Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers

Rune Boen; Tobias Kaufmann; Dennis van der Meer; Dorret I. Boomsma; Eco J.C. de Geus; Dennis van ’t Ent; Dag Alnæs; Ole A. Andreassen; Ida E. Sønderby; ENIGMA-CNV working group

doi:10.1016/j.biopsych.2023.08.018

Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers

Rune Boen^*, Tobias Kaufmann, Dennis van der Meer, Dorret I. Boomsma, Eco J.C. de Geus, Dennis van ’t Ent, Dag Alnæs, Ole A. Andreassen, Ida E. Sønderby, ENIGMA-CNV working group

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Background: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure. Methods: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual's regional difference and global difference, were used to test for regional differences that diverge from the global difference. Results: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness. Conclusions: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.

Original language	English
Pages (from-to)	147-160
Number of pages	14
Journal	Biological psychiatry
Volume	95
Issue number	2
DOIs	https://doi.org/10.1016/j.biopsych.2023.08.018
Publication status	Published - 15 Jan 2024

Bibliographical note

Funding Information:
The OATS Study was facilitated through access to Twins Research Australia, a national resource supported by a Centre of Research Excellence Grant (Grant No. 1079102) from the NHMRC. We thank the participants for their time and generosity in contributing to this research. We acknowledge the contribution of the OATS research team ( https://cheba.unsw.edu.au/project/older-australian-twins-study ) to this study.

Funding Information:
1000BRAINS. This work was supported by the Institute of Neuroscience and Medicine (INM-1) , Research Centre Julich , European Union’s Horizon 2020 Research and Innovation Programme (Grant No. 945539 [HBP SGA3; SC]), and Joint Lab Supercomputing and Modeling for the Human Brain .

Funding Information:
UCLA-Utrecht: This work was supported by the NIMH (Grant No. R01 MH090553 [to RAO]). The NIMH had no further role in study design, in the collection, analysis, and interpretation of the data, in the writing of the report, and in the decision to submit the paper for publication.

Funding Information:
OATS ( Older Australian Twins Study ): This work was supported by the NHMRC and Australian Research Council Strategic Award Grant of the Ageing Well, Ageing Productively Program (Grant No. 401162), NHMRC project (seed) grants (Grant Nos. 1024224 and 1025243), NHMRC project grants (Grant Nos. 1045325 and 1085606), and NHMRC program grants (Grant Nos. 568969 and 1093083).

Funding Information:
ECHO-DEFINE: This work was supported by the Wellcome Trust (Institutional Strategic Support Fund [to MBMvdB] and Clinical Research Training Fellowship Grant No. 102003/Z/13/Z [to JLD]), Waterloo Foundation (Grant No. WF 918-1234 [to MBMvdB]), Baily Thomas Charitable Fund (Grant No. 2315/1 [to MBMvdB]), NIMH (Grant Nos. 5UO1MH101724 and U01MH119738 [to MBMvdB]), IMAGINE-ID and IMAGINE-2 studies (funded by Medical Research Council Grant Nos. MR/N022572/1 and MR/T033045/1 [to MBMvdB]), and Medical Research Council (Centre Grant No. MR/P005748/1 [to MJO]). The DEFINE study was supported by a Wellcome Trust Strategic Award (Grant No. 100202/Z/12/Z [to MJO]).

Funding Information:
ENIGMA-CNV W orking G roup. This work was supported by the Research Council of Norway (Grant No. 223273 [to OAA]), South-Eastern Norway Regional Health Authority (Grant No. 2020060 [to IES, RB]), European Union’s Horizon 2020 Research and Innovation Programme (CoMorMent project; Grant No. 847776 [to IES]), Kristian Gerhard Jebsen Stiftelsen (Grant No. SKGJ-MED-021 [to IES]), and National Institute of Mental Health (NIMH) (Grant Nos. U01MH119736, R21MH116473, R01MH085953 [to CEB]), and 1R01MH129858-01A1 [to SJ].

Funding Information:
IMAGEN: This work was supported by the European Union–funded FP6 Integrated Project IMAGEN (Reinforcement-Related Behavior in Normal Brain Function and Psychopathology) (Grant No. LSHM-CT-2007-037286), Horizon 2020–funded ERC Advanced Grant STRATIFY (Brain Network Based Stratification of Reinforcement-Related Disorders) (Grant No. 695313), Medical Research Foundation and Medical Research Council (Grants Nos. MR/R00465X/1 and MRF-058-0004-RG-DESRI [Neurobiological Underpinning of Eating Disorders: Integrative Biopsychosocial Longitudinal Analyses in Adolescents] and MR/S020306/1 and MRF-058-0009-RG-DESR-C0759 [Establishing Causal Relationships Between Biopsychosocial Predictors and Correlates of Eating Disorders and Their Mediation by Neural Pathways]), National Institutes of Health (NIH) (Consortium Grant No. U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence, and Grant No. 1R56AG058854-01), National Institute for Health Research Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, ERANID (Understanding the Interplay Between Cultural, Biological and Subjective Factors in Drug Use Pathways) (Grant No. PR-ST-0416-10004), BRIDGET (JPND: BRain Imaging, cognition Dementia and next generation GEnomics) (Grant No. MR/N027558/1), Human Brain Project (HBP SGA 2) (Grant No. 785907), FP7 project MATRICS (Grant No. 603016), Medical Research Council Grant Consortium on Vulnerability to Externalizing Disorders and Addictions (Grant No. MR/N000390/1), Bundesministerium für Bildung und Forschung (Grant Nos. 01GS08152, 01EV0711, Forschungsnetz AERIAL 01EE1406A, and 01EE1406B), Deutsche Forschungsgemeinschaft (Grant Nos. SM 80/7-2, SFB 940/2, and NE 1383/14-1), Agence Nationale de la Recherche (ANR) (Grant Nos. ANR-12-SAMA-0004 and AAPG2019 [GeBra]), Eranet Neuron (Grant Nos. AF12-NEUR0008-01 [WM2NA], ANR-18-NEUR00002-01 [ADORe], and ANR-12-SAMA-0004), Fondation de France (Grant No. 00081242), Fondation pour la Recherche Médicale (Grant No. DPA20140629802), Mission Interministérielle de Lutte contre les Drogues et les Conduites Addictives, Assistance Publique Hôpitaux de Paris and Institut National de la Santé et de la Recherche Médicale (Interface Grant), Paris Sud University IDEX 2012, Fondation de l’Avenir (Grant No. AP-RM-17-013), and Fédération pour la Recherche sur le Cerveau.

Funding Information:
FOR2107 Marburg and Münster: This work is part of the German multicenter consortium “Neurobiology of Affective Disorders: A Translational Perspective on Brain Structure and Function,” supported by the German Research Foundation (Deutsche Forschungsgemeinschaft; Forschungsgruppe/Research Unit FOR2107). Principal investigators with respective areas of responsibility in the FOR2107 consortium: Work Package WP1, FOR2107/MACS cohort and brainimaging: TK (speaker FOR2107; DFG Grant Nos. KI 588/14-1, KI 588/14-2, KI 588/20-1, and KI 588/22-1), UD (co-speaker FOR2107; Grant Nos. DA 1151/5-1, DA 1151/5-2, and DA 1151/6-1), Axel Krug (Grant Nos. KR 3822/5-1 and KR 3822/7-2), IN (Grant Nos. NE 2254/1-2, NE 2254/3-1, and NE 2254/4-1), Carsten Konrad (Grant No. KO 4291/3-1). WP5, genetics: Marcella Rietschel (Grant Nos. RI 908/11-1 and RI 908/11-2), MMN (Grant Nos. NO 246/10-1 and NO 246/10-2), Stephanie Witt (Grant Nos. WI 3439/3-1 and WI 3439/3-2). WP6, multi-method data analytics: AJ (Grant Nos. JA 1890/7-1 and JA 1890/7-2), TH (Grant No. HA 7070/2-2).

Funding Information:
TOP: This work was supported by Research Council of Norway (Grant Nos. 23273 (Centre of Excellence, Norwegian Centre for Mental Disorders, NORMENT), Grant Nos. 324252 and 226971).

Funding Information:
NTR (Netherlands Twin Register): This work was supported by the Netherlands Organization for Scientific Research (NWO) and Netherlands Organisation for Health Research and Development (Grant Nos. 904-61-090, 985-10-002, 912-10-020, 904-61-193, 480-04-004,463-06-001, 451-04-034, 400-05-717, Addiction-31160008, 016-115-035, 481-08-011, 056-32-010, Middelgroot-911-09-032, OCW_NWO Gravity programme—024.001.003, and NWO-Groot 480-15-001/674), Center for Medical Systems Biology (NWO Genomics), NBIC/BioAssist/RK (Grant No. 2008.024), Biobanking and Biomolecular Resources Research Infrastructure The Netherlands (Grant Nos. 184.021.007 and 184.033.111), Spinozapremie (Grant No. NWO-56-464-14192), Royal Netherlands Academy of Arts and Sciences Academy Professor Award (Grant No. PAH/6635) and University Research Fellow grant (to DIB), Amsterdam Public Health research institute (former EMGO+ Institute for Health and Care Research), Amsterdam Neuroscience (former Neuoscience Campus Amsterdam), European Science Foundation (Grant No. EU/QLRT-2001-01254), European Community’s Seventh Framework Programme (FP7- HEALTH-F4-2007-2013, Grant Nos. 01413: ENGAGE and 602768: ACTION), European Research Council (Grant Nos. ERC Starting 284167, ERC Consolidator 771057, and ERC Advanced 230374), Rutgers University Cell and DNA Repository (NIMH Grant No. U24 MH068457-06), NIH (Grant Nos. R01D0042157-01A1, R01MH58799-03, MH081802, DA018673, and R01 DK092127-04 and Grand Opportunity Grant Nos. 1RC2 MH089951 and 1RC2 MH089995), and Avera Institute for Human Genetics.

Funding Information:
PING (Pediatric Imaging, Neurocognition, and Genetics): This work was supported by the National Institute on Drug Abuse and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Grant Nos. RC2DA029475 and R01 HD061414).

Funding Information:
QTIM: This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Grant No. R01 HD050735) and the NHMRC (Grant Nos. 486682 and 1009064). Genotyping was supported by the NHMRC (Grant No. 389875).

Funding Information:
SHIP (Study of Health in Pomerania): This work is part of the Community Medicine Research net of the University of Greifswald, Germany, which is supported by the Federal Ministry of Education and Research (Grant Nos. 01ZZ9603, 01ZZ0103, and 01ZZ0403), Ministry of Cultural Affairs, and Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data in SHIP have been supported by the Federal Ministry of Education and Research (Grant No. 03ZIK012) and a joint grant from Siemens Healthineers and the Federal State of Mecklenburg-West Pomerania. MRI scans in SHIP and SHIP-TREND have been supported by a joint grant from Siemens Healthineers and the Federal State of Mecklenburg-West Pomerania.

Funding Information:
Osaka: This work was supported by the Japan Agency for Medical Research and Development (Grant Nos. JP21wm0425012, JP18dm0307002, JP22wm0525019, and JP22dk0207060) and Japan Society for the Promotion of Science KAKENHI (Grant Nos. JP20H03611, JP22H04926, and 20K15778).

Funding Information:
PAFIP (Programa de Atención a las Fases Iniciales de Psicosis): This work was supported by the Instituto de Salud Carlos III (Grant Nos. 00/3095, 01/3129, PI020499, PI14/00639, PI17/01056, and PI14/00918), SENY Fundació (Research Grant No. CI2005 0308007), and Fundación Marqués de Valdecilla Instituto de Investigación Sanitaria Valdecilla (Grant Nos. A/02/07, NCT0235832, and NCT02534363).

Funding Information:
The genotyping and analyses were partly funded by the Genetic Association Information Network of the Foundation for the National Institutes of Health. Computing was supported by NWO (Grant No. 2018/EW/00408559), BiG Grid, Dutch e-Science Grid, and SURFsara.

Funding Information:
MCIC (Mind Clinical Imaging Consortium): This work was supported by the NIH (NIH/National Center for Research Resources Grant No. P41RR14075 [to VC] and Grant No. R01EB005846 [to VC]), Department of Energy (Grant No. DE-FG02-99ER62764), Mind Research Network, Morphometry Biomedical Informatics Research Network (Grant Nos. 1U24 and RR021382A), Function Biomedical Informatics Research Network (Grant No. U24RR021992-01 [to VC], NIH/National Center for Research Resources Grant No. MO1 RR025758-01 [to VC], and NIMH Grant No. 1RC1MH089257 [to VC]), Deutsche Forschungsgemeinschaft (research fellowship [to SE]), and Brain and Behavior Research Foundation (NARSAD Young Investigator Award [to SE]).

Funding Information:
Dublin: This work was supported by the European Research Council (Grant No. ERC-2015-STG-677467 [to GD]) and Science Foundation Ireland (Grant No. SFI-16/ERCS/3787 [to GD]).

Funding Information:
BETULA: This work was supported by the Knut and Alice Wallenberg Foundation (scholar grant [to LN]).

Funding Information:
OSR (Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffele)-Milan: This work was supported by the European Union H2020 (EU.3.1.1 Grant No. 754740 MOODSTRATIFICATION.EU), Italian Ministry of Health (Grant No. RF-2018-12367249) and Italian Ministry of University and Scientific Research (Grant No. A_201779W93T).

Funding Information:
Australian Schizophrenia Research Bank: This work was supported by the Australian National Health and Medical Research Council (NHMRC) (Enabling Grant No. 386500, L3 Investigator Grant No. 1196508 [to CP]), and Program Grant No. APP1150083 [to CP]), Pratt Foundation, Ramsay Health Care, Viertel Charitable Foundation, and Schizophrenia Research Institute. Chief Investigators for the Australian Schizophrenia Research Bank were Vaughan Carr, US, RJS, Assen Jablensky, BJM, Patricia Michie, Stanley Catts, FAH, and CP.

Funding Information:
Brain Imaging Genetics (BIG): This work makes use of the BIG database, first established in Nijmegen, the Netherlands, in 2007. This resource is now part of Cognomics ( www.cognomics.nl ), a joint initiative by researchers from the Donders Centre for Cognitive Neuroimaging, Human Genetics and Cognitive Neuroscience departments of Radboud University Medical Centre, and Max Planck Institute for Psycholinguistics in Nijmegen. The Cognomics Initiative is supported by the participating departments and centers and Biobanking and Biomolecular Resources Research Infrastructure (Netherlands), Hersenstichting Nederland, and NWO. The research leading to these results also receives funding from the NWO (Gravitation Grant No. 024.001.006 Language in Interaction), European Community’s Seventh Framework Programme (FP7/2007-2013) (Grant Nos. 602450 IMAGEMEND, 278948 TACTICS, and 602805 Aggressotype), European Community’s Horizon 2020 programme (Grant Nos. 643051 MiND, and ERC-2010-AdG 268800-NEUROSCHEMA). In addition, the work was supported by the ENIGMA Consortium (Grant No. U54 EB020403) from the BD2K Initiative of a cross-NIH partnership.

Funding Information:
OAA has received speaker’s honorarium from Lundbeck, Janssen, and Sunovion and is a consultant to Coretechs.ai. TRM reports personal fees from Pfizer, Lundbeck, Astellas, Janssen, and Angelini outside the submitted work. He is an employee and shareholder of Pasithea Therapeutics. CRKC has received partial research support from Biogen for work unrelated to the topic of this article (principal investigator, PMT). PMT has received partial research support from Biogen for work unrelated to the topic of this article. MBMvdB and MJO report grants from Takeda Pharmaceuticals outside the submitted work. MJO reports a grant from Akrivia Health outside the submitted work. HJG has received travel grants and speaker’s honoraria from Fresenius Medical Care, Neuraxpharm, Servier, and Janssen as well as research funding from Fresenius Medical Care. GS has received honoraria for participating at advisory board meetings from Roche and Biogen regarding new Alzheimer’s disease drugs. KKS has received consultant and speaker’s honoraria from Roche and OrionPharma, reimbursement of travel and accommodation costs at a meeting from Kolpharma, and sponsorships for arranging conferences from Desitin and Eisai AB. IG has received speaker’s honorarium from Lundbeck. MMN has received fees for membership in an advisory board from HMG Systems Engineering GmbH, for membership in the Medical-Scientific Editorial Office of the Deutsches Ärzteblatt, and for serving as a consultant for Everis Belgium in a project of the European Commission (REFORM/SC2020/029). MMN also receives salary payments from Life & Brain GmbH and holds shares in Life & Brain GmbH. All these concerned activities outside the submitted work. CP received honoraria for talks from Lundbeck, Australia Pty Ltd. outside the submitted work. DJS has received consultancy honoraria from Discovery Vitality, Johnson & Johnson, Kanna, L’Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda and Vistagen. JH has received speaker’s honorarium from Medice and Takeda outside the submitted work. KP reports work with Novo Nordisk and Roche clinical trials outside the submitted work. All other authors report no biomedical financial interests or potential conflicts of interest.

Funding Information:
EPIGEN-London/University College London: The work was partly undertaken at University College London Hospitals NHS Foundation Trust/University College London, which received a proportion of funding from the UK Department of Health National Institute for Health Research Biomedical Research Centres funding scheme.

Publisher Copyright:
© 2023

Funding

The OATS Study was facilitated through access to Twins Research Australia, a national resource supported by a Centre of Research Excellence Grant (Grant No. 1079102) from the NHMRC. We thank the participants for their time and generosity in contributing to this research. We acknowledge the contribution of the OATS research team ( https://cheba.unsw.edu.au/project/older-australian-twins-study ) to this study. 1000BRAINS. This work was supported by the Institute of Neuroscience and Medicine (INM-1) , Research Centre Julich , European Union’s Horizon 2020 Research and Innovation Programme (Grant No. 945539 [HBP SGA3; SC]), and Joint Lab Supercomputing and Modeling for the Human Brain . UCLA-Utrecht: This work was supported by the NIMH (Grant No. R01 MH090553 [to RAO]). The NIMH had no further role in study design, in the collection, analysis, and interpretation of the data, in the writing of the report, and in the decision to submit the paper for publication. OATS ( Older Australian Twins Study ): This work was supported by the NHMRC and Australian Research Council Strategic Award Grant of the Ageing Well, Ageing Productively Program (Grant No. 401162), NHMRC project (seed) grants (Grant Nos. 1024224 and 1025243), NHMRC project grants (Grant Nos. 1045325 and 1085606), and NHMRC program grants (Grant Nos. 568969 and 1093083). ECHO-DEFINE: This work was supported by the Wellcome Trust (Institutional Strategic Support Fund [to MBMvdB] and Clinical Research Training Fellowship Grant No. 102003/Z/13/Z [to JLD]), Waterloo Foundation (Grant No. WF 918-1234 [to MBMvdB]), Baily Thomas Charitable Fund (Grant No. 2315/1 [to MBMvdB]), NIMH (Grant Nos. 5UO1MH101724 and U01MH119738 [to MBMvdB]), IMAGINE-ID and IMAGINE-2 studies (funded by Medical Research Council Grant Nos. MR/N022572/1 and MR/T033045/1 [to MBMvdB]), and Medical Research Council (Centre Grant No. MR/P005748/1 [to MJO]). The DEFINE study was supported by a Wellcome Trust Strategic Award (Grant No. 100202/Z/12/Z [to MJO]). ENIGMA-CNV W orking G roup. This work was supported by the Research Council of Norway (Grant No. 223273 [to OAA]), South-Eastern Norway Regional Health Authority (Grant No. 2020060 [to IES, RB]), European Union’s Horizon 2020 Research and Innovation Programme (CoMorMent project; Grant No. 847776 [to IES]), Kristian Gerhard Jebsen Stiftelsen (Grant No. SKGJ-MED-021 [to IES]), and National Institute of Mental Health (NIMH) (Grant Nos. U01MH119736, R21MH116473, R01MH085953 [to CEB]), and 1R01MH129858-01A1 [to SJ]. IMAGEN: This work was supported by the European Union–funded FP6 Integrated Project IMAGEN (Reinforcement-Related Behavior in Normal Brain Function and Psychopathology) (Grant No. LSHM-CT-2007-037286), Horizon 2020–funded ERC Advanced Grant STRATIFY (Brain Network Based Stratification of Reinforcement-Related Disorders) (Grant No. 695313), Medical Research Foundation and Medical Research Council (Grants Nos. MR/R00465X/1 and MRF-058-0004-RG-DESRI [Neurobiological Underpinning of Eating Disorders: Integrative Biopsychosocial Longitudinal Analyses in Adolescents] and MR/S020306/1 and MRF-058-0009-RG-DESR-C0759 [Establishing Causal Relationships Between Biopsychosocial Predictors and Correlates of Eating Disorders and Their Mediation by Neural Pathways]), National Institutes of Health (NIH) (Consortium Grant No. U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence, and Grant No. 1R56AG058854-01), National Institute for Health Research Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, ERANID (Understanding the Interplay Between Cultural, Biological and Subjective Factors in Drug Use Pathways) (Grant No. PR-ST-0416-10004), BRIDGET (JPND: BRain Imaging, cognition Dementia and next generation GEnomics) (Grant No. MR/N027558/1), Human Brain Project (HBP SGA 2) (Grant No. 785907), FP7 project MATRICS (Grant No. 603016), Medical Research Council Grant Consortium on Vulnerability to Externalizing Disorders and Addictions (Grant No. MR/N000390/1), Bundesministerium für Bildung und Forschung (Grant Nos. 01GS08152, 01EV0711, Forschungsnetz AERIAL 01EE1406A, and 01EE1406B), Deutsche Forschungsgemeinschaft (Grant Nos. SM 80/7-2, SFB 940/2, and NE 1383/14-1), Agence Nationale de la Recherche (ANR) (Grant Nos. ANR-12-SAMA-0004 and AAPG2019 [GeBra]), Eranet Neuron (Grant Nos. AF12-NEUR0008-01 [WM2NA], ANR-18-NEUR00002-01 [ADORe], and ANR-12-SAMA-0004), Fondation de France (Grant No. 00081242), Fondation pour la Recherche Médicale (Grant No. DPA20140629802), Mission Interministérielle de Lutte contre les Drogues et les Conduites Addictives, Assistance Publique Hôpitaux de Paris and Institut National de la Santé et de la Recherche Médicale (Interface Grant), Paris Sud University IDEX 2012, Fondation de l’Avenir (Grant No. AP-RM-17-013), and Fédération pour la Recherche sur le Cerveau. FOR2107 Marburg and Münster: This work is part of the German multicenter consortium “Neurobiology of Affective Disorders: A Translational Perspective on Brain Structure and Function,” supported by the German Research Foundation (Deutsche Forschungsgemeinschaft; Forschungsgruppe/Research Unit FOR2107). Principal investigators with respective areas of responsibility in the FOR2107 consortium: Work Package WP1, FOR2107/MACS cohort and brainimaging: TK (speaker FOR2107; DFG Grant Nos. KI 588/14-1, KI 588/14-2, KI 588/20-1, and KI 588/22-1), UD (co-speaker FOR2107; Grant Nos. DA 1151/5-1, DA 1151/5-2, and DA 1151/6-1), Axel Krug (Grant Nos. KR 3822/5-1 and KR 3822/7-2), IN (Grant Nos. NE 2254/1-2, NE 2254/3-1, and NE 2254/4-1), Carsten Konrad (Grant No. KO 4291/3-1). WP5, genetics: Marcella Rietschel (Grant Nos. RI 908/11-1 and RI 908/11-2), MMN (Grant Nos. NO 246/10-1 and NO 246/10-2), Stephanie Witt (Grant Nos. WI 3439/3-1 and WI 3439/3-2). WP6, multi-method data analytics: AJ (Grant Nos. JA 1890/7-1 and JA 1890/7-2), TH (Grant No. HA 7070/2-2). TOP: This work was supported by Research Council of Norway (Grant Nos. 23273 (Centre of Excellence, Norwegian Centre for Mental Disorders, NORMENT), Grant Nos. 324252 and 226971). NTR (Netherlands Twin Register): This work was supported by the Netherlands Organization for Scientific Research (NWO) and Netherlands Organisation for Health Research and Development (Grant Nos. 904-61-090, 985-10-002, 912-10-020, 904-61-193, 480-04-004,463-06-001, 451-04-034, 400-05-717, Addiction-31160008, 016-115-035, 481-08-011, 056-32-010, Middelgroot-911-09-032, OCW_NWO Gravity programme—024.001.003, and NWO-Groot 480-15-001/674), Center for Medical Systems Biology (NWO Genomics), NBIC/BioAssist/RK (Grant No. 2008.024), Biobanking and Biomolecular Resources Research Infrastructure The Netherlands (Grant Nos. 184.021.007 and 184.033.111), Spinozapremie (Grant No. NWO-56-464-14192), Royal Netherlands Academy of Arts and Sciences Academy Professor Award (Grant No. PAH/6635) and University Research Fellow grant (to DIB), Amsterdam Public Health research institute (former EMGO+ Institute for Health and Care Research), Amsterdam Neuroscience (former Neuoscience Campus Amsterdam), European Science Foundation (Grant No. EU/QLRT-2001-01254), European Community’s Seventh Framework Programme (FP7- HEALTH-F4-2007-2013, Grant Nos. 01413: ENGAGE and 602768: ACTION), European Research Council (Grant Nos. ERC Starting 284167, ERC Consolidator 771057, and ERC Advanced 230374), Rutgers University Cell and DNA Repository (NIMH Grant No. U24 MH068457-06), NIH (Grant Nos. R01D0042157-01A1, R01MH58799-03, MH081802, DA018673, and R01 DK092127-04 and Grand Opportunity Grant Nos. 1RC2 MH089951 and 1RC2 MH089995), and Avera Institute for Human Genetics. PING (Pediatric Imaging, Neurocognition, and Genetics): This work was supported by the National Institute on Drug Abuse and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Grant Nos. RC2DA029475 and R01 HD061414). QTIM: This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Grant No. R01 HD050735) and the NHMRC (Grant Nos. 486682 and 1009064). Genotyping was supported by the NHMRC (Grant No. 389875). SHIP (Study of Health in Pomerania): This work is part of the Community Medicine Research net of the University of Greifswald, Germany, which is supported by the Federal Ministry of Education and Research (Grant Nos. 01ZZ9603, 01ZZ0103, and 01ZZ0403), Ministry of Cultural Affairs, and Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data in SHIP have been supported by the Federal Ministry of Education and Research (Grant No. 03ZIK012) and a joint grant from Siemens Healthineers and the Federal State of Mecklenburg-West Pomerania. MRI scans in SHIP and SHIP-TREND have been supported by a joint grant from Siemens Healthineers and the Federal State of Mecklenburg-West Pomerania. Osaka: This work was supported by the Japan Agency for Medical Research and Development (Grant Nos. JP21wm0425012, JP18dm0307002, JP22wm0525019, and JP22dk0207060) and Japan Society for the Promotion of Science KAKENHI (Grant Nos. JP20H03611, JP22H04926, and 20K15778). PAFIP (Programa de Atención a las Fases Iniciales de Psicosis): This work was supported by the Instituto de Salud Carlos III (Grant Nos. 00/3095, 01/3129, PI020499, PI14/00639, PI17/01056, and PI14/00918), SENY Fundació (Research Grant No. CI2005 0308007), and Fundación Marqués de Valdecilla Instituto de Investigación Sanitaria Valdecilla (Grant Nos. A/02/07, NCT0235832, and NCT02534363). The genotyping and analyses were partly funded by the Genetic Association Information Network of the Foundation for the National Institutes of Health. Computing was supported by NWO (Grant No. 2018/EW/00408559), BiG Grid, Dutch e-Science Grid, and SURFsara. MCIC (Mind Clinical Imaging Consortium): This work was supported by the NIH (NIH/National Center for Research Resources Grant No. P41RR14075 [to VC] and Grant No. R01EB005846 [to VC]), Department of Energy (Grant No. DE-FG02-99ER62764), Mind Research Network, Morphometry Biomedical Informatics Research Network (Grant Nos. 1U24 and RR021382A), Function Biomedical Informatics Research Network (Grant No. U24RR021992-01 [to VC], NIH/National Center for Research Resources Grant No. MO1 RR025758-01 [to VC], and NIMH Grant No. 1RC1MH089257 [to VC]), Deutsche Forschungsgemeinschaft (research fellowship [to SE]), and Brain and Behavior Research Foundation (NARSAD Young Investigator Award [to SE]). Dublin: This work was supported by the European Research Council (Grant No. ERC-2015-STG-677467 [to GD]) and Science Foundation Ireland (Grant No. SFI-16/ERCS/3787 [to GD]). BETULA: This work was supported by the Knut and Alice Wallenberg Foundation (scholar grant [to LN]). OSR (Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffele)-Milan: This work was supported by the European Union H2020 (EU.3.1.1 Grant No. 754740 MOODSTRATIFICATION.EU), Italian Ministry of Health (Grant No. RF-2018-12367249) and Italian Ministry of University and Scientific Research (Grant No. A_201779W93T). Australian Schizophrenia Research Bank: This work was supported by the Australian National Health and Medical Research Council (NHMRC) (Enabling Grant No. 386500, L3 Investigator Grant No. 1196508 [to CP]), and Program Grant No. APP1150083 [to CP]), Pratt Foundation, Ramsay Health Care, Viertel Charitable Foundation, and Schizophrenia Research Institute. Chief Investigators for the Australian Schizophrenia Research Bank were Vaughan Carr, US, RJS, Assen Jablensky, BJM, Patricia Michie, Stanley Catts, FAH, and CP. Brain Imaging Genetics (BIG): This work makes use of the BIG database, first established in Nijmegen, the Netherlands, in 2007. This resource is now part of Cognomics ( www.cognomics.nl ), a joint initiative by researchers from the Donders Centre for Cognitive Neuroimaging, Human Genetics and Cognitive Neuroscience departments of Radboud University Medical Centre, and Max Planck Institute for Psycholinguistics in Nijmegen. The Cognomics Initiative is supported by the participating departments and centers and Biobanking and Biomolecular Resources Research Infrastructure (Netherlands), Hersenstichting Nederland, and NWO. The research leading to these results also receives funding from the NWO (Gravitation Grant No. 024.001.006 Language in Interaction), European Community’s Seventh Framework Programme (FP7/2007-2013) (Grant Nos. 602450 IMAGEMEND, 278948 TACTICS, and 602805 Aggressotype), European Community’s Horizon 2020 programme (Grant Nos. 643051 MiND, and ERC-2010-AdG 268800-NEUROSCHEMA). In addition, the work was supported by the ENIGMA Consortium (Grant No. U54 EB020403) from the BD2K Initiative of a cross-NIH partnership. OAA has received speaker’s honorarium from Lundbeck, Janssen, and Sunovion and is a consultant to Coretechs.ai. TRM reports personal fees from Pfizer, Lundbeck, Astellas, Janssen, and Angelini outside the submitted work. He is an employee and shareholder of Pasithea Therapeutics. CRKC has received partial research support from Biogen for work unrelated to the topic of this article (principal investigator, PMT). PMT has received partial research support from Biogen for work unrelated to the topic of this article. MBMvdB and MJO report grants from Takeda Pharmaceuticals outside the submitted work. MJO reports a grant from Akrivia Health outside the submitted work. HJG has received travel grants and speaker’s honoraria from Fresenius Medical Care, Neuraxpharm, Servier, and Janssen as well as research funding from Fresenius Medical Care. GS has received honoraria for participating at advisory board meetings from Roche and Biogen regarding new Alzheimer’s disease drugs. KKS has received consultant and speaker’s honoraria from Roche and OrionPharma, reimbursement of travel and accommodation costs at a meeting from Kolpharma, and sponsorships for arranging conferences from Desitin and Eisai AB. IG has received speaker’s honorarium from Lundbeck. MMN has received fees for membership in an advisory board from HMG Systems Engineering GmbH, for membership in the Medical-Scientific Editorial Office of the Deutsches Ärzteblatt, and for serving as a consultant for Everis Belgium in a project of the European Commission (REFORM/SC2020/029). MMN also receives salary payments from Life & Brain GmbH and holds shares in Life & Brain GmbH. All these concerned activities outside the submitted work. CP received honoraria for talks from Lundbeck, Australia Pty Ltd. outside the submitted work. DJS has received consultancy honoraria from Discovery Vitality, Johnson & Johnson, Kanna, L’Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda and Vistagen. JH has received speaker’s honorarium from Medice and Takeda outside the submitted work. KP reports work with Novo Nordisk and Roche clinical trials outside the submitted work. All other authors report no biomedical financial interests or potential conflicts of interest. EPIGEN-London/University College London: The work was partly undertaken at University College London Hospitals NHS Foundation Trust/University College London, which received a proportion of funding from the UK Department of Health National Institute for Health Research Biomedical Research Centres funding scheme.

Funders	Funder number
Amsterdam Public Health Research Institute
BRIDGET
Biobanking and Biomolecular Resources Research Infrastructure The Netherlands	184.033.111, 184.021.007, NWO-56-464-14192
Carsten Konrad	JA 1890/7-2, KO 4291/3-1, HA 7070/2-2, JA 1890/7-1
Centre of Excellence
ENGAGE	602768
ENIGMA Consortium
EraNet Neuron	WM2NA, ANR-18-NEUR00002-01, AF12-NEUR0008-01, ANR-12-SAMA-0004
European Community’s Horizon 2020 Programme	ERC-2010-AdG 268800-NEUROSCHEMA, 643051 MiND
European Union H2020	754740 MOODSTRATIFICATION.EU
Federal State of Mecklenburg-West Pomerania	03ZIK012
Function Biomedical Informatics Research Network	U24RR021992-01, MO1 RR025758-01
Fundación Marqués de Valdecilla Instituto de Investigación Sanitaria Valdecilla	A/02/07, NCT0235832, NCT02534363
IMAGINE-ID
Institute of Neuroscience and Medicine
Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffele
Joint Lab Supercomputing and Modeling
Mind Research Network
Morphometry Biomedical Informatics Research Network	RR021382A, 1U24
NBIC/BioAssist/RK	2008.024
National Institute for Health Research Biomedical Research Centre at South London and Maudsley NHS Foundation Trust
Norwegian Centre for Mental Disorders	226971, 324252
Research Centre Julich
Koninklijke Nederlandse Akademie van Wetenschappen	PAH/6635
SENY Fundació	CI2005 0308007
UK Department of Health National Institute for Health Research Biomedical Research Centres
University College London Hospitals NHS Foundation Trust/University College London
National Institutes of Health	1R56AG058854-01, U54 EB020403
National Institutes of Health
U.S. Department of Energy	DE-FG02-99ER62764
U.S. Department of Energy
National Institute of Mental Health	R21MH116473, U01MH119736, 1R01MH129858-01A1, R01 MH090553, U01MH119738, 5UO1MH101724, R01MH085953, 1RC1MH089257, U24 MH068457-06
National Institute of Mental Health
National Institute on Drug Abuse
National Center for Research Resources	P41RR14075, R01EB005846
National Center for Research Resources
Brain and Behavior Research Foundation
Biogen
Fondation de l'Avenir pour la Recherche Médicale Appliquée	AP-RM-17-013
Fondation de l'Avenir pour la Recherche Médicale Appliquée
Stiftelsen Kristian Gerhard Jebsen	SKGJ-MED-021
Stiftelsen Kristian Gerhard Jebsen
Sylvia and Charles Viertel Charitable Foundation
King's College London	PR-ST-0416-10004
King's College London
Japan Agency for Medical Research and Development	JP21wm0425012, JP18dm0307002, JP22dk0207060, JP22wm0525019
Japan Agency for Medical Research and Development
Eunice Kennedy Shriver National Institute of Child Health and Human Development	RC2DA029475, R01 HD050735, R01 HD061414
Eunice Kennedy Shriver National Institute of Child Health and Human Development
National Alliance for Research on Schizophrenia and Depression
Wellcome Trust	102003/Z/13/Z
Wellcome Trust
Horizon 2020 Framework Programme	945539, 847776
Horizon 2020 Framework Programme
Seventh Framework Programme	602805, 602450, HEALTH-F4-2007-2013, 278948, MR/N000390/1, 01413, 603016
Seventh Framework Programme
Sixth Framework Programme	LSHM-CT-2007-037286
Sixth Framework Programme
Waterloo Foundation	WF 918-1234
Waterloo Foundation
Pratt Foundation
EU Joint Programme – Neurodegenerative Disease Research	785907, MR/N027558/1
EU Joint Programme – Neurodegenerative Disease Research
Fresenius Medical Care North America
Medical Research Council	MRF-058-0004-RG-DESRI, MRF-058-0009-RG-DESR-C0759, MR/R00465X/1, MR/T033045/1, MR/N022572/1, MR/P005748/1, 100202/Z/12/Z, MR/S020306/1
Medical Research Council
European Commission
European Research Council	695313, 230374, 771057, ERC-2015-STG-677467
European Research Council
European Science Foundation	EU/QLRT-2001-01254
European Science Foundation
Australian Research Council	1024224, 568969, 1093083, 1085606, 1045325, 1025243, 401162
Australian Research Council
National Health and Medical Research Council	386500, 486682, 389875, APP1150083, 1196508, 1009064
National Health and Medical Research Council
Baily Thomas Charitable Fund	2315/1
Baily Thomas Charitable Fund
Science Foundation Ireland	SFI-16/ERCS/3787
Science Foundation Ireland
Deutsche Forschungsgemeinschaft	KI 588/20-1, NE 1383/14-1, NE 2254/4-1, NE 2254/3-1, SM 80/7-2, FOR2107, NE 2254/1-2, KI 588/14-2, SFB 940/2, KI 588/14-1, KI 588/22-1, DA 1151/5-2, DA 1151/6-1, KR 3822/7-2, DA 1151/5-1, KR 3822/5-1
Deutsche Forschungsgemeinschaft
Agence Nationale de la Recherche	AAPG2019
Agence Nationale de la Recherche
Institut national de la santé et de la recherche médicale
Japan Society for the Promotion of Science	JP20H03611, 20K15778, JP22H04926
Japan Society for the Promotion of Science
ZonMw	016-115-035, 481-08-011, 904-61-090, 400-05-717, 451-04-034, 024.001.003, 056-32-010, 904-61-193, 480-04-004,463-06-001, 985-10-002, NWO-Groot 480-15-001/674, 912-10-020
ZonMw
Bundesministerium für Bildung und Forschung	01GS08152, 01ZZ0403, 01EV0711, AERIAL 01EE1406A, 01EE1406B, 01ZZ0103, 01ZZ9603
Bundesministerium für Bildung und Forschung
Assistance Publique - Hôpitaux de Paris
Fondation pour la Recherche Médicale	DPA20140629802
Fondation pour la Recherche Médicale
Ministero della Salute	RF-2018-12367249
Ministero della Salute
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	2018/EW/00408559, 024.001.006
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Ministero dell’Istruzione, dell’Università e della Ricerca
Knut och Alice Wallenbergs Stiftelse
Fondation de France	00081242
Fondation de France
Instituto de Salud Carlos III	01/3129, PI17/01056, 00/3095, PI14/00639, PI020499, PI14/00918
Instituto de Salud Carlos III
Norges forskningsråd	223273, 23273
Norges forskningsråd
Helse Sør-Øst RHF	2020060
Helse Sør-Øst RHF
Fédération pour la Recherche sur le Cerveau
Université Paris-Sud
Horizon 2020
Hersenstichting
Medical Research Foundation
Mission Interministérielle de Lutte Contre les Drogues et les Conduites Addictives
Siemens Healthineers
Norges Idrettshøgskole	1RC2 MH089951, 1RC2 MH089995, R01 DK092127-04, DA018673, MH081802, R01D0042157-01A1, R01MH58799-03
Norges Idrettshøgskole
Centre for Medical Systems Biology
Ramsay Health Care
Amsterdam Neuroscience
Avera Institute for Human Genetics
Ministry of Cultural Affairs

Keywords

15q11.2 BP1-BP2
1q21.1 distal
Brain structure
Copy number variants
Intraindividual variability
Magnetic resonance imaging

Cohort Studies

Netherlands Twin Register (NTR)

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10.1016/j.biopsych.2023.08.018

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Cite this

Boen, R., Kaufmann, T., van der Meer, D., Boomsma, D. I., de Geus, E. J. C., van ’t Ent, D., Alnæs, D., Andreassen, O. A., Sønderby, I. E., & ENIGMA-CNV working group (2024). Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers. Biological psychiatry, 95(2), 147-160. https://doi.org/10.1016/j.biopsych.2023.08.018

@article{8a2b70054fe545f287462c4bcc63acbe,

title = "Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers",

abstract = "Background: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure. Methods: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual's regional difference and global difference, were used to test for regional differences that diverge from the global difference. Results: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness. Conclusions: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.",

keywords = "15q11.2 BP1-BP2, 1q21.1 distal, Brain structure, Copy number variants, Intraindividual variability, Magnetic resonance imaging",

author = "Rune Boen and Tobias Kaufmann and {van der Meer}, Dennis and Oleksandr Frei and Ingrid Agartz and David Ames and Micael Andersson and Armstrong, {Nicola J.} and Eric Artiges and Atkins, {Joshua R.} and Jochen Bauer and Francesco Benedetti and Boomsma, {Dorret I.} and Henry Brodaty and Katharina Brosch and Buckner, {Randy L.} and Cairns, {Murray J.} and Vince Calhoun and Svenja Caspers and Sven Cichon and Corvin, {Aiden P.} and Benedicto Crespo-Facorro and Udo Dannlowski and David, {Friederike S.} and {de Geus}, {Eco J.C.} and {de Zubicaray}, {Greig I.} and Sylvane Desrivi{\`e}res and Doherty, {Joanne L.} and Gary Donohoe and Stefan Ehrlich and Else Eising and Thomas Espeseth and Fisher, {Simon E.} and Forstner, {Andreas J.} and Lidia Fortaner-Uy{\`a} and Vincent Frouin and Masaki Fukunaga and Tian Ge and Glahn, {David C.} and Janik Goltermann and Grabe, {Hans J.} and Green, {Melissa J.} and Groenewold, {Nynke A.} and Dominik Grotegerd and Gr{\o}ntvedt, {G{\o}ril Rolfseng} and Tim Hahn and Ryota Hashimoto and Hehir-Kwa, {Jayne Y.} and Henskens, {Frans A.} and Holmes, {Avram J.} and H{\aa}berg, {Asta K.} and Jan Haavik and Sebastien Jacquemont and Andreas Jansen and Christiane Jockwitz and J{\"o}nsson, {Erik G.} and Masataka Kikuchi and Tilo Kircher and Kuldeep Kumar and {Le Hellard}, Stephanie and Costin Leu and Linden, {David E.} and Jingyu Liu and Robert Loughnan and Mather, {Karen A.} and McMahon, {Katie L.} and McRae, {Allan F.} and Medland, {Sarah E.} and Susanne Meinert and Moreau, {Clara A.} and Morris, {Derek W.} and Mowry, {Bryan J.} and M{\"u}hleisen, {Thomas W.} and Igor Nenadi{\'c} and N{\"o}then, {Markus M.} and Lars Nyberg and Ophoff, {Roel A.} and Owen, {Michael J.} and Christos Pantelis and Marco Paolini and Tomas Paus and Zdenka Pausova and Karin Persson and Yann Quid{\'e} and Marques, {Tiago Reis} and Sachdev, {Perminder S.} and Sando, {Sigrid B.} and Ulrich Schall and Scott, {Rodney J.} and Geir Selb{\ae}k and Elena Shumskaya and Silva, {Ana I.} and Sisodiya, {Sanjay M.} and Frederike Stein and Stein, {Dan J.} and Benjamin Straube and Fabian Streit and Strike, {Lachlan T.} and Alexander Teumer and Lea Teutenberg and Anbupalam Thalamuthu and Tooney, {Paul A.} and Diana Tordesillas-Gutierrez and Trollor, {Julian N.} and {van {\textquoteright}t Ent}, Dennis and {van den Bree}, {Marianne B.M.} and {van Haren}, {Neeltje E.M.} and Javier V{\'a}zquez-Bourgon and Henry V{\"o}lzke and Wei Wen and Katharina Wittfeld and Ching, {Christopher R.K.} and Westlye, {Lars T.} and Thompson, {Paul M.} and Bearden, {Carrie E.} and Selmer, {Kaja K.} and Dag Aln{\ae}s and Andreassen, {Ole A.} and S{\o}nderby, {Ida E.} and {ENIGMA-CNV working group}",

note = "Funding Information: The OATS Study was facilitated through access to Twins Research Australia, a national resource supported by a Centre of Research Excellence Grant (Grant No. 1079102) from the NHMRC. We thank the participants for their time and generosity in contributing to this research. We acknowledge the contribution of the OATS research team ( https://cheba.unsw.edu.au/project/older-australian-twins-study ) to this study. Funding Information: 1000BRAINS. This work was supported by the Institute of Neuroscience and Medicine (INM-1) , Research Centre Julich , European Union{\textquoteright}s Horizon 2020 Research and Innovation Programme (Grant No. 945539 [HBP SGA3; SC]), and Joint Lab Supercomputing and Modeling for the Human Brain . Funding Information: UCLA-Utrecht: This work was supported by the NIMH (Grant No. R01 MH090553 [to RAO]). The NIMH had no further role in study design, in the collection, analysis, and interpretation of the data, in the writing of the report, and in the decision to submit the paper for publication. Funding Information: OATS ( Older Australian Twins Study ): This work was supported by the NHMRC and Australian Research Council Strategic Award Grant of the Ageing Well, Ageing Productively Program (Grant No. 401162), NHMRC project (seed) grants (Grant Nos. 1024224 and 1025243), NHMRC project grants (Grant Nos. 1045325 and 1085606), and NHMRC program grants (Grant Nos. 568969 and 1093083). Funding Information: ECHO-DEFINE: This work was supported by the Wellcome Trust (Institutional Strategic Support Fund [to MBMvdB] and Clinical Research Training Fellowship Grant No. 102003/Z/13/Z [to JLD]), Waterloo Foundation (Grant No. WF 918-1234 [to MBMvdB]), Baily Thomas Charitable Fund (Grant No. 2315/1 [to MBMvdB]), NIMH (Grant Nos. 5UO1MH101724 and U01MH119738 [to MBMvdB]), IMAGINE-ID and IMAGINE-2 studies (funded by Medical Research Council Grant Nos. MR/N022572/1 and MR/T033045/1 [to MBMvdB]), and Medical Research Council (Centre Grant No. MR/P005748/1 [to MJO]). The DEFINE study was supported by a Wellcome Trust Strategic Award (Grant No. 100202/Z/12/Z [to MJO]). Funding Information: ENIGMA-CNV W orking G roup. This work was supported by the Research Council of Norway (Grant No. 223273 [to OAA]), South-Eastern Norway Regional Health Authority (Grant No. 2020060 [to IES, RB]), European Union{\textquoteright}s Horizon 2020 Research and Innovation Programme (CoMorMent project; Grant No. 847776 [to IES]), Kristian Gerhard Jebsen Stiftelsen (Grant No. SKGJ-MED-021 [to IES]), and National Institute of Mental Health (NIMH) (Grant Nos. U01MH119736, R21MH116473, R01MH085953 [to CEB]), and 1R01MH129858-01A1 [to SJ]. Funding Information: IMAGEN: This work was supported by the European Union–funded FP6 Integrated Project IMAGEN (Reinforcement-Related Behavior in Normal Brain Function and Psychopathology) (Grant No. LSHM-CT-2007-037286), Horizon 2020–funded ERC Advanced Grant STRATIFY (Brain Network Based Stratification of Reinforcement-Related Disorders) (Grant No. 695313), Medical Research Foundation and Medical Research Council (Grants Nos. MR/R00465X/1 and MRF-058-0004-RG-DESRI [Neurobiological Underpinning of Eating Disorders: Integrative Biopsychosocial Longitudinal Analyses in Adolescents] and MR/S020306/1 and MRF-058-0009-RG-DESR-C0759 [Establishing Causal Relationships Between Biopsychosocial Predictors and Correlates of Eating Disorders and Their Mediation by Neural Pathways]), National Institutes of Health (NIH) (Consortium Grant No. U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence, and Grant No. 1R56AG058854-01), National Institute for Health Research Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London, ERANID (Understanding the Interplay Between Cultural, Biological and Subjective Factors in Drug Use Pathways) (Grant No. PR-ST-0416-10004), BRIDGET (JPND: BRain Imaging, cognition Dementia and next generation GEnomics) (Grant No. MR/N027558/1), Human Brain Project (HBP SGA 2) (Grant No. 785907), FP7 project MATRICS (Grant No. 603016), Medical Research Council Grant Consortium on Vulnerability to Externalizing Disorders and Addictions (Grant No. MR/N000390/1), Bundesministerium f{\"u}r Bildung und Forschung (Grant Nos. 01GS08152, 01EV0711, Forschungsnetz AERIAL 01EE1406A, and 01EE1406B), Deutsche Forschungsgemeinschaft (Grant Nos. SM 80/7-2, SFB 940/2, and NE 1383/14-1), Agence Nationale de la Recherche (ANR) (Grant Nos. ANR-12-SAMA-0004 and AAPG2019 [GeBra]), Eranet Neuron (Grant Nos. AF12-NEUR0008-01 [WM2NA], ANR-18-NEUR00002-01 [ADORe], and ANR-12-SAMA-0004), Fondation de France (Grant No. 00081242), Fondation pour la Recherche M{\'e}dicale (Grant No. DPA20140629802), Mission Interminist{\'e}rielle de Lutte contre les Drogues et les Conduites Addictives, Assistance Publique H{\^o}pitaux de Paris and Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale (Interface Grant), Paris Sud University IDEX 2012, Fondation de l{\textquoteright}Avenir (Grant No. AP-RM-17-013), and F{\'e}d{\'e}ration pour la Recherche sur le Cerveau. Funding Information: FOR2107 Marburg and M{\"u}nster: This work is part of the German multicenter consortium “Neurobiology of Affective Disorders: A Translational Perspective on Brain Structure and Function,” supported by the German Research Foundation (Deutsche Forschungsgemeinschaft; Forschungsgruppe/Research Unit FOR2107). Principal investigators with respective areas of responsibility in the FOR2107 consortium: Work Package WP1, FOR2107/MACS cohort and brainimaging: TK (speaker FOR2107; DFG Grant Nos. KI 588/14-1, KI 588/14-2, KI 588/20-1, and KI 588/22-1), UD (co-speaker FOR2107; Grant Nos. DA 1151/5-1, DA 1151/5-2, and DA 1151/6-1), Axel Krug (Grant Nos. KR 3822/5-1 and KR 3822/7-2), IN (Grant Nos. NE 2254/1-2, NE 2254/3-1, and NE 2254/4-1), Carsten Konrad (Grant No. KO 4291/3-1). WP5, genetics: Marcella Rietschel (Grant Nos. RI 908/11-1 and RI 908/11-2), MMN (Grant Nos. NO 246/10-1 and NO 246/10-2), Stephanie Witt (Grant Nos. WI 3439/3-1 and WI 3439/3-2). WP6, multi-method data analytics: AJ (Grant Nos. JA 1890/7-1 and JA 1890/7-2), TH (Grant No. HA 7070/2-2). Funding Information: TOP: This work was supported by Research Council of Norway (Grant Nos. 23273 (Centre of Excellence, Norwegian Centre for Mental Disorders, NORMENT), Grant Nos. 324252 and 226971). Funding Information: NTR (Netherlands Twin Register): This work was supported by the Netherlands Organization for Scientific Research (NWO) and Netherlands Organisation for Health Research and Development (Grant Nos. 904-61-090, 985-10-002, 912-10-020, 904-61-193, 480-04-004,463-06-001, 451-04-034, 400-05-717, Addiction-31160008, 016-115-035, 481-08-011, 056-32-010, Middelgroot-911-09-032, OCW_NWO Gravity programme—024.001.003, and NWO-Groot 480-15-001/674), Center for Medical Systems Biology (NWO Genomics), NBIC/BioAssist/RK (Grant No. 2008.024), Biobanking and Biomolecular Resources Research Infrastructure The Netherlands (Grant Nos. 184.021.007 and 184.033.111), Spinozapremie (Grant No. NWO-56-464-14192), Royal Netherlands Academy of Arts and Sciences Academy Professor Award (Grant No. PAH/6635) and University Research Fellow grant (to DIB), Amsterdam Public Health research institute (former EMGO+ Institute for Health and Care Research), Amsterdam Neuroscience (former Neuoscience Campus Amsterdam), European Science Foundation (Grant No. EU/QLRT-2001-01254), European Community{\textquoteright}s Seventh Framework Programme (FP7- HEALTH-F4-2007-2013, Grant Nos. 01413: ENGAGE and 602768: ACTION), European Research Council (Grant Nos. ERC Starting 284167, ERC Consolidator 771057, and ERC Advanced 230374), Rutgers University Cell and DNA Repository (NIMH Grant No. U24 MH068457-06), NIH (Grant Nos. R01D0042157-01A1, R01MH58799-03, MH081802, DA018673, and R01 DK092127-04 and Grand Opportunity Grant Nos. 1RC2 MH089951 and 1RC2 MH089995), and Avera Institute for Human Genetics. Funding Information: PING (Pediatric Imaging, Neurocognition, and Genetics): This work was supported by the National Institute on Drug Abuse and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Grant Nos. RC2DA029475 and R01 HD061414). Funding Information: QTIM: This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Grant No. R01 HD050735) and the NHMRC (Grant Nos. 486682 and 1009064). Genotyping was supported by the NHMRC (Grant No. 389875). Funding Information: SHIP (Study of Health in Pomerania): This work is part of the Community Medicine Research net of the University of Greifswald, Germany, which is supported by the Federal Ministry of Education and Research (Grant Nos. 01ZZ9603, 01ZZ0103, and 01ZZ0403), Ministry of Cultural Affairs, and Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data in SHIP have been supported by the Federal Ministry of Education and Research (Grant No. 03ZIK012) and a joint grant from Siemens Healthineers and the Federal State of Mecklenburg-West Pomerania. MRI scans in SHIP and SHIP-TREND have been supported by a joint grant from Siemens Healthineers and the Federal State of Mecklenburg-West Pomerania. Funding Information: Osaka: This work was supported by the Japan Agency for Medical Research and Development (Grant Nos. JP21wm0425012, JP18dm0307002, JP22wm0525019, and JP22dk0207060) and Japan Society for the Promotion of Science KAKENHI (Grant Nos. JP20H03611, JP22H04926, and 20K15778). Funding Information: PAFIP (Programa de Atenci{\'o}n a las Fases Iniciales de Psicosis): This work was supported by the Instituto de Salud Carlos III (Grant Nos. 00/3095, 01/3129, PI020499, PI14/00639, PI17/01056, and PI14/00918), SENY Fundaci{\'o} (Research Grant No. CI2005 0308007), and Fundaci{\'o}n Marqu{\'e}s de Valdecilla Instituto de Investigaci{\'o}n Sanitaria Valdecilla (Grant Nos. A/02/07, NCT0235832, and NCT02534363). Funding Information: The genotyping and analyses were partly funded by the Genetic Association Information Network of the Foundation for the National Institutes of Health. Computing was supported by NWO (Grant No. 2018/EW/00408559), BiG Grid, Dutch e-Science Grid, and SURFsara. Funding Information: MCIC (Mind Clinical Imaging Consortium): This work was supported by the NIH (NIH/National Center for Research Resources Grant No. P41RR14075 [to VC] and Grant No. R01EB005846 [to VC]), Department of Energy (Grant No. DE-FG02-99ER62764), Mind Research Network, Morphometry Biomedical Informatics Research Network (Grant Nos. 1U24 and RR021382A), Function Biomedical Informatics Research Network (Grant No. U24RR021992-01 [to VC], NIH/National Center for Research Resources Grant No. MO1 RR025758-01 [to VC], and NIMH Grant No. 1RC1MH089257 [to VC]), Deutsche Forschungsgemeinschaft (research fellowship [to SE]), and Brain and Behavior Research Foundation (NARSAD Young Investigator Award [to SE]). Funding Information: Dublin: This work was supported by the European Research Council (Grant No. ERC-2015-STG-677467 [to GD]) and Science Foundation Ireland (Grant No. SFI-16/ERCS/3787 [to GD]). Funding Information: BETULA: This work was supported by the Knut and Alice Wallenberg Foundation (scholar grant [to LN]). Funding Information: OSR (Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffele)-Milan: This work was supported by the European Union H2020 (EU.3.1.1 Grant No. 754740 MOODSTRATIFICATION.EU), Italian Ministry of Health (Grant No. RF-2018-12367249) and Italian Ministry of University and Scientific Research (Grant No. A_201779W93T). Funding Information: Australian Schizophrenia Research Bank: This work was supported by the Australian National Health and Medical Research Council (NHMRC) (Enabling Grant No. 386500, L3 Investigator Grant No. 1196508 [to CP]), and Program Grant No. APP1150083 [to CP]), Pratt Foundation, Ramsay Health Care, Viertel Charitable Foundation, and Schizophrenia Research Institute. Chief Investigators for the Australian Schizophrenia Research Bank were Vaughan Carr, US, RJS, Assen Jablensky, BJM, Patricia Michie, Stanley Catts, FAH, and CP. Funding Information: Brain Imaging Genetics (BIG): This work makes use of the BIG database, first established in Nijmegen, the Netherlands, in 2007. This resource is now part of Cognomics ( www.cognomics.nl ), a joint initiative by researchers from the Donders Centre for Cognitive Neuroimaging, Human Genetics and Cognitive Neuroscience departments of Radboud University Medical Centre, and Max Planck Institute for Psycholinguistics in Nijmegen. The Cognomics Initiative is supported by the participating departments and centers and Biobanking and Biomolecular Resources Research Infrastructure (Netherlands), Hersenstichting Nederland, and NWO. The research leading to these results also receives funding from the NWO (Gravitation Grant No. 024.001.006 Language in Interaction), European Community{\textquoteright}s Seventh Framework Programme (FP7/2007-2013) (Grant Nos. 602450 IMAGEMEND, 278948 TACTICS, and 602805 Aggressotype), European Community{\textquoteright}s Horizon 2020 programme (Grant Nos. 643051 MiND, and ERC-2010-AdG 268800-NEUROSCHEMA). In addition, the work was supported by the ENIGMA Consortium (Grant No. U54 EB020403) from the BD2K Initiative of a cross-NIH partnership. Funding Information: OAA has received speaker{\textquoteright}s honorarium from Lundbeck, Janssen, and Sunovion and is a consultant to Coretechs.ai. TRM reports personal fees from Pfizer, Lundbeck, Astellas, Janssen, and Angelini outside the submitted work. He is an employee and shareholder of Pasithea Therapeutics. CRKC has received partial research support from Biogen for work unrelated to the topic of this article (principal investigator, PMT). PMT has received partial research support from Biogen for work unrelated to the topic of this article. MBMvdB and MJO report grants from Takeda Pharmaceuticals outside the submitted work. MJO reports a grant from Akrivia Health outside the submitted work. HJG has received travel grants and speaker{\textquoteright}s honoraria from Fresenius Medical Care, Neuraxpharm, Servier, and Janssen as well as research funding from Fresenius Medical Care. GS has received honoraria for participating at advisory board meetings from Roche and Biogen regarding new Alzheimer{\textquoteright}s disease drugs. KKS has received consultant and speaker{\textquoteright}s honoraria from Roche and OrionPharma, reimbursement of travel and accommodation costs at a meeting from Kolpharma, and sponsorships for arranging conferences from Desitin and Eisai AB. IG has received speaker{\textquoteright}s honorarium from Lundbeck. MMN has received fees for membership in an advisory board from HMG Systems Engineering GmbH, for membership in the Medical-Scientific Editorial Office of the Deutsches {\"A}rzteblatt, and for serving as a consultant for Everis Belgium in a project of the European Commission (REFORM/SC2020/029). MMN also receives salary payments from Life & Brain GmbH and holds shares in Life & Brain GmbH. All these concerned activities outside the submitted work. CP received honoraria for talks from Lundbeck, Australia Pty Ltd. outside the submitted work. DJS has received consultancy honoraria from Discovery Vitality, Johnson & Johnson, Kanna, L{\textquoteright}Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda and Vistagen. JH has received speaker{\textquoteright}s honorarium from Medice and Takeda outside the submitted work. KP reports work with Novo Nordisk and Roche clinical trials outside the submitted work. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: EPIGEN-London/University College London: The work was partly undertaken at University College London Hospitals NHS Foundation Trust/University College London, which received a proportion of funding from the UK Department of Health National Institute for Health Research Biomedical Research Centres funding scheme. Publisher Copyright: {\textcopyright} 2023",

year = "2024",

month = jan,

day = "15",

doi = "10.1016/j.biopsych.2023.08.018",

language = "English",

volume = "95",

pages = "147--160",

journal = "Biological psychiatry",

issn = "0006-3223",

publisher = "Elsevier USA",

number = "2",

}

Boen, R, Kaufmann, T, van der Meer, D, Boomsma, DI , de Geus, EJC , van ’t Ent, D, Alnæs, D, Andreassen, OA, Sønderby, IE & ENIGMA-CNV working group 2024, 'Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers', Biological psychiatry, vol. 95, no. 2, pp. 147-160. https://doi.org/10.1016/j.biopsych.2023.08.018

TY - JOUR

T1 - Beyond the Global Brain Differences

T2 - Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers

AU - Boen, Rune

AU - Kaufmann, Tobias

AU - van der Meer, Dennis

AU - Frei, Oleksandr

AU - Agartz, Ingrid

AU - Ames, David

AU - Andersson, Micael

AU - Armstrong, Nicola J.

AU - Artiges, Eric

AU - Atkins, Joshua R.

AU - Bauer, Jochen

AU - Benedetti, Francesco

AU - Boomsma, Dorret I.

AU - Brodaty, Henry

AU - Brosch, Katharina

AU - Buckner, Randy L.

AU - Cairns, Murray J.

AU - Calhoun, Vince

AU - Caspers, Svenja

AU - Cichon, Sven

AU - Corvin, Aiden P.

AU - Crespo-Facorro, Benedicto

AU - Dannlowski, Udo

AU - David, Friederike S.

AU - de Geus, Eco J.C.

AU - de Zubicaray, Greig I.

AU - Desrivières, Sylvane

AU - Doherty, Joanne L.

AU - Donohoe, Gary

AU - Ehrlich, Stefan

AU - Eising, Else

AU - Espeseth, Thomas

AU - Fisher, Simon E.

AU - Forstner, Andreas J.

AU - Fortaner-Uyà, Lidia

AU - Frouin, Vincent

AU - Fukunaga, Masaki

AU - Ge, Tian

AU - Glahn, David C.

AU - Goltermann, Janik

AU - Grabe, Hans J.

AU - Green, Melissa J.

AU - Groenewold, Nynke A.

AU - Grotegerd, Dominik

AU - Grøntvedt, Gøril Rolfseng

AU - Hahn, Tim

AU - Hashimoto, Ryota

AU - Hehir-Kwa, Jayne Y.

AU - Henskens, Frans A.

AU - Holmes, Avram J.

AU - Håberg, Asta K.

AU - Haavik, Jan

AU - Jacquemont, Sebastien

AU - Jansen, Andreas

AU - Jockwitz, Christiane

AU - Jönsson, Erik G.

AU - Kikuchi, Masataka

AU - Kircher, Tilo

AU - Kumar, Kuldeep

AU - Le Hellard, Stephanie

AU - Leu, Costin

AU - Linden, David E.

AU - Liu, Jingyu

AU - Loughnan, Robert

AU - Mather, Karen A.

AU - McMahon, Katie L.

AU - McRae, Allan F.

AU - Medland, Sarah E.

AU - Meinert, Susanne

AU - Moreau, Clara A.

AU - Morris, Derek W.

AU - Mowry, Bryan J.

AU - Mühleisen, Thomas W.

AU - Nenadić, Igor

AU - Nöthen, Markus M.

AU - Nyberg, Lars

AU - Ophoff, Roel A.

AU - Owen, Michael J.

AU - Pantelis, Christos

AU - Paolini, Marco

AU - Paus, Tomas

AU - Pausova, Zdenka

AU - Persson, Karin

AU - Quidé, Yann

AU - Marques, Tiago Reis

AU - Sachdev, Perminder S.

AU - Sando, Sigrid B.

AU - Schall, Ulrich

AU - Scott, Rodney J.

AU - Selbæk, Geir

AU - Shumskaya, Elena

AU - Silva, Ana I.

AU - Sisodiya, Sanjay M.

AU - Stein, Frederike

AU - Stein, Dan J.

AU - Straube, Benjamin

AU - Streit, Fabian

AU - Strike, Lachlan T.

AU - Teumer, Alexander

AU - Teutenberg, Lea

AU - Thalamuthu, Anbupalam

AU - Tooney, Paul A.

AU - Tordesillas-Gutierrez, Diana

AU - Trollor, Julian N.

AU - van ’t Ent, Dennis

AU - van den Bree, Marianne B.M.

AU - van Haren, Neeltje E.M.

AU - Vázquez-Bourgon, Javier

AU - Völzke, Henry

AU - Wen, Wei

AU - Wittfeld, Katharina

AU - Ching, Christopher R.K.

AU - Westlye, Lars T.

AU - Thompson, Paul M.

AU - Bearden, Carrie E.

AU - Selmer, Kaja K.

AU - Alnæs, Dag

AU - Andreassen, Ole A.

AU - Sønderby, Ida E.

AU - ENIGMA-CNV working group

N1 - Funding Information: The OATS Study was facilitated through access to Twins Research Australia, a national resource supported by a Centre of Research Excellence Grant (Grant No. 1079102) from the NHMRC. We thank the participants for their time and generosity in contributing to this research. We acknowledge the contribution of the OATS research team ( https://cheba.unsw.edu.au/project/older-australian-twins-study ) to this study. Funding Information: 1000BRAINS. This work was supported by the Institute of Neuroscience and Medicine (INM-1) , Research Centre Julich , European Union’s Horizon 2020 Research and Innovation Programme (Grant No. 945539 [HBP SGA3; SC]), and Joint Lab Supercomputing and Modeling for the Human Brain . Funding Information: UCLA-Utrecht: This work was supported by the NIMH (Grant No. R01 MH090553 [to RAO]). The NIMH had no further role in study design, in the collection, analysis, and interpretation of the data, in the writing of the report, and in the decision to submit the paper for publication. Funding Information: OATS ( Older Australian Twins Study ): This work was supported by the NHMRC and Australian Research Council Strategic Award Grant of the Ageing Well, Ageing Productively Program (Grant No. 401162), NHMRC project (seed) grants (Grant Nos. 1024224 and 1025243), NHMRC project grants (Grant Nos. 1045325 and 1085606), and NHMRC program grants (Grant Nos. 568969 and 1093083). Funding Information: ECHO-DEFINE: This work was supported by the Wellcome Trust (Institutional Strategic Support Fund [to MBMvdB] and Clinical Research Training Fellowship Grant No. 102003/Z/13/Z [to JLD]), Waterloo Foundation (Grant No. WF 918-1234 [to MBMvdB]), Baily Thomas Charitable Fund (Grant No. 2315/1 [to MBMvdB]), NIMH (Grant Nos. 5UO1MH101724 and U01MH119738 [to MBMvdB]), IMAGINE-ID and IMAGINE-2 studies (funded by Medical Research Council Grant Nos. MR/N022572/1 and MR/T033045/1 [to MBMvdB]), and Medical Research Council (Centre Grant No. MR/P005748/1 [to MJO]). The DEFINE study was supported by a Wellcome Trust Strategic Award (Grant No. 100202/Z/12/Z [to MJO]). Funding Information: ENIGMA-CNV W orking G roup. This work was supported by the Research Council of Norway (Grant No. 223273 [to OAA]), South-Eastern Norway Regional Health Authority (Grant No. 2020060 [to IES, RB]), European Union’s Horizon 2020 Research and Innovation Programme (CoMorMent project; Grant No. 847776 [to IES]), Kristian Gerhard Jebsen Stiftelsen (Grant No. SKGJ-MED-021 [to IES]), and National Institute of Mental Health (NIMH) (Grant Nos. U01MH119736, R21MH116473, R01MH085953 [to CEB]), and 1R01MH129858-01A1 [to SJ]. Funding Information: IMAGEN: This work was supported by the European Union–funded FP6 Integrated Project IMAGEN (Reinforcement-Related Behavior in Normal Brain Function and Psychopathology) (Grant No. LSHM-CT-2007-037286), Horizon 2020–funded ERC Advanced Grant STRATIFY (Brain Network Based Stratification of Reinforcement-Related Disorders) (Grant No. 695313), Medical Research Foundation and Medical Research Council (Grants Nos. MR/R00465X/1 and MRF-058-0004-RG-DESRI [Neurobiological Underpinning of Eating Disorders: Integrative Biopsychosocial Longitudinal Analyses in Adolescents] and MR/S020306/1 and MRF-058-0009-RG-DESR-C0759 [Establishing Causal Relationships Between Biopsychosocial Predictors and Correlates of Eating Disorders and Their Mediation by Neural Pathways]), National Institutes of Health (NIH) (Consortium Grant No. U54 EB020403, supported by a cross-NIH alliance that funds Big Data to Knowledge Centres of Excellence, and Grant No. 1R56AG058854-01), National Institute for Health Research Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, ERANID (Understanding the Interplay Between Cultural, Biological and Subjective Factors in Drug Use Pathways) (Grant No. PR-ST-0416-10004), BRIDGET (JPND: BRain Imaging, cognition Dementia and next generation GEnomics) (Grant No. MR/N027558/1), Human Brain Project (HBP SGA 2) (Grant No. 785907), FP7 project MATRICS (Grant No. 603016), Medical Research Council Grant Consortium on Vulnerability to Externalizing Disorders and Addictions (Grant No. MR/N000390/1), Bundesministerium für Bildung und Forschung (Grant Nos. 01GS08152, 01EV0711, Forschungsnetz AERIAL 01EE1406A, and 01EE1406B), Deutsche Forschungsgemeinschaft (Grant Nos. SM 80/7-2, SFB 940/2, and NE 1383/14-1), Agence Nationale de la Recherche (ANR) (Grant Nos. ANR-12-SAMA-0004 and AAPG2019 [GeBra]), Eranet Neuron (Grant Nos. AF12-NEUR0008-01 [WM2NA], ANR-18-NEUR00002-01 [ADORe], and ANR-12-SAMA-0004), Fondation de France (Grant No. 00081242), Fondation pour la Recherche Médicale (Grant No. DPA20140629802), Mission Interministérielle de Lutte contre les Drogues et les Conduites Addictives, Assistance Publique Hôpitaux de Paris and Institut National de la Santé et de la Recherche Médicale (Interface Grant), Paris Sud University IDEX 2012, Fondation de l’Avenir (Grant No. AP-RM-17-013), and Fédération pour la Recherche sur le Cerveau. Funding Information: FOR2107 Marburg and Münster: This work is part of the German multicenter consortium “Neurobiology of Affective Disorders: A Translational Perspective on Brain Structure and Function,” supported by the German Research Foundation (Deutsche Forschungsgemeinschaft; Forschungsgruppe/Research Unit FOR2107). Principal investigators with respective areas of responsibility in the FOR2107 consortium: Work Package WP1, FOR2107/MACS cohort and brainimaging: TK (speaker FOR2107; DFG Grant Nos. KI 588/14-1, KI 588/14-2, KI 588/20-1, and KI 588/22-1), UD (co-speaker FOR2107; Grant Nos. DA 1151/5-1, DA 1151/5-2, and DA 1151/6-1), Axel Krug (Grant Nos. KR 3822/5-1 and KR 3822/7-2), IN (Grant Nos. NE 2254/1-2, NE 2254/3-1, and NE 2254/4-1), Carsten Konrad (Grant No. KO 4291/3-1). WP5, genetics: Marcella Rietschel (Grant Nos. RI 908/11-1 and RI 908/11-2), MMN (Grant Nos. NO 246/10-1 and NO 246/10-2), Stephanie Witt (Grant Nos. WI 3439/3-1 and WI 3439/3-2). WP6, multi-method data analytics: AJ (Grant Nos. JA 1890/7-1 and JA 1890/7-2), TH (Grant No. HA 7070/2-2). Funding Information: TOP: This work was supported by Research Council of Norway (Grant Nos. 23273 (Centre of Excellence, Norwegian Centre for Mental Disorders, NORMENT), Grant Nos. 324252 and 226971). Funding Information: NTR (Netherlands Twin Register): This work was supported by the Netherlands Organization for Scientific Research (NWO) and Netherlands Organisation for Health Research and Development (Grant Nos. 904-61-090, 985-10-002, 912-10-020, 904-61-193, 480-04-004,463-06-001, 451-04-034, 400-05-717, Addiction-31160008, 016-115-035, 481-08-011, 056-32-010, Middelgroot-911-09-032, OCW_NWO Gravity programme—024.001.003, and NWO-Groot 480-15-001/674), Center for Medical Systems Biology (NWO Genomics), NBIC/BioAssist/RK (Grant No. 2008.024), Biobanking and Biomolecular Resources Research Infrastructure The Netherlands (Grant Nos. 184.021.007 and 184.033.111), Spinozapremie (Grant No. NWO-56-464-14192), Royal Netherlands Academy of Arts and Sciences Academy Professor Award (Grant No. PAH/6635) and University Research Fellow grant (to DIB), Amsterdam Public Health research institute (former EMGO+ Institute for Health and Care Research), Amsterdam Neuroscience (former Neuoscience Campus Amsterdam), European Science Foundation (Grant No. EU/QLRT-2001-01254), European Community’s Seventh Framework Programme (FP7- HEALTH-F4-2007-2013, Grant Nos. 01413: ENGAGE and 602768: ACTION), European Research Council (Grant Nos. ERC Starting 284167, ERC Consolidator 771057, and ERC Advanced 230374), Rutgers University Cell and DNA Repository (NIMH Grant No. U24 MH068457-06), NIH (Grant Nos. R01D0042157-01A1, R01MH58799-03, MH081802, DA018673, and R01 DK092127-04 and Grand Opportunity Grant Nos. 1RC2 MH089951 and 1RC2 MH089995), and Avera Institute for Human Genetics. Funding Information: PING (Pediatric Imaging, Neurocognition, and Genetics): This work was supported by the National Institute on Drug Abuse and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Grant Nos. RC2DA029475 and R01 HD061414). Funding Information: QTIM: This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Grant No. R01 HD050735) and the NHMRC (Grant Nos. 486682 and 1009064). Genotyping was supported by the NHMRC (Grant No. 389875). Funding Information: SHIP (Study of Health in Pomerania): This work is part of the Community Medicine Research net of the University of Greifswald, Germany, which is supported by the Federal Ministry of Education and Research (Grant Nos. 01ZZ9603, 01ZZ0103, and 01ZZ0403), Ministry of Cultural Affairs, and Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data in SHIP have been supported by the Federal Ministry of Education and Research (Grant No. 03ZIK012) and a joint grant from Siemens Healthineers and the Federal State of Mecklenburg-West Pomerania. MRI scans in SHIP and SHIP-TREND have been supported by a joint grant from Siemens Healthineers and the Federal State of Mecklenburg-West Pomerania. Funding Information: Osaka: This work was supported by the Japan Agency for Medical Research and Development (Grant Nos. JP21wm0425012, JP18dm0307002, JP22wm0525019, and JP22dk0207060) and Japan Society for the Promotion of Science KAKENHI (Grant Nos. JP20H03611, JP22H04926, and 20K15778). Funding Information: PAFIP (Programa de Atención a las Fases Iniciales de Psicosis): This work was supported by the Instituto de Salud Carlos III (Grant Nos. 00/3095, 01/3129, PI020499, PI14/00639, PI17/01056, and PI14/00918), SENY Fundació (Research Grant No. CI2005 0308007), and Fundación Marqués de Valdecilla Instituto de Investigación Sanitaria Valdecilla (Grant Nos. A/02/07, NCT0235832, and NCT02534363). Funding Information: The genotyping and analyses were partly funded by the Genetic Association Information Network of the Foundation for the National Institutes of Health. Computing was supported by NWO (Grant No. 2018/EW/00408559), BiG Grid, Dutch e-Science Grid, and SURFsara. Funding Information: MCIC (Mind Clinical Imaging Consortium): This work was supported by the NIH (NIH/National Center for Research Resources Grant No. P41RR14075 [to VC] and Grant No. R01EB005846 [to VC]), Department of Energy (Grant No. DE-FG02-99ER62764), Mind Research Network, Morphometry Biomedical Informatics Research Network (Grant Nos. 1U24 and RR021382A), Function Biomedical Informatics Research Network (Grant No. U24RR021992-01 [to VC], NIH/National Center for Research Resources Grant No. MO1 RR025758-01 [to VC], and NIMH Grant No. 1RC1MH089257 [to VC]), Deutsche Forschungsgemeinschaft (research fellowship [to SE]), and Brain and Behavior Research Foundation (NARSAD Young Investigator Award [to SE]). Funding Information: Dublin: This work was supported by the European Research Council (Grant No. ERC-2015-STG-677467 [to GD]) and Science Foundation Ireland (Grant No. SFI-16/ERCS/3787 [to GD]). Funding Information: BETULA: This work was supported by the Knut and Alice Wallenberg Foundation (scholar grant [to LN]). Funding Information: OSR (Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffele)-Milan: This work was supported by the European Union H2020 (EU.3.1.1 Grant No. 754740 MOODSTRATIFICATION.EU), Italian Ministry of Health (Grant No. RF-2018-12367249) and Italian Ministry of University and Scientific Research (Grant No. A_201779W93T). Funding Information: Australian Schizophrenia Research Bank: This work was supported by the Australian National Health and Medical Research Council (NHMRC) (Enabling Grant No. 386500, L3 Investigator Grant No. 1196508 [to CP]), and Program Grant No. APP1150083 [to CP]), Pratt Foundation, Ramsay Health Care, Viertel Charitable Foundation, and Schizophrenia Research Institute. Chief Investigators for the Australian Schizophrenia Research Bank were Vaughan Carr, US, RJS, Assen Jablensky, BJM, Patricia Michie, Stanley Catts, FAH, and CP. Funding Information: Brain Imaging Genetics (BIG): This work makes use of the BIG database, first established in Nijmegen, the Netherlands, in 2007. This resource is now part of Cognomics ( www.cognomics.nl ), a joint initiative by researchers from the Donders Centre for Cognitive Neuroimaging, Human Genetics and Cognitive Neuroscience departments of Radboud University Medical Centre, and Max Planck Institute for Psycholinguistics in Nijmegen. The Cognomics Initiative is supported by the participating departments and centers and Biobanking and Biomolecular Resources Research Infrastructure (Netherlands), Hersenstichting Nederland, and NWO. The research leading to these results also receives funding from the NWO (Gravitation Grant No. 024.001.006 Language in Interaction), European Community’s Seventh Framework Programme (FP7/2007-2013) (Grant Nos. 602450 IMAGEMEND, 278948 TACTICS, and 602805 Aggressotype), European Community’s Horizon 2020 programme (Grant Nos. 643051 MiND, and ERC-2010-AdG 268800-NEUROSCHEMA). In addition, the work was supported by the ENIGMA Consortium (Grant No. U54 EB020403) from the BD2K Initiative of a cross-NIH partnership. Funding Information: OAA has received speaker’s honorarium from Lundbeck, Janssen, and Sunovion and is a consultant to Coretechs.ai. TRM reports personal fees from Pfizer, Lundbeck, Astellas, Janssen, and Angelini outside the submitted work. He is an employee and shareholder of Pasithea Therapeutics. CRKC has received partial research support from Biogen for work unrelated to the topic of this article (principal investigator, PMT). PMT has received partial research support from Biogen for work unrelated to the topic of this article. MBMvdB and MJO report grants from Takeda Pharmaceuticals outside the submitted work. MJO reports a grant from Akrivia Health outside the submitted work. HJG has received travel grants and speaker’s honoraria from Fresenius Medical Care, Neuraxpharm, Servier, and Janssen as well as research funding from Fresenius Medical Care. GS has received honoraria for participating at advisory board meetings from Roche and Biogen regarding new Alzheimer’s disease drugs. KKS has received consultant and speaker’s honoraria from Roche and OrionPharma, reimbursement of travel and accommodation costs at a meeting from Kolpharma, and sponsorships for arranging conferences from Desitin and Eisai AB. IG has received speaker’s honorarium from Lundbeck. MMN has received fees for membership in an advisory board from HMG Systems Engineering GmbH, for membership in the Medical-Scientific Editorial Office of the Deutsches Ärzteblatt, and for serving as a consultant for Everis Belgium in a project of the European Commission (REFORM/SC2020/029). MMN also receives salary payments from Life & Brain GmbH and holds shares in Life & Brain GmbH. All these concerned activities outside the submitted work. CP received honoraria for talks from Lundbeck, Australia Pty Ltd. outside the submitted work. DJS has received consultancy honoraria from Discovery Vitality, Johnson & Johnson, Kanna, L’Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda and Vistagen. JH has received speaker’s honorarium from Medice and Takeda outside the submitted work. KP reports work with Novo Nordisk and Roche clinical trials outside the submitted work. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: EPIGEN-London/University College London: The work was partly undertaken at University College London Hospitals NHS Foundation Trust/University College London, which received a proportion of funding from the UK Department of Health National Institute for Health Research Biomedical Research Centres funding scheme. Publisher Copyright: © 2023

PY - 2024/1/15

Y1 - 2024/1/15

N2 - Background: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure. Methods: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual's regional difference and global difference, were used to test for regional differences that diverge from the global difference. Results: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness. Conclusions: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.

AB - Background: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure. Methods: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual's regional difference and global difference, were used to test for regional differences that diverge from the global difference. Results: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness. Conclusions: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.

KW - 15q11.2 BP1-BP2

KW - 1q21.1 distal

KW - Brain structure

KW - Copy number variants

KW - Intraindividual variability

KW - Magnetic resonance imaging

UR - http://www.scopus.com/inward/record.url?scp=85178151168&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85178151168&partnerID=8YFLogxK

U2 - 10.1016/j.biopsych.2023.08.018

DO - 10.1016/j.biopsych.2023.08.018

M3 - Article

C2 - 37661008

AN - SCOPUS:85178151168

SN - 0006-3223

VL - 95

SP - 147

EP - 160

JO - Biological psychiatry

JF - Biological psychiatry

IS - 2

ER -

Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers

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