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321 results on '"Bree, Marianne B. M."'

2. Author Correction: Using rare genetic mutations to revisit structural brain asymmetry

Author

Kopal, Jakub, Kumar, Kuldeep, Shafighi, Kimia, Saltoun, Karin, Modenato, Claudia, Moreau, Clara A., Huguet, Guillaume, Jean-Louis, Martineau, Martin, Charles-Olivier, Saci, Zohra, Younis, Nadine, Douard, Elise, Jizi, Khadije, Beauchamp-Chatel, Alexis, Kushan, Leila, Silva, Ana I., van den Bree, Marianne B. M., Linden, David E. J., Owen, Michael J., Hall, Jeremy, Lippé, Sarah, Draganski, Bogdan, Sønderby, Ida E., Andreassen, Ole A., Glahn, David C., Thompson, Paul M., Bearden, Carrie E., Zatorre, Robert, Jacquemont, Sébastien, and Bzdok, Danilo

Published
2024
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3. Using rare genetic mutations to revisit structural brain asymmetry

Author

Kopal, Jakub, Kumar, Kuldeep, Shafighi, Kimia, Saltoun, Karin, Modenato, Claudia, Moreau, Clara A., Huguet, Guillaume, Jean-Louis, Martineau, Martin, Charles-Olivier, Saci, Zohra, Younis, Nadine, Douard, Elise, Jizi, Khadije, Beauchamp-Chatel, Alexis, Kushan, Leila, Silva, Ana I., van den Bree, Marianne B. M., Linden, David E. J., Owen, Michael J., Hall, Jeremy, Lippé, Sarah, Draganski, Bogdan, Sønderby, Ida E., Andreassen, Ole A., Glahn, David C., Thompson, Paul M., Bearden, Carrie E., Zatorre, Robert, Jacquemont, Sébastien, and Bzdok, Danilo

Published
2024
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6. Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS

Author

Zhao, Yingjie, Wang, Yujue, Shi, Lijie, McDonald-McGinn, Donna M., Crowley, T. Blaine, McGinn, Daniel E., Tran, Oanh T., Miller, Daniella, Lin, Jhih-Rong, Zackai, Elaine, Johnston, H. Richard, Chow, Eva W. C., Vorstman, Jacob A. S., Vingerhoets, Claudia, van Amelsvoort, Therese, Gothelf, Doron, Swillen, Ann, Breckpot, Jeroen, Vermeesch, Joris R., Eliez, Stephan, Schneider, Maude, van den Bree, Marianne B. M., Owen, Michael J., Kates, Wendy R., Repetto, Gabriela M., Shashi, Vandana, Schoch, Kelly, Bearden, Carrie E., Digilio, M. Cristina, Unolt, Marta, Putotto, Carolina, Marino, Bruno, Pontillo, Maria, Armando, Marco, Vicari, Stefano, Angkustsiri, Kathleen, Campbell, Linda, Busa, Tiffany, Heine-Suñer, Damian, Murphy, Kieran C., Murphy, Declan, García-Miñaúr, Sixto, Fernández, Luis, Zhang, Zhengdong D., Goldmuntz, Elizabeth, Gur, Raquel E., Emanuel, Beverly S., Zheng, Deyou, Marshall, Christian R., Bassett, Anne S., Wang, Tao, and Morrow, Bernice E.

Published
2023
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9. Rare CNVs and phenome-wide profiling highlight brain structural divergence and phenotypical convergence

Author

Kopal, Jakub, Kumar, Kuldeep, Saltoun, Karin, Modenato, Claudia, Moreau, Clara A., Martin-Brevet, Sandra, Huguet, Guillaume, Jean-Louis, Martineau, Martin, Charles-Olivier, Saci, Zohra, Younis, Nadine, Tamer, Petra, Douard, Elise, Maillard, Anne M., Rodriguez-Herreros, Borja, Pain, Aurèlie, Richetin, Sonia, Kushan, Leila, Silva, Ana I., van den Bree, Marianne B. M., Linden, David E. J., Owen, Michael J., Hall, Jeremy, Lippé, Sarah, Draganski, Bogdan, Sønderby, Ida E., Andreassen, Ole A., Glahn, David C., Thompson, Paul M., Bearden, Carrie E., Jacquemont, Sébastien, and Bzdok, Danilo

Published
2023
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10. Neuropsychiatric risk in children with intellectual disability of genetic origin: IMAGINE, a UK national cohort study

Author

Wolstencroft, Jeanne, Wicks, Francesca, Srinivasan, Ramya, Erwood, Marie, Lafont, Amy, Timur, Husne, Ye, Zheng, Walker, Susan, Printzlau, Frida, Juj, Manoj, Davies, Sarah, Denyer, Hayley, Watkins, Alice, Kerry, Eleanor, Coscini, Nadia, Fatih, Nasrtullah, Lucock, Anna, Denaxas, Spiros, Mandy, William, Walker, Neil, Wallwork, Sarah, Dewhurst, Eleanor, Cuthbert, Andrew, Challenger, Aimee, Andrews, Sophie, Holmans, Peter, Bowen, Samantha, Bradley, Karen, Birch, Philippa, Tong, Molly, Lewis, Nicola, Ray, Sinead, Sopp, Matthew, Moss, Hayley, Wynn, Sarah, Searle, Beverley, Robertson, Lisa, Berg, Jonathan, Lampe, Anne, Joss, Shelagh, Brennan, Paul, Kraus, Alison, Lahiri, Nayana, Weber, Astrid, Rawson, Myfanwy, Johnson, Diana, Vasudevan, Pradeep, Harrison, Rachel, Williams, Denise, Maher, Eamonn, Kini, Usha, Van Dijk, Fleur, Clowes, Virginia, Gurasashvilli, Jana, Mansour, Sahar, Holder-Espinasse, Muriel, Watford, Amy, Rankin, Julia, Baralle, Diana, Procter, Annie, Ford, Tamsin, Baker, Kate, Chawner, Samuel, Hall, Jeremy, Van den Bree, Marianne B M, Owen, Michael J, Skuse, David, Raymond, F Lucy, Chawner, Samuel J R A, and van den Bree, Marianne B M

Published
2022
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13. Effects of eight neuropsychiatric copy number variants on human brain structure

Author

Modenato, Claudia, Kumar, Kuldeep, Moreau, Clara, Martin-Brevet, Sandra, Huguet, Guillaume, Schramm, Catherine, Jean-Louis, Martineau, Martin, Charles-Olivier, Younis, Nadine, Tamer, Petra, Douard, Elise, Thébault-Dagher, Fanny, Côté, Valérie, Charlebois, Audrey-Rose, Deguire, Florence, Maillard, Anne M., Rodriguez-Herreros, Borja, Pain, Aurèlie, Richetin, Sonia, Melie-Garcia, Lester, Kushan, Leila, Silva, Ana I., van den Bree, Marianne B. M., Linden, David E. J., Owen, Michael J., Hall, Jeremy, Lippé, Sarah, Chakravarty, Mallar, Bzdok, Danilo, Bearden, Carrie E., Draganski, Bogdan, and Jacquemont, Sébastien

Published
2021
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15. The psychiatric phenotypes of 1q21 distal deletion and duplication

Author

Linden, Stefanie C., Watson, Cameron J., Smith, Jacqueline, Chawner, Samuel J. R. A., Lancaster, Thomas M., Evans, Ffion, Williams, Nigel, Skuse, David, Raymond, F. Lucy, Hall, Jeremy, Owen, Michael J., Linden, David E. J., Green-Snyder, LeeAnne, Chung, Wendy K., Maillard, Anne M., Jacquemont, Sébastien, and van den Bree, Marianne B. M.

Published
2021
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22. Using rare genetic mutations to revisit structural brain asymmetry

Author

Kopal, Jakub, primary, Kumar, Kuldeep, additional, Shafighi, Kimia, additional, Saltoun, Karin, additional, Modenato, Claudia, additional, Moreau, Clara A., additional, Huguet, Guillaume, additional, Jean-Louis, Martineau, additional, Martin, Charles-Olivier, additional, Saci, Zohra, additional, Younis, Nadine, additional, Douard, Elise, additional, Jizi, Khadije, additional, Beauchamp-Chatel, Alexis, additional, Kushan, Leila, additional, Silva, Ana I., additional, van den Bree, Marianne B. M., additional, Linden, David E. J., additional, Owen, Michael J., additional, Hall, Jeremy, additional, Lippé, Sarah, additional, Draganski, Bogdan, additional, Sønderby, Ida E., additional, Andreassen, Ole A., additional, Glahn, David C., additional, Thompson, Paul M., additional, Bearden, Carrie E., additional, Zatorre, Robert, additional, Jacquemont, Sébastien, additional, and Bzdok, Danilo, additional

Published
2023
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23. DRAGON-Data: a platform and protocol for integrating genomic and phenotypic data across large psychiatric cohorts

Author

Lynham, Amy J., primary, Knott, Sarah, additional, Underwood, Jack F. G., additional, Hubbard, Leon, additional, Agha, Sharifah S., additional, Bisson, Jonathan I., additional, van den Bree, Marianne B. M., additional, Chawner, Samuel J. R. A., additional, Craddock, Nicholas, additional, O'Donovan, Michael, additional, Jones, Ian R., additional, Kirov, George, additional, Langley, Kate, additional, Martin, Joanna, additional, Rice, Frances, additional, Roberts, Neil P., additional, Thapar, Anita, additional, Anney, Richard, additional, Owen, Michael J., additional, Hall, Jeremy, additional, Pardiñas, Antonio F., additional, and Walters, James T. R., additional

Published
2023
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25. Psychiatric disorders in children with 16p11.2 deletion and duplication

Author

Niarchou, Maria, Chawner, Samuel J. R. A., Doherty, Joanne L., Maillard, Anne M., Jacquemont, Sébastien, Chung, Wendy K., Green-Snyder, LeeAnne, Bernier, Raphael A., Goin-Kochel, Robin P., Hanson, Ellen, Linden, David E. J., Linden, Stefanie C., Raymond, F. Lucy, Skuse, David, Hall, Jeremy, Owen, Michael J., and Bree, Marianne B. M. van den

Published
2019
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26. Brain functional connectivity mirrors genetic pleiotropy in psychiatric conditions

Author

Moreau, Clara A, primary, Kumar, Kuldeep, additional, Harvey, Annabelle, additional, Huguet, Guillaume, additional, Urchs, Sebastian G W, additional, Schultz, Laura M, additional, Sharmarke, Hanad, additional, Jizi, Khadije, additional, Martin, Charles-Olivier, additional, Younis, Nadine, additional, Tamer, Petra, additional, Martineau, Jean-Louis, additional, Orban, Pierre, additional, Silva, Ana Isabel, additional, Hall, Jeremy, additional, van den Bree, Marianne B M, additional, Owen, Michael J, additional, Linden, David E J, additional, Lippé, Sarah, additional, Bearden, Carrie E, additional, Almasy, Laura, additional, Glahn, David C, additional, Thompson, Paul M, additional, Bourgeron, Thomas, additional, Bellec, Pierre, additional, and Jacquemont, Sebastien, additional

Published
2022
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28. Psychopathology in mothers of children with pathogenic Copy Number Variants.

Author

Niarchou, Maria, Cunningham, Adam C., Chawner, Samuel J. R. A., Moulding, Hayley, Sopp, Matthew, Hall, Jeremy, Owen, Michael J., and van den Bree, Marianne B. M.

Abstract

Background Caring for children with pathogenic neurodevelopmental Copy Number Variants (CNVs) (ie, deletions and duplications of genetic material) can place a considerable burden on parents and their quality of life. Our study is the first to examine the frequency of psychiatric diagnoses in mothers of children with CNVs compared with the frequency of psychiatric problems in age-matched mothers from a large community study. Methods Case-control study. 268 mothers of children with a CNV diagnosed in a medical genetics clinic and 2680 age-matched mothers taking part in the Avon Longitudinal Study of Parents and Children study. Results Mothers of children with CNVs reported higher frequency of depression, anorexia, bulimia, alcohol abuse and drug addiction problems compared with the age-matched mothers from the community sample. Focusing on psychiatric problems arising immediately after the birth of the index child, we found that the levels of depression symptoms were similar between the two groups (48% in mothers of children with CNVs vs 44% in mothers of the community sample, p=0.43), but mothers of children with CNVs had higher frequency of anxiety symptoms (55%) compared with mothers from the community sample (30%, p=0.03). Conclusion Our study highlights the need for healthcare providers to devise treatment plans that not only focus on meeting the child's needs but also assess and, if needed, address the mental health needs of the parent. [ABSTRACT FROM AUTHOR]

Published
2023
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29. Neurodevelopmental dimensional assessment of young children at high genomic risk of neuropsychiatric conditions.

Author

Chawner, Samuel J. R. A., Paine, Amy L., Dunn, Matt J., Walsh, Alice, Sloane, Poppy, Thomas, Megan, Evans, Alexandra, Hopkins-Jones, Lucinda, Struik, Siske, Hall, Jeremy, Erichsen, Jonathan T., Leekam, Susan R., Owen, Michael J., Hay, Dale, and den Bree, Marianne B. M. van

Subjects
DIGEORGE syndrome, NEURAL development, INTRACLASS correlation, CHILDREN with autism spectrum disorders, TODDLERS development, AUTISTIC children, AUTISM in children
Abstract

Background: Individuals with 22q11.2 deletion are at considerably increased risk of neurodevelopmental and psychiatric conditions. There have been very few studies investigating how this risk manifests in early childhood and what factors may underlie developmental variability. Insights into this can elucidate transdiagnostic markers of risk that may underlie later development of neuropsychiatric outcomes. Methods: Thirty two children with 22q11.2 Deletion Syndrome (22q11.2DS) (mean age = 4.1 [SD = 1.2] years) and 12 sibling controls (mean age = 4.1 [SD = 1.5] years) underwent in-depth dimensional phenotyping across several developmental domains selected as being potential early indicators of neurodevelopmental and psychiatric liability. Comparisons were conducted of the dimensional developmental phenotype of 22q11.2DS and sibling controls. For autistic traits, both parents and children were phenotyped using the Social Responsiveness Scale. Results: Young children with 22q11.2DS exhibited large impairments (Hedge's g ≥ 0.8) across a range of developmental domains relative to sibling controls, as well as high rates of transdiagnostic neurodevelopmental and psychiatric traits. Cluster analysis revealed a subgroup of children with 22q11.2DS (n = 16; 53%) in whom neurodevelopmental and psychiatric liability was particularly increased and who differed from other children with 22q11.2DS and non-carrier siblings. Exploratory analyses revealed that early motor and sleep impairments indexed liability for neurodevelopmental and psychiatric outcomes. Maternal autism trait scores were predictive of autism traits in children with 22q11.2DS (intraclass correlation coefficients = 0.47, p = 0.046, n = 31). Conclusions: Although psychiatric conditions typically emerge later in adolescence and adulthood in 22q11.2DS, our exploratory study was able to identify a range of early risk indicators. Furthermore, findings indicate the presence of a subgroup who appeared to have increased neurodevelopmental and psychiatric liability. Our findings highlight the scope for future studies of early risk mechanisms and early intervention within this high genetic risk patient group. [ABSTRACT FROM AUTHOR]

Published
2023
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30. The Moderating Effects of Pubertal Timing on the Longitudinal Associations between Parent-Child Relationship Quality and Adolescent Substance Use

Author

Shelton, Katherine H. and Van Den Bree, Marianne B. M.

Abstract

This prospective, longitudinal study investigated the moderating role of pubertal timing on reciprocal links between adolescent appraisals of parent-child relationship quality and girls' (N = 1,335) and boys' (N = 1,203) cigarette and alcohol use across a 12-month period. Reciprocal effects were found between parent-child relations and on-time maturing boys and girls' cigarette and alcohol use, after estimating stability in these constructs across time. Parent-child relationship quality was associated with increased alcohol use 12 months later for early maturing girls. Cigarette and alcohol use were associated with increased problems in the parent-child relationship for late maturing girls. No effects were observed for early and late maturing boys in the pathways between parent-child relationship quality and substance use. Pubertal timing moderated the pathway linking parent-child relationship quality with cigarette use 1 year later such that the association was stronger for late maturing girls compared with early and on-time maturing girls. The findings indicate interplay between the psychosocial aspects of maturation, family relationships, and adolescent substance use and highlight possible gender-specific influences.

Published
2010
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31. Examining Differences in Psychological Adjustment Problems among Children Conceived by Assisted Reproductive Technologies

Author

Shelton, Katherine H., Boivin, Jacky, Hay, Dale, van den Bree, Marianne B. M., Rice, Frances J., Harold, Gordon T., and Thapar, Anita

Abstract

The aim of this study was to examine whether there was variation in levels of psychological adjustment among children conceived through Assisted Reproductive Technologies using the parents' gametes (homologous), sperm donation, egg donation, embryo donation and surrogacy. Information was provided by parents about the psychological functioning of 769 children aged 5 to 9 years who had been born using ART (from the five groups described). Comparisons were made between the different conception groups, to UK national norms and, for a sub-sample of multiple births, to an age-matched twin sample. No differences were found between the conception groups except that fathers from the egg donation group rated children higher in conduct problems compared to other ART groups. No effects were observed by ART treatment type (ICSI vs. IVF, GIFT and IUI). There was some evidence of lower conduct problems and prosocial behaviour among children conceived through homologous IVF compared to national norms. Taken together, however, consistent differences between groups and in comparison to naturally conceived children were not apparent for mother- or father-rated adjustment problems. Children conceived with assisted reproductive technologies, regardless of whether they are genetically related or unrelated to their parents or born by gestational surrogacy do not differ in their levels of psychological adjustment. Nor do they appear to be at greater risk of psychological adjustment problems in middle childhood compared to naturally conceived children. (Contains 3 tables.)

Published
2009
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33. Subthreshold Psychosis in 22q11.2 Deletion Syndrome: Multisite Naturalistic Study

Author

Weisman, Omri, Guri, Yael, Gur, Raquel E, McDonald-McGinn, Donna M, Calkins, Monica E, Tang, Sunny X, Emanuel, Beverly, Zackai, Elaine H, Eliez, Stephan, Schneider, Maude, Schaer, Marie, Kates, Wendy R, Antshel, Kevin M, Fremont, Wanda, Shashi, Vandana, Hooper, Stephen R, Armando, Marco, Vicari, Stefano, Pontillo, Maria, Kushan, Leila, Jalbrzikowski, Maria, Bearden, Carrie E, Cubells, Joseph F, Ousley, Opal Y, Walker, Elaine F, Simon, Tony J, Stoddard, Joel, Niendam, Tara A, van den Bree, Marianne B. M, and Gothelf, Doron

Published
2017
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34. Brain functional connectivity mirrors genetic pleiotropy in psychiatric conditions.

Author

Moreau, Clara A, Kumar, Kuldeep, Harvey, Annabelle, Huguet, Guillaume, Urchs, Sebastian G W, Schultz, Laura M, Sharmarke, Hanad, Jizi, Khadije, Martin, Charles-Olivier, Younis, Nadine, Tamer, Petra, Martineau, Jean-Louis, Orban, Pierre, Silva, Ana Isabel, Hall, Jeremy, Bree, Marianne B M van den, Owen, Michael J, Linden, David E J, Lippé, Sarah, and Bearden, Carrie E

Subjects
GENETIC pleiotropy, LARGE-scale brain networks, FUNCTIONAL connectivity, FLUID intelligence, FUNCTIONAL magnetic resonance imaging, GENETIC variation
Abstract

Pleiotropy occurs when a genetic variant influences more than one trait. This is a key property of the genomic architecture of psychiatric disorders and has been observed for rare and common genomic variants. It is reasonable to hypothesize that the microscale genetic overlap (pleiotropy) across psychiatric conditions and cognitive traits may lead to similar overlaps at the macroscale brain level such as large-scale brain functional networks. We took advantage of brain connectivity, measured by resting-state functional MRI to measure the effects of pleiotropy on large-scale brain networks, a putative step from genes to behaviour. We processed nine resting-state functional MRI datasets including 32 726 individuals and computed connectome-wide profiles of seven neuropsychiatric copy-number-variants, five polygenic scores, neuroticism and fluid intelligence as well as four idiopathic psychiatric conditions. Nine out of 19 pairs of conditions and traits showed significant functional connectivity correlations (r Functional connectivity), which could be explained by previously published levels of genomic (r Genetic) and transcriptomic (r Transcriptomic) correlations with moderate to high concordance: r Genetic— r Functional connectivity = 0.71 [0.40–0.87] and r Transcriptomic— r Functional connectivity = 0.83 [0.52; 0.94]. Extending this analysis to functional connectivity profiles associated with rare and common genetic risk showed that 30 out of 136 pairs of connectivity profiles were correlated above chance. These similarities between genetic risks and psychiatric disorders at the connectivity level were mainly driven by the overconnectivity of the thalamus and the somatomotor networks. Our findings suggest a substantial genetic component for shared connectivity profiles across conditions and traits, opening avenues to delineate general mechanisms—amenable to intervention—across psychiatric conditions and genetic risks. [ABSTRACT FROM AUTHOR]

Published
2023
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36. Psychopathology in adults with copy number variants

Author

Adams, Rachael L., primary, Baird, Alister, additional, Smith, Jacqueline, additional, Williams, Nigel, additional, van den Bree, Marianne B. M., additional, Linden, David E. J., additional, Owen, Michael J., additional, Hall, Jeremy, additional, and Linden, Stefanie C., additional

Published
2022
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38. Defining the Effect of the 16p11.2 Duplication on Cognition, Behavior, and Medical Comorbidities

Author

D’Angelo, Debra, Lebon, Sébastien, Chen, Qixuan, Martin-Brevet, Sandra, Snyder, LeeAnne Green, Hippolyte, Loyse, Hanson, Ellen, Maillard, Anne M., Faucett, W. Andrew, Macé, Aurélien, Pain, Aurélie, Bernier, Raphael, Chawner, Samuel J. R. A., David, Albert, Andrieux, Joris, Aylward, Elizabeth, Baujat, Genevieve, Caldeira, Ines, Conus, Philippe, Ferrari, Carrina, Forzano, Francesca, Gérard, Marion, Goin-Kochel, Robin P., Grant, Ellen, Hunter, Jill V., Isidor, Bertrand, Jacquette, Aurélia, Jønch, Aia E., Keren, Boris, Lacombe, Didier, Le Caignec, Cédric, Martin, Christa Lese, Männik, Katrin, Metspalu, Andres, Mignot, Cyril, Mukherjee, Pratik, Owen, Michael J., Passeggeri, Marzia, Rooryck-Thambo, Caroline, Rosenfeld, Jill A., Spence, Sarah J., Steinman, Kyle J., Tjernagel, Jennifer, Van Haelst, Mieke, Shen, Yiping, Draganski, Bogdan, Sherr, Elliott H., Ledbetter, David H., van den Bree, Marianne B. M., Beckmann, Jacques S., Spiro, John E., Reymond, Alexandre, Jacquemont, Sébastien, and Chung, Wendy K.

Published
2016
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42. Using induced pluripotent stem cells to investigate human neuronal phenotypes in 1q21.1 deletion and duplication syndrome

Author

Chapman, Gareth, primary, Alsaqati, Mouhamed, additional, Lunn, Sharna, additional, Singh, Tanya, additional, Linden, Stefanie C., additional, Linden, David E. J., additional, van den Bree, Marianne B. M., additional, Ziller, Mike, additional, Owen, Michael J., additional, Hall, Jeremy, additional, Harwood, Adrian J., additional, and Syed, Yasir Ahmed, additional

Published
2021
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43. Effects of copy number variations on brain structure and risk for psychiatric illness: Large-scale studies from the ENIGMA working groups on CNVs

Author

Sønderby, Ida E, Ching, Christopher R K, Ayesa-Arriola, Rosa, Thompson, Paul M, Bearden, Carrie E, Andreassen, Ole A, Group, ENIGMA-CNV Working, 2 Deletion Syndrome Working Group, ENIGMA 22q11., Bernard, Manon, Blackburn, Nicholas B, Bøen, Rune, de Geus, Eco, de Zwarte, Sonja M C, Bakker, Geor, Forti, Marta Di, Frei, Oleksandr, Fukunaga, Masaki, Hehir-Kwa, Jayne Y, Hillegers, Manon H J, Hoffmann, Per, Homuth, Georg, Jahanshad, Neda, Koops, Sanne, Kumar, Kuldeep, Bassett, Anne S, Kikuchi, Masataka, Le Hellard, Stephanie, Leu, Costin, Murray, Robin M, Naerland, Terje, Nyberg, Lars, Ophoff, Roel A, Pike, G Bruce, Sando, Sigrid B, Shin, Jean, Boomsma, Dorret I, Shumskaya, Elena, Sisodiya, Sanjay M, Steen, Vidar M, Teumer, Alexander, Uhlmann, Anne, Wright, Margaret J, Antshel, Kevin M, Campbell, Linda E, Crossley, Nicolas A, Crowley, T Blaine, Bülow, Robin, Daly, Eileen, Fiksinski, Ania M, Forsyth, Jennifer K, Fremont, Wanda, Goodrich-Hunsaker, Naomi J, Gudbrandsen, Maria, Jonas, Rachel K, Kates, Wendy R, Lin, Amy, McCabe, Kathryn L, Butcher, Nancy J, Moss, Hayley, Murphy, Declan G, Murphy, Kieran C, Owen, Michael J, Ruparel, Kosha, Simon, Tony J, van Amelsvoort, Therese, Vorstman, Jacob A S, Calhoun, Vince D, Caspers, Svenja, Chow, Eva W C, Cichon, Sven, Thomopoulos, Sophia I, Ciufolini, Simone, Craig, Michael C, Crespo-Facorro, Benedicto, Cunningham, Adam C, Dale, Anders M, Dazzan, Paola, de Zubicaray, Greig I, Djurovic, Srdjan, Doherty, Joanne L, Donohoe, Gary, van der Meer, Dennis, Draganski, Bogdan, Durdle, Courtney A, Ehrlich, Stefan, Emanuel, Beverly S, Espeseth, Thomas, Fisher, Simon E, Ge, Tian, Glahn, David C, Grabe, Hans J, Gur, Raquel E, Sun, Daqiang, Gutman, Boris A, Haavik, Jan, Håberg, Asta K, Hansen, Laura A, Hashimoto, Ryota, Hibar, Derrek P, Holmes, Avram J, Hottenga, Jouke-Jan, Hulshoff Pol, Hilleke E, Jalbrzikowski, Maria, Villalon-Reina, Julio E, Knowles, Emma E M, Kushan, Leila, Linden, David E J, Liu, Jingyu, Lundervold, Astri J, Martin-Brevet, Sandra, Martínez, Kenia, Mather, Karen A, Mathias, Samuel R, McDonald-McGinn, Donna M, Agartz, Ingrid, McRae, Allan F, Medland, Sarah E, Moberget, Torgeir, Modenato, Claudia, Monereo Sánchez, Jennifer, Moreau, Clara A, Mühleisen, Thomas W, Paus, Tomas, Pausova, Zdenka, Prieto, Carlos, Amunts, Katrin, Ragothaman, Anjanibhargavi, Reinbold, Céline S, Reis Marques, Tiago, Repetto, Gabriela M, Reymond, Alexandre, Roalf, David R, Rodriguez-Herreros, Borja, Rucker, James J, Sachdev, Perminder S, Schmitt, James E, Arango, Celso, Schofield, Peter R, Silva, Ana I, Stefansson, Hreinn, Stein, Dan J, Tamnes, Christian K, Tordesillas-Gutiérrez, Diana, Ulfarsson, Magnus O, Vajdi, Ariana, van 't Ent, Dennis, van den Bree, Marianne B M, Armstrong, Nicola J, Vassos, Evangelos, Vázquez-Bourgon, Javier, Vila-Rodriguez, Fidel, Walters, G Bragi, Wen, Wei, Westlye, Lars T, Wittfeld, Katharina, Zackai, Elaine H, Stefánsson, Kári, Jacquemont, Sebastien, the ENIGMA-CNV Working Group, the ENIGMA 22q11.2 Deletion Syndrome Working Group, Stochastics, Biological Psychology, APH - Mental Health, APH - Methodology, APH - Personalized Medicine, APH - Health Behaviors & Chronic Diseases, ENIGMA-CNV Working Group, ENIGMA 22q11.2 Deletion Syndrome Working Group, and Universidad de Cantabria

Subjects
Review Article, genetics [Mental Disorders], 0302 clinical medicine, genetics-first approach, pathology [Brain], Multicenter Studies as Topic, Copy-number variation, Review Articles, education.field_of_study, brain structural imaging, Radiological and Ultrasound Technology, genetics [Neurodevelopmental Disorders], Mental Disorders, neurodevelopmental disorders, 05 social sciences, growth & development [Brain], Brain, pathology [Mental Disorders], Cognition, Human brain, diffusion tensor imaging, Magnetic Resonance Imaging, diagnostic imaging [Neurodevelopmental Disorders], medicine.anatomical_structure, psychiatric disorders, Neurology, Anatomy, medicine.medical_specialty, Brain development, DNA Copy Number Variations, Population, Neuroimaging, Biology, 050105 experimental psychology, 03 medical and health sciences, evolution, medicine, pathology [Neurodevelopmental Disorders], Humans, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, Deletion syndrome, copy number variant, ddc:610, genetics‐first approach, education, Psychiatry, diagnostic imaging [Brain], Neurology (clinical), Working group, 030217 neurology & neurosurgery, diagnostic imaging [Mental Disorders]
Abstract

The Enhancing NeuroImaging Genetics through Meta‐Analysis copy number variant (ENIGMA‐CNV) and 22q11.2 Deletion Syndrome Working Groups (22q‐ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA‐CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q‐ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest‐ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi‐site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene‐dosage effects on distinct brain regions also emerged, providing further insight into genotype–phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This “genotype‐first” approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior., The enhancing neuroimaging genetics through meta‐analysis (ENIGMA) copy number variant (CNV) and 22q11.2 Working Groups focus on gaining insight into how rare genetic variants affect human brain development, cognition, and behavior. The two ENIGMA working groups have collated CNV and brain‐imaging data from numerous individuals, gathered by numerous international research centers, and analyzed this data with standardized processing and analysis pipelines. Future directions for the ENIGMA CNV and 22q11.2 working groups are to analyze CNVs with larger sample sizes and more imaging modalities to better understand how rare genetic variants affect the brain, and their clinical and behavioral consequences.

Published
2021

44. 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans

Author

Sønderby, Ida E., van der Meer, Dennis, Moreau, Clara, Kaufmann, Tobias, Walters, G Bragi, Ellegaard, Maria, Abdellaoui, Abdel, Ames, David, Amunts, Katrin, Andersson, Micael, Armstrong, Nicola J., Bernard, Manon, Blackburn, Nicholas B., Blangero, John, Boomsma, Dorret I., Brodaty, Henry, Brouwer, Rachel M., Bülow, Robin, Bøen, Rune, Cahn, Wiepke, Calhoun, Vince D., Caspers, Svenja, Ching, Christopher R K, Cichon, Sven, Ciufolini, Simone, Crespo-Facorro, Benedicto, Curran, Joanne E., Dale, Anders M., Dalvie, Shareefa, Dazzan, Paola, de Geus, Eco J C, de Zubicaray, Greig I., de Zwarte, Sonja M C, Desrivieres, Sylvane, Doherty, Joanne L., Donohoe, Gary, Draganski, Bogdan, Ehrlich, Stefan, Eising, Else, Espeseth, Thomas, Fejgin, Kim, Fisher, Simon E., Fladby, Tormod, Frei, Oleksandr, Frouin, Vincent, Fukunaga, Masaki, Gareau, Thomas, Ge, Tian, Glahn, David C., Grabe, Hans J., Groenewold, Nynke A., Gústafsson, Ómar, Haavik, Jan, Haberg, Asta K., Hall, Jeremy, Hashimoto, Ryota, Hehir-Kwa, Jayne Y., Hibar, Derrek P., Hillegers, Manon H J, Hoffmann, Per, Holleran, Laurena, Holmes, Avram J., Homuth, Georg, Hottenga, Jouke-Jan, Hulshoff Pol, Hilleke E., Ikeda, Masashi, Jahanshad, Neda, Jockwitz, Christiane, Johansson, Stefan, Jönsson, Erik G., Jørgensen, Niklas R., Kikuchi, Masataka, Knowles, Emma E M, Kumar, Kuldeep, Le Hellard, Stephanie, Leu, Costin, Linden, David E J, Liu, Jingyu, Lundervold, Arvid, Lundervold, Astri Johansen, Maillard, Anne M., Martin, Nicholas G., Martin-Brevet, Sandra, Mather, Karen A., Mathias, Samuel R., McMahon, Katie L., McRae, Allan F., Medland, Sarah E., Meyer-Lindenberg, Andreas, Moberget, Torgeir, Modenato, Claudia, Sánchez, Jennifer Monereo, Morris, Derek W., Mühleisen, Thomas W., Murray, Robin M., Nielsen, Jacob, Nordvik, Jan E., Nyberg, Lars, Loohuis, Loes M Olde, Ophoff, Roel A., Owen, Michael J., Paus, Tomas, Pausova, Zdenka, Peralta, Juan M., Pike, G Bruce, Prieto, Carlos, Quinlan, Erin B., Reinbold, Céline S, Marques, Tiago Reis, Rucker, James J H, Sachdev, Perminder S., Sando, Sigrid B., Schofield, Peter R., Schork, Andrew J., Schumann, Gunter, Shin, Jean, Shumskaya, Elena, Silva, Ana I., Sisodiya, Sanjay M., Steen, Vidar M., Stein, Dan J., Strike, Lachlan T., Suzuki, Ikuo K., Tamnes, Christian K., Teumer, Alexander, Thalamuthu, Anbupalam, Tordesillas-Gutiérrez, Diana, Uhlmann, Anne, Ulfarsson, Magnus O., van 't Ent, Dennis, van den Bree, Marianne B M, Vanderhaeghen, Pierre, Vassos, Evangelos, Wen, Wei, Wittfeld, Katharina, Wright, Margaret J., Agartz, Ingrid, Djurovic, Srdjan, Westlye, Lars T., Stefansson, Hreinn, Stefansson, Kari, Jacquemont, Sébastien, Thompson, Paul M., Andreassen, Ole A., Sønderby, Ida E., van der Meer, Dennis, Moreau, Clara, Kaufmann, Tobias, Walters, G Bragi, Ellegaard, Maria, Abdellaoui, Abdel, Ames, David, Amunts, Katrin, Andersson, Micael, Armstrong, Nicola J., Bernard, Manon, Blackburn, Nicholas B., Blangero, John, Boomsma, Dorret I., Brodaty, Henry, Brouwer, Rachel M., Bülow, Robin, Bøen, Rune, Cahn, Wiepke, Calhoun, Vince D., Caspers, Svenja, Ching, Christopher R K, Cichon, Sven, Ciufolini, Simone, Crespo-Facorro, Benedicto, Curran, Joanne E., Dale, Anders M., Dalvie, Shareefa, Dazzan, Paola, de Geus, Eco J C, de Zubicaray, Greig I., de Zwarte, Sonja M C, Desrivieres, Sylvane, Doherty, Joanne L., Donohoe, Gary, Draganski, Bogdan, Ehrlich, Stefan, Eising, Else, Espeseth, Thomas, Fejgin, Kim, Fisher, Simon E., Fladby, Tormod, Frei, Oleksandr, Frouin, Vincent, Fukunaga, Masaki, Gareau, Thomas, Ge, Tian, Glahn, David C., Grabe, Hans J., Groenewold, Nynke A., Gústafsson, Ómar, Haavik, Jan, Haberg, Asta K., Hall, Jeremy, Hashimoto, Ryota, Hehir-Kwa, Jayne Y., Hibar, Derrek P., Hillegers, Manon H J, Hoffmann, Per, Holleran, Laurena, Holmes, Avram J., Homuth, Georg, Hottenga, Jouke-Jan, Hulshoff Pol, Hilleke E., Ikeda, Masashi, Jahanshad, Neda, Jockwitz, Christiane, Johansson, Stefan, Jönsson, Erik G., Jørgensen, Niklas R., Kikuchi, Masataka, Knowles, Emma E M, Kumar, Kuldeep, Le Hellard, Stephanie, Leu, Costin, Linden, David E J, Liu, Jingyu, Lundervold, Arvid, Lundervold, Astri Johansen, Maillard, Anne M., Martin, Nicholas G., Martin-Brevet, Sandra, Mather, Karen A., Mathias, Samuel R., McMahon, Katie L., McRae, Allan F., Medland, Sarah E., Meyer-Lindenberg, Andreas, Moberget, Torgeir, Modenato, Claudia, Sánchez, Jennifer Monereo, Morris, Derek W., Mühleisen, Thomas W., Murray, Robin M., Nielsen, Jacob, Nordvik, Jan E., Nyberg, Lars, Loohuis, Loes M Olde, Ophoff, Roel A., Owen, Michael J., Paus, Tomas, Pausova, Zdenka, Peralta, Juan M., Pike, G Bruce, Prieto, Carlos, Quinlan, Erin B., Reinbold, Céline S, Marques, Tiago Reis, Rucker, James J H, Sachdev, Perminder S., Sando, Sigrid B., Schofield, Peter R., Schork, Andrew J., Schumann, Gunter, Shin, Jean, Shumskaya, Elena, Silva, Ana I., Sisodiya, Sanjay M., Steen, Vidar M., Stein, Dan J., Strike, Lachlan T., Suzuki, Ikuo K., Tamnes, Christian K., Teumer, Alexander, Thalamuthu, Anbupalam, Tordesillas-Gutiérrez, Diana, Uhlmann, Anne, Ulfarsson, Magnus O., van 't Ent, Dennis, van den Bree, Marianne B M, Vanderhaeghen, Pierre, Vassos, Evangelos, Wen, Wei, Wittfeld, Katharina, Wright, Margaret J., Agartz, Ingrid, Djurovic, Srdjan, Westlye, Lars T., Stefansson, Hreinn, Stefansson, Kari, Jacquemont, Sébastien, Thompson, Paul M., and Andreassen, Ole A.

Abstract

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

Published
2021
Full Text
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45. 1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans

Author

Helmholtz Association, European Commission, Netherlands Organization for Scientific Research, European Research Council, Knut and Alice Wallenberg Foundation, Innovative Medicines Initiative, European Federation of Pharmaceutical Industries and Associations, Science Foundation Ireland, Medical Research Council (UK), Wellcome Trust, Waterloo Foundation, National Institute of Mental Health (US), National Institutes of Health (US), Department of Health & Social Care (UK), NIHR Biomedical Research Centre (UK), NHS Foundation Trust, Harvard University, Massachusetts General Hospital, Swedish Research Council, Norwegian University of Science and Technology, Swedish Research Council for Sustainable Development, Kings College London, Federal Ministry of Education and Research (Germany), German Research Foundation, Agence Nationale de la Recherche (France), Fondation de France, Fondation pour la Recherche Médicale, Research Council of Norway, University of Bergen, European Science Foundation, National Health and Medical Research Council (Australia), Australian Research Council, Japan Agency for Medical Research and Development, Instituto de Salud Carlos III, Fundación Marques de Valdecilla, National Institute on Drug Abuse (US), Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), University of Greifswald, Mecklenburg-Western Pomerania, University of Oslo, Sønderby, Ida E., van der Meer, Dennis, Moreau, Clara, Kaufmann, Tobias, Bragi Walters, G., Ellegaard, Maria, Abdellaoui, Abdel, Ames, David, Amunts, Katrin, Andersson, Micael, Armstrong, Nicola J., Modenato, Claudia, Monereo Sánchez, Jennifer, Morris, Derek W., Mühleisen, Thomas W., Pausova, Zdenka, Olde Loohuis, Loes M., Peralta, Juan M., Pike, G. Bruce, Prieto, Carlos, Quinlan, Erin B., Wright, Margaret J., Reinbold, Céline S., Stefansson, Hreinn, Reis Marques, Tiago, Bernard, Manon, Rucker, James J. H., Sachdev, Perminder S., Sando, Sigrid B., Schofield, Peter R., Schork, Andrew J., Schumann, Gunter, Agartz, Ingrid, Shin, Jean, Shumskaya, Elena, Stefansson, Kari, Silva, Ana I., Sisodiya, Sanjay M., Blackburn, Nicholas B., Steen, Vidar M., Stein, Dan J., Strike, Lachlan T., Suzuki, Ikuo K., Djurovic, Srdjan, Tamnes, Christian K., Teumer, Alexander, Thalamuthu, Anbupalam, Jacquemont, Sébastien, Tordesillas-Gutiérrez, Diana, Uhlmann, Anne, Ulfarsson, Magnus O., Blangero, John, van't Ent, Dennis, van den Bree, Marianne B. M., Westlye, Lars T., Vanderhaeghen, Pierre, Vassos, Evangelos, Wen, Wei, Wittfeld, Katharina, Thompson, Paul M., Boomsma, Dorret I., Andreassen, Ole A., Brodaty, Henry, Brouwer, Rachel M., Bülow, Robin, Bøen, Rune, Groenewold, Nynke A., Cahn, Wiepke, Hashimoto, Ryota, Calhoun, Vincent, Caspers, Svenja, Ching, Christopher R. K., Cichon, Sven, Ciufolini, Simone, Crespo-Facorro, Benedicto, Curran, Joanne E., Dale, Anders M., Gústafsson, Ómar, Dalvie, Shareefa, Dazzan, Paola, Hehir-Kwa, Jayne Y., de Geus, de Geus, Zubicaray, Greig I. de, de Zwarte, Sonja M. C., Desrivieres, Sylvane, Doherty, Joanne L., Donohoe, Gary, Draganski, Bogdan, Haavik, Jan, Ehrlich, Stefan, Eising, Else, Espeseth, Thomas, Hibar, Derrek P., Fejgin, Kim, Fisher, Simon E., Fladby, Tormod, Frei, Oleksandr, Frouin, Vincent, Fukunaga, Masaki, Haberg, Asta K., Gareau, Thomas, Ge,Tian, Glahn, David C., Grabe, Hans-Jörgen, Hillegers, Manon H. J., Hall, Jeremy, Hoffmann, Per, Holleran, Laurena, Holmes, Avram J., Homuth, Georg, Hottenga, Jouke-Jan, Murray, Robin M., Hulshoff Pol, Hilleke E., Ophoff, Roel A., Ikeda, Masashi, Jahanshad, Neda, Jockwitz, Christiane, Johansson, Stefan, Jönsson, Erik G., Jørgensen, Niklas R., Kikuchi, Masataka, Knowles, Emma E. M., Nielsen, Jacob, Kumar, Kuldeep, Le Hellard, Stephanie, Owen, Michael J., Leu, Costin, Linden, David E. J., Liu, Jingyu, Lundervold, Arvid, Lundervold, Astri Johansen, Maillard, Anne M., Martin, Nicholas G., Nordvik, Jan E., Martin-Brevet, Sandra, Mather, Karen A., Mathias, Samuel R., Paus, Tomas, McMahon, Katie L., McRae, Allan F., Medland, Sarah E., Meyer-Lindenberg, Andreas, Moberget, Torgeir, Nyberg, Lars, Helmholtz Association, European Commission, Netherlands Organization for Scientific Research, European Research Council, Knut and Alice Wallenberg Foundation, Innovative Medicines Initiative, European Federation of Pharmaceutical Industries and Associations, Science Foundation Ireland, Medical Research Council (UK), Wellcome Trust, Waterloo Foundation, National Institute of Mental Health (US), National Institutes of Health (US), Department of Health & Social Care (UK), NIHR Biomedical Research Centre (UK), NHS Foundation Trust, Harvard University, Massachusetts General Hospital, Swedish Research Council, Norwegian University of Science and Technology, Swedish Research Council for Sustainable Development, Kings College London, Federal Ministry of Education and Research (Germany), German Research Foundation, Agence Nationale de la Recherche (France), Fondation de France, Fondation pour la Recherche Médicale, Research Council of Norway, University of Bergen, European Science Foundation, National Health and Medical Research Council (Australia), Australian Research Council, Japan Agency for Medical Research and Development, Instituto de Salud Carlos III, Fundación Marques de Valdecilla, National Institute on Drug Abuse (US), Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), University of Greifswald, Mecklenburg-Western Pomerania, University of Oslo, Sønderby, Ida E., van der Meer, Dennis, Moreau, Clara, Kaufmann, Tobias, Bragi Walters, G., Ellegaard, Maria, Abdellaoui, Abdel, Ames, David, Amunts, Katrin, Andersson, Micael, Armstrong, Nicola J., Modenato, Claudia, Monereo Sánchez, Jennifer, Morris, Derek W., Mühleisen, Thomas W., Pausova, Zdenka, Olde Loohuis, Loes M., Peralta, Juan M., Pike, G. Bruce, Prieto, Carlos, Quinlan, Erin B., Wright, Margaret J., Reinbold, Céline S., Stefansson, Hreinn, Reis Marques, Tiago, Bernard, Manon, Rucker, James J. H., Sachdev, Perminder S., Sando, Sigrid B., Schofield, Peter R., Schork, Andrew J., Schumann, Gunter, Agartz, Ingrid, Shin, Jean, Shumskaya, Elena, Stefansson, Kari, Silva, Ana I., Sisodiya, Sanjay M., Blackburn, Nicholas B., Steen, Vidar M., Stein, Dan J., Strike, Lachlan T., Suzuki, Ikuo K., Djurovic, Srdjan, Tamnes, Christian K., Teumer, Alexander, Thalamuthu, Anbupalam, Jacquemont, Sébastien, Tordesillas-Gutiérrez, Diana, Uhlmann, Anne, Ulfarsson, Magnus O., Blangero, John, van't Ent, Dennis, van den Bree, Marianne B. M., Westlye, Lars T., Vanderhaeghen, Pierre, Vassos, Evangelos, Wen, Wei, Wittfeld, Katharina, Thompson, Paul M., Boomsma, Dorret I., Andreassen, Ole A., Brodaty, Henry, Brouwer, Rachel M., Bülow, Robin, Bøen, Rune, Groenewold, Nynke A., Cahn, Wiepke, Hashimoto, Ryota, Calhoun, Vincent, Caspers, Svenja, Ching, Christopher R. K., Cichon, Sven, Ciufolini, Simone, Crespo-Facorro, Benedicto, Curran, Joanne E., Dale, Anders M., Gústafsson, Ómar, Dalvie, Shareefa, Dazzan, Paola, Hehir-Kwa, Jayne Y., de Geus, de Geus, Zubicaray, Greig I. de, de Zwarte, Sonja M. C., Desrivieres, Sylvane, Doherty, Joanne L., Donohoe, Gary, Draganski, Bogdan, Haavik, Jan, Ehrlich, Stefan, Eising, Else, Espeseth, Thomas, Hibar, Derrek P., Fejgin, Kim, Fisher, Simon E., Fladby, Tormod, Frei, Oleksandr, Frouin, Vincent, Fukunaga, Masaki, Haberg, Asta K., Gareau, Thomas, Ge,Tian, Glahn, David C., Grabe, Hans-Jörgen, Hillegers, Manon H. J., Hall, Jeremy, Hoffmann, Per, Holleran, Laurena, Holmes, Avram J., Homuth, Georg, Hottenga, Jouke-Jan, Murray, Robin M., Hulshoff Pol, Hilleke E., Ophoff, Roel A., Ikeda, Masashi, Jahanshad, Neda, Jockwitz, Christiane, Johansson, Stefan, Jönsson, Erik G., Jørgensen, Niklas R., Kikuchi, Masataka, Knowles, Emma E. M., Nielsen, Jacob, Kumar, Kuldeep, Le Hellard, Stephanie, Owen, Michael J., Leu, Costin, Linden, David E. J., Liu, Jingyu, Lundervold, Arvid, Lundervold, Astri Johansen, Maillard, Anne M., Martin, Nicholas G., Nordvik, Jan E., Martin-Brevet, Sandra, Mather, Karen A., Mathias, Samuel R., Paus, Tomas, McMahon, Katie L., McRae, Allan F., Medland, Sarah E., Meyer-Lindenberg, Andreas, Moberget, Torgeir, and Nyberg, Lars

Abstract

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

Published
2021

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