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JAMA Psychiatry. 2019 Oct 30:1-11. doi: 10.1001/jamapsychiatry.2019.3779. [Epub ahead of print]

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, van der Meer D1,2, Sønderby IE1, Kaufmann T1, Walters GB3,4, Abdellaoui A5,6, Ames D7,8, Amunts K9,10,11, Andersson M12,13, Armstrong NJ14, Bernard M15, Blackburn NB16, Blangero J16, Boomsma DI6,17,18, Brodaty H19,20, Brouwer RM21, Bülow R22, Cahn W21,23, Calhoun VD24,25, Caspers S9,11,26, Cavalleri GL27,28, Ching CRK29,30, Cichon S9,31,32, Ciufolini S33, Corvin A34, Crespo-Facorro B35,36, Curran JE16, Dalvie S37, Dazzan P33, de Geus EJC6,17,18, de Zubicaray GI38, de Zwarte SMC21, Delanty N28,39, den Braber A6,17,40, Desrivieres S41, Di Forti M41, Doherty JL42,43, Donohoe G44, Ehrlich S45, Eising E46, Espeseth T47, Fisher SE46,48, Fladby T49,50, Frei O1, Frouin V51, Fukunaga M52,53, Gareau T51, Glahn DC54,55,56, Grabe HJ57,58, Groenewold NA37, Gústafsson Ó3, Haavik J59,60, Haberg AK61,62, Hashimoto R63,64, Hehir-Kwa JY65, Hibar DP66, Hillegers MHJ67, Hoffmann P68,32, Holleran L44, Hottenga JJ6,17,18, Hulshoff Pol HE21, Ikeda M69, Jacquemont S70,71, Jahanshad N30, Jockwitz C9,72, Johansson S73,74, Jönsson EG1,75, Kikuchi M76, Knowles EEM54,56, Kwok JB77,78, Le Hellard S79,80, Linden DEJ2,42, Liu J24, Lundervold A59,81, Lundervold AJ82, Martin NG83, Mather KA19,84, Mathias SR54,56, McMahon KL85, McRae AF86,87, Medland SE88, Moberget T1, Moreau C70,89, Morris DW44, Mühleisen TW9,10,31, Murray RM41, Nordvik JE90, Nyberg L12,13,91, Olde Loohuis LM92, Ophoff RA92, Owen MJ42, Paus T93,94, Pausova Z15,94, Peralta JM16, Pike B95, Prieto C96, Quinlan EB97, Reinbold CS31,32,47, Reis Marques T33,98, Rucker JJH41, Sachdev PS19,99, Sando SB61,100, Schofield PR78,101, Schork AJ102, Schumann G97, Shin J15,94, Shumskaya E48,103, Silva AI43,104, Sisodiya SM105, Steen VM79,80, Stein DJ37,106, Strike LT87, Tamnes CK1,107,108, Teumer A109, Thalamuthu A19, Tordesillas-Gutiérrez D110, Uhlmann A37, Úlfarsson MÖ3,111, van 't Ent D6,17, van den Bree MBM42,112, Vassos E41,113, Wen W19, Wittfeld K57,58, Wright MJ87, Zayats T59,114,115, Dale AM116, Djurovic S79,117, Agartz I1,74,108, Westlye LT1,47, Stefánsson H3, Stefánsson K3,4, Thompson PM30, Andreassen OA1.

Author information

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.

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.

PMID:
31665216
PMCID:
PMC6822096
[Available on 2020-10-30]
DOI:
10.1001/jamapsychiatry.2019.3779

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