J, Shen J, An Y, et al. Intra-family phenotypic heterogeneity of 16p11.2 deletion carriers in a three-generation Chinese family. Am J Med Genet B Neuropsychiatr Genet. 2011;156:225–32. - PubMed
1. Tabet AC, Pilorge M, Delorme R, Amsellem F, Pinard JM, Leboyer M, et al. Autism multiplex family with 16p11.2p12.2 microduplication syndrome in monozygotic twins and distal 16p11.2 deletion in their brother. Eur J Human Genet. 2012;20:540–6. - PMC - PubMed

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Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia

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Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia

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