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4. Data from Drug Sensitivity Prediction Models Reveal a Link between DNA Repair Defects and Poor Prognosis in HNSCC

Author

Conchita Vens, Marcel Verheij, Harry Bartelink, Michiel W.M. van den Brekel, Ruud H. Brakenhoff, C. René Leemans, Reinout H. de Roest, Emily M. Ploeg, Caroline V.M. Verhagen, Martijn van der Heijden, and Paul B.M. Essers

Abstract

Head and neck squamous cell carcinoma (HNSCC) is characterized by the frequent manifestation of DNA crosslink repair defects. We established novel expression-based DNA repair defect markers to determine the clinical impact of such repair defects. Using hypersensitivity to the DNA crosslinking agents, mitomycin C and olaparib, as proxies for functional DNA repair defects in a panel of 25 HNSCC cell lines, we applied machine learning to define gene expression models that predict repair defects. The expression profiles established predicted hypersensitivity to DNA-damaging agents and were associated with mutations in crosslink repair genes, as well as downregulation of DNA damage response and repair genes, in two independent datasets. The prognostic value of the repair defect prediction profiles was assessed in two retrospective cohorts with a total of 180 patients with advanced HPV-negative HNSCC, who were treated with cisplatin-based chemoradiotherapy. DNA repair defects, as predicted by the profiles, were associated with poor outcome in both patient cohorts. The poor prognosis association was particularly strong in normoxic tumor samples and was linked to an increased risk of distant metastasis. In vitro, only crosslink repair–defective HNSCC cell lines are highly migratory and invasive. This phenotype could also be induced in cells by inhibiting rad51 in repair competent and reduced by DNA-PK inhibition. In conclusion, DNA crosslink repair prediction expression profiles reveal a poor prognosis association in HNSCC.Significance:This study uses innovative machine learning-based approaches to derive models that predict the effect of DNA repair defects on treatment outcome in HNSCC.

Published
2023

5. Supplementary Data from Drug Sensitivity Prediction Models Reveal a Link between DNA Repair Defects and Poor Prognosis in HNSCC

Author

Conchita Vens, Marcel Verheij, Harry Bartelink, Michiel W.M. van den Brekel, Ruud H. Brakenhoff, C. René Leemans, Reinout H. de Roest, Emily M. Ploeg, Caroline V.M. Verhagen, Martijn van der Heijden, and Paul B.M. Essers

Abstract

Figure S1: Genetic alterations in the cell line panel. Figure S2: Strategy for internal cross validation of prediction performance. Figure S3: Cross validation at different drug sensitivity cutoffs. Figure S4: Mitomycin C and olaparib sensitivity in the CGP dataset. Figure S5: Relationship between model predictions and clinical parameters. Figure S6: Univariate analysis of variables used in multi-variate analyses. Figure S7: DNA repair defects and hypoxia share downstream effector pathways. Figure S8: Relation of DNA repair defects and cisplatin treatment. Figure S9: Prognostic value of the threeClass model ensemble. Figure S10. Multivariate analysis using disease stage as predictor. Figure S11: Rad51 inhibitor induced growth inhibition in DNA repair defective HNSCC cell lines. Figure S12: Inhibition of migration in scratch assays. Figure S13: Relationship between EMT and DNA repair defects.

Published
2023

8. Epithelial-to-mesenchymal transition is a prognostic marker for patient outcome in advanced stage HNSCC patients treated with chemoradiotherapy

Author

van der Heijden, Martijn, primary, Essers, Paul B.M., additional, Verhagen, Caroline V.M., additional, Willems, Stefan M., additional, Sanders, Joyce, additional, de Roest, Reinout H., additional, Vossen, David M., additional, Leemans, C. René, additional, Verheij, Marcel, additional, Brakenhoff, Ruud H., additional, van den Brekel, Michiel W.M., additional, and Vens, Conchita, additional

Published
2020
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9. Ovarian cancer‐derived copy number alterations signatures are prognostic in chemoradiotherapy‐treated head and neck squamous cell carcinoma

Author

Essers, Paul B.M., primary, Heijden, Martijn, additional, Vossen, David, additional, Roest, Reinout H., additional, Leemans, C. René, additional, Brakenhoff, Ruud H., additional, Brekel, Michiel W.M., additional, Bartelink, Harry, additional, Verheij, Marcel, additional, and Vens, Conchita, additional

Published
2020
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10. Genetic factors associated with a poor outcome in head and neck cancer patients receiving definitive chemoradiotherapy

Author

Vossen, David M. (author), Verhagen, Caroline V.M. (author), van der Heijden, Martijn (author), Essers, Paul B.M. (author), Bartelink, Harry (author), Verheij, Marcel (author), Wessels, L.F.A. (author), van den Brekel, Michiel W.M. (author), Vens, Conchita (author), Vossen, David M. (author), Verhagen, Caroline V.M. (author), van der Heijden, Martijn (author), Essers, Paul B.M. (author), Bartelink, Harry (author), Verheij, Marcel (author), Wessels, L.F.A. (author), van den Brekel, Michiel W.M. (author), and Vens, Conchita (author)

Abstract

About half of advanced stage head and neck squamous cell carcinoma (HNSCC) patients can be cured by chemoradiotherapy. Patient outcome may be partially determined by the genetic alterations in HNSCC, rendering these alterations promising candidate prognostic factors and/or therapeutic targets. However, their relevance in patient outcome prognosis remains to be assessed in patients that receive standard-of-care chemoradiotherapy. We therefore tested whether frequent genetic alterations were associated with progression free survival (PFS) in advanced stage HNSCC patients who were uniformly treated with definitive platinum-based chemoradiotherapy. To this end, we performed targeted DNA sequencing on frozen pre-treatment tumor biopsy material from 77 patients with advanced stage oro- and hypopharyngeal carcinoma. This provided somatic point mutation and copy number aberration data of 556 genes. The most frequently mutated genes, TP53 (62%), CCND1 (51%), CDKN2A (30%) and PIK3CA (21%), were not associated with PFS. However, co-occurring CCND1 and CDKN2A mutations were associated with short PFS (HR 2.24, p = 0.028) in HPV-negative tumors. Furthermore, tumor mutational burden (sum of somatic point mutations) showed a trend towards decreased PFS (HR 1.9, p = 0.089), and chromosomal instability (CIN) was associated with shorter PFS (HR 2.3, p = 0.023), independent of HPV status. Our results show that tumor mutational burden, CIN markers, and co-occurring CCND1 and CDKN2A mutations are associated with chemoradiotherapy outcomes in advanced stage oro- and hypopharyngeal HNSCC patients, thereby highlighting their prognostic potential. Given their poor prognosis association and link to biological targets, they may also identify patients for novel targeted therapies and immunotherapies, Pattern Recognition and Bioinformatics

Published
2019
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11. Drug Sensitivity Prediction Models Reveal a Link between DNA Repair Defects and Poor Prognosis in HNSCC

Author

Essers, Paul B.M., primary, van der Heijden, Martijn, additional, Verhagen, Caroline V.M., additional, Ploeg, Emily M., additional, de Roest, Reinout H., additional, Leemans, C. René, additional, Brakenhoff, Ruud H., additional, van den Brekel, Michiel W.M., additional, Bartelink, Harry, additional, Verheij, Marcel, additional, and Vens, Conchita, additional

Published
2019
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16. Potential Impact of Alternative Agricultural Technologies to Ensure Food Security and Raise Income of Farm Households in Rwanda.

Author

Bidogeza, Jean-Claude, Berentsen, Paul B.M., de Graaff, Jan, and Oude Lansink, Alfons

Subjects
*AGRICULTURAL innovations, *AGROTECHNOLOGY transfer, *TECHNOLOGICAL innovations, *FOOD security
Abstract

Rapid population growth and stagnation of agricultural yields in Rwanda have caused a steady decline in food production per capita, a continuous expansion towards the use of marginal land and a strong degradation of land. The challenge of simultaneously achieving food security, rural welfare, land protection and soil fertility regeneration in the face of its high population is overwhelming to Rwanda. The objectives of this article are to assess the potential impacts of the alternative agricultural technologies on income, food production and soil loss for four arable farm household types and to assess policies that could induce adoption of these technologies. These include combined use ofTithonia diversifolia(green manure) and Diammonium phosphate. The bio-economic farm household model used has a form of a mathematical form of quadratic programming model. Model results show that these alternative agricultural technologies will clearly enhance food production and income for all farm household types except the full-time farm household for which cash at the beginning of the season is too restricted to switch to the new technologies. The outcomes of the model also reveal that with alternative technologies soil loss and soil organic carbon do not entail negative economic consequences. Off-farm employment policy will have a high impact on adoption among households with small farms and less off-farm opportunities because it provides cash that is needed to adopt the new technologies. [ABSTRACT FROM AUTHOR]

Published
2015
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17. Guideline adherence and health outcomes in diabetes mellitus type 2 patients: a cross-sectional study.

Author

Oude Wesselink, Sandra F., Lingsma, Hester F., Robben, Paul B.M., and Mackenbach, Johan P.

Subjects
PEOPLE with diabetes, HEALTH of patients, PATIENT compliance, BLOOD pressure, EYE examination
Abstract

Background: The complex disease of diabetes mellitus type 2 (T2DM) requires a high standard of quality of care. Clinical practice guidelines define norms for diabetes care that ensure regular monitoring of T2DM patients, including annual diagnostic tests. This study aims to quantify guideline adherence in Dutch general practices providing care to T2DM patients and explores the association between guideline adherence and patients' health outcomes. Methods: In this cross-sectional study, we studied 363 T2DM patients in 32 general practices in 2011 and 2012. Guideline adherence was measured by comparing structure and process indicators of care with recommendations in the national diabetes care guideline. Health outcomes included biomedical measures and health behaviours. Data was extracted from medical records. The association between guideline adherence and health outcomes was analysed using hierarchical linear and logistic regression models. Results: Guideline adherence varied between different recommendations. For example 53% of the practices had a system for collecting patient experience feedback, while 97% had a policy for no-show patients. With regard to process indicators of care, guideline adherence was below 50% for foot, eye and urine albumin examination and high (>85%) for blood pressure, HbA1c and smoking behaviour assessment. Although guideline adherence varied considerably between practices, after adjusting for patient characteristics we found guideline adherence not to be associated with patients' health outcomes. Conclusions: Guideline adherence in Dutch general practices offering diabetes care was not optimal. Despite considerable variations between general practices, we found no clear relationship between guideline adherence and health outcomes. More research is needed to better understand the relationship between guideline adherence and health outcomes, specifically for guidelines that are based on limited scientific evidence. [ABSTRACT FROM AUTHOR]

Published
2015
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18. Genetic Factors Associated with a Poor Outcome in Head and Neck Cancer Patients Receiving Definitive Chemoradiotherapy.

Author

Vossen, David M., Verhagen, Caroline V.M., van der Heijden, Martijn, Essers, Paul B.M., Bartelink, Harry, Verheij, Marcel, Wessels, Lodewyk F.A., van den Brekel, Michiel W.M., and Vens, Conchita

Subjects
DNA analysis, BIOPSY, CANCER patients, GENETICS, EVALUATION of medical care, GENETIC mutation, HEAD & neck cancer, PHARYNX tumors, RESEARCH funding, DESCRIPTIVE statistics, SQUAMOUS cell carcinoma, SEQUENCE analysis, ODDS ratio, CHEMORADIOTHERAPY, PROGNOSIS
Abstract

About half of advanced stage head and neck squamous cell carcinoma (HNSCC) patients can be cured by chemoradiotherapy. Patient outcome may be partially determined by the genetic alterations in HNSCC, rendering these alterations promising candidate prognostic factors and/or therapeutic targets. However, their relevance in patient outcome prognosis remains to be assessed in patients that receive standard-of-care chemoradiotherapy. We therefore tested whether frequent genetic alterations were associated with progression free survival (PFS) in advanced stage HNSCC patients who were uniformly treated with definitive platinum-based chemoradiotherapy. To this end, we performed targeted DNA sequencing on frozen pre-treatment tumor biopsy material from 77 patients with advanced stage oro- and hypopharyngeal carcinoma. This provided somatic point mutation and copy number aberration data of 556 genes. The most frequently mutated genes, TP53 (62%), CCND1 (51%), CDKN2A (30%) and PIK3CA (21%), were not associated with PFS. However, co-occurring CCND1 and CDKN2A mutations were associated with short PFS (HR 2.24, p = 0.028) in HPV-negative tumors. Furthermore, tumor mutational burden (sum of somatic point mutations) showed a trend towards decreased PFS (HR 1.9, p = 0.089), and chromosomal instability (CIN) was associated with shorter PFS (HR 2.3, p = 0.023), independent of HPV status. Our results show that tumor mutational burden, CIN markers, and co-occurring CCND1 and CDKN2A mutations are associated with chemoradiotherapy outcomes in advanced stage oro- and hypopharyngeal HNSCC patients, thereby highlighting their prognostic potential. Given their poor prognosis association and link to biological targets, they may also identify patients for novel targeted therapies and immunotherapies. [ABSTRACT FROM AUTHOR]

Published
2019
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19. Effects of eight neuropsychiatric copy number variants on human brain structure

Author

Modenato, C., Kumar, K., Moreau, C., Martin-Brevet, S., Huguet, G., Schramm, C., Jean-Louis, M., Martin, C. -O., Younis, N., Tamer, P., Douard, E., Thebault-Dagher, F., Cote, V., Charlebois, A. -R., Deguire, F., Maillard, A. M., Rodriguez-Herreros, B., Pain, A., Richetin, S., Addor, M. -C., Andrieux, J., Arveiler, B., Baujat, G., Sloan-Bena, F., Belfiore, M., Bonneau, D., Bouquillon, S., Boute, O., Brusco, A., Busa, T., Caberg, J. -H., Campion, D., Colombert, V., Cordier, M. -P., David, A., Debray, F. -G., Delrue, M. -A., Doco-Fenzy, M., Dunkhase-Heinl, U., Edery, P., Fagerberg, C., Faivre, L., Forzano, F., Genevieve, D., Gerard, M., Giachino, D., Guichet, A., Guillin, O., Heron, D., Isidor, B., Jacquette, A., Jaillard, S., Journel, H., Keren, B., Lacombe, D., Lebon, S., Le Caignec, C., Lemaitre, M. -P., Lespinasse, J., Mathieu-Dramart, M., Mercier, S., Mignot, C., Missirian, C., Petit, F., Pilekaer Sorensen, K., Pinson, L., Plessis, G., Prieur, F., Raymond, A., Rooryck-Thambo, C., Rossi, M., Sanlaville, D., Schlott Kristiansen, B., Schluth-Bolard, C., Till, M., Van Haelst, M., Van Maldergem, L., Alupay, H., Aaronson, B., Ackerman, S., Ankenman, K., Anwar, A., Atwell, C., Bowe, A., Beaudet, A. L., Benedetti, M., Berg, J., Berman, J., Berry, L. N., Bibb, A. L., Blaskey, L., Brennan, J., Brewton, C. M., Buckner, R., Bukshpun, P., Burko, J., Cali, P., Cerban, B., Chang, Y., Cheong, M., Chow, V., Chu, Z., Chudnovskaya, D., Cornew, L., Dale, C., Dell, J., Dempsey, A. G., Deschamps, T., Earl, R., Edgar, J., Elgin, J., Olson, J. E., Evans, Y. L., Findlay, A., Fischbach, G. D., Fisk, C., Fregeau, B., Gaetz, B., Gaetz, L., Garza, S., Gerdts, J., Glenn, O., Gobuty, S. E., Golembski, R., Greenup, M., Heiken, K., Hines, K., Hinkley, L., Jackson, F. I., Jenkins, J., Jeremy, R. J., Johnson, K., Kanne, S. M., Kessler, S., Khan, S. Y., Ku, M., Kuschner, E., Laakman, A. L., Lam, P., Lasala, M. W., Lee, H., Laguerre, K., Levy, S., Cavanagh, A. L., Llorens, A. V., Campe, K. L., Luks, T. L., Marco, E. J., Martin, S., Martin, A. J., Marzano, G., Masson, C., Mcgovern, K. E., Keehn, R. M. N., Miller, D. T., Miller, F. K., Moss, T. J., Murray, R., Nagarajan, S. S., Nowell, K. P., Owen, J., Paal, A. M., Packer, A., Page, P. Z., Paul, B. M., Peters, A., Peterson, D., Poduri, A., Pojman, N. J., Porche, K., Proud, M. B., Qasmieh, S., Ramocki, M. B., Reilly, B., Roberts, T. P. L., Shaw, D., Sinha, T., Smith-Packard, B., Gallagher, A. S., Swarnakar, V., Thieu, T., Triantafallou, C., Vaughan, R., Wakahiro, M., Wallace, A., Ward, T., Wenegrat, J., Wolken, A., Melie-Garcia, L., Kushan, L., Silva, A. I., van den Bree, M. B. M., Linden, D. E. J., Owen, M. J., Hall, J., Lippe, S., Chakravarty, M., Bzdok, D., Bearden, C. E., Draganski, B., Jacquemont, S., Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), 16p11.2 European Consortium, Simons Searchlight Consortium, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, School for Mental Health & Neuroscience, RS: MHeNs - R3 - Neuroscience, Addor, M.C., Andrieux, J., Arveiler, B., Baujat, G., Sloan-Béna, F., Belfiore, M., Bonneau, D., Bouquillon, S., Boute, O., Brusco, A., Busa, T., Caberg, J.H., Campion, D., Colombert, V., Cordier, M.P., David, A., Debray, F.G., Delrue, M.A., Doco-Fenzy, M., Dunkhase-Heinl, U., Edery, P., Fagerberg, C., Faivre, L., Forzano, F., Genevieve, D., Gérard, M., Giachino, D., Guichet, A., Guillin, O., Héron, D., Isidor, B., Jacquette, A., Jaillard, S., Journel, H., Keren, B., Lacombe, D., Lebon, S., Le Caignec, C., Lemaître, M.P., Lespinasse, J., Mathieu-Dramart, M., Mercier, S., Mignot, C., Missirian, C., Petit, F., Pilekær Sørensen, K., Pinson, L., Plessis, G., Prieur, F., Raymond, A., Rooryck-Thambo, C., Rossi, M., Sanlaville, D., Schlott Kristiansen, B., Schluth-Bolard, C., Till, M., Van Haelst, M., Van Maldergem, L., Alupay, H., Aaronson, B., Ackerman, S., Ankenman, K., Anwar, A., Atwell, C., Bowe, A., Beaudet, A.L., Benedetti, M., Berg, J., Berman, J., Berry, L.N., Bibb, A.L., Blaskey, L., Brennan, J., Brewton, C.M., Buckner, R., Bukshpun, P., Burko, J., Cali, P., Cerban, B., Chang, Y., Cheong, M., Chow, V., Chu, Z., Chudnovskaya, D., Cornew, L., Dale, C., Dell, J., Dempsey, A.G., Deschamps, T., Earl, R., Edgar, J., Elgin, J., Olson, J.E., Evans, Y.L., Findlay, A., Fischbach, G.D., Fisk, C., Fregeau, B., Gaetz, B., Gaetz, L., Garza, S., Gerdts, J., Glenn, O., Gobuty, S.E., Golembski, R., Greenup, M., Heiken, K., Hines, K., Hinkley, L., Jackson, F.I., Jenkins, J., Jeremy, R.J., Johnson, K., Kanne, S.M., Kessler, S., Khan, S.Y., Ku, M., Kuschner, E., Laakman, A.L., Lam, P., Lasala, M.W., Lee, H., LaGuerre, K., Levy, S., Cavanagh, A.L., Llorens, A.V., Campe, K.L., Luks, T.L., Marco, E.J., Martin, S., Martin, A.J., Marzano, G., Masson, C., McGovern, K.E., Keehn, R.M., Miller, D.T., Miller, F.K., Moss, T.J., Murray, R., Nagarajan, S.S., Nowell, K.P., Owen, J., Paal, A.M., Packer, A., Page, P.Z., Paul, B.M., Peters, A., Peterson, D., Poduri, A., Pojman, N.J., Porche, K., Proud, M.B., Qasmieh, S., Ramocki, M.B., Reilly, B., Roberts, TPL, Shaw, D., Sinha, T., Smith-Packard, B., Gallagher, A.S., Swarnakar, V., Thieu, T., Triantafallou, C., Vaughan, R., Wakahiro, M., Wallace, A., Ward, T., Wenegrat, J., and Wolken, A.

Subjects
0301 basic medicine, Simons Searchlight Consortium, Autism, 0302 clinical medicine, Gyrus, Gene duplication, 2.1 Biological and endogenous factors, Psychology, Copy-number variation, Aetiology, Genetics, Brain, Human brain, Magnetic Resonance Imaging, Psychiatry and Mental health, Mental Health, medicine.anatomical_structure, Schizophrenia, Neurological, Public Health and Health Services, RC321-571, DNA Copy Number Variations, Intellectual and Developmental Disabilities (IDD), Clinical Sciences, 16p11.2 European Consortium, Neurosciences. Biological psychiatry. Neuropsychiatry, Neuroimaging, Biology, Basic Behavioral and Social Science, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Clinical Research, Behavioral and Social Science, mental disorders, medicine, Humans, 22Q11.2 DELETION SYNDROME, Clinical genetics, AUTISM, COMMON, Biological Psychiatry, Prevention, Human Genome, Brain morphometry, Neurosciences, medicine.disease, DUPLICATION, Brain Disorders, 030104 developmental biology, 030217 neurology & neurosurgery, Neuroscience
Abstract

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions.

Published
2021

20. Quantifying the effects of 16p11.2 copy number variants on brain structure: A multisite genetic-first study

Author

Sandra Martin-Brevet, Borja Rodríguez-Herreros, Jared A. Nielsen, Clara Moreau, Claudia Modenato, Anne M. Maillard, Aurélie Pain, Sonia Richetin, Aia E. Jønch, Abid Y. Qureshi, Nicole R. Zürcher, Philippe Conus, Wendy K. Chung, Elliott H. Sherr, John E. Spiro, Ferath Kherif, Jacques S. Beckmann, Nouchine Hadjikhani, Alexandre Reymond, Randy L. Buckner, Bogdan Draganski, Sébastien Jacquemont, Marie-Claude Addor, Joris Andrieux, Benoît Arveiler, Geneviève Baujat, Frédérique Sloan-Béna, Marco Belfiore, Dominique Bonneau, Sonia Bouquillon, Odile Boute, Alfredo Brusco, Tiffany Busa, Jean-Hubert Caberg, Dominique Campion, Vanessa Colombert, Marie-Pierre Cordier, Albert David, François-Guillaume Debray, Marie-Ange Delrue, Martine Doco-Fenzy, Ulrike Dunkhase-Heinl, Patrick Edery, Christina Fagerberg, Laurence Faivre, Francesca Forzano, David Genevieve, Marion Gérard, Daniela Giachino, Agnès Guichet, Olivier Guillin, Delphine Héron, Bertrand Isidor, Aurélia Jacquette, Sylvie Jaillard, Hubert Journel, Boris Keren, Didier Lacombe, Sébastien Lebon, Cédric Le Caignec, Marie-Pierre Lemaître, James Lespinasse, Michèle Mathieu-Dramart, Sandra Mercier, Cyril Mignot, Chantal Missirian, Florence Petit, Kristina Pilekær Sørensen, Lucile Pinson, Ghislaine Plessis, Fabienne Prieur, Caroline Rooryck-Thambo, Massimiliano Rossi, Damien Sanlaville, Britta Schlott Kristiansen, Caroline Schluth-Bolard, Marianne Till, Mieke Van Haelst, Lionel Van Maldergem, Hanalore Alupay, Benjamin Aaronson, Sean Ackerman, Katy Ankenman, Ayesha Anwar, Constance Atwell, Alexandra Bowe, Arthur L. Beaudet, Marta Benedetti, Jessica Berg, Jeffrey Berman, Leandra N. Berry, Audrey L. Bibb, Lisa Blaskey, Jonathan Brennan, Christie M. Brewton, Randy Buckner, Polina Bukshpun, Jordan Burko, Phil Cali, Bettina Cerban, Yishin Chang, Maxwell Cheong, Vivian Chow, Zili Chu, Darina Chudnovskaya, Lauren Cornew, Corby Dale, John Dell, Allison G. Dempsey, Trent Deschamps, Rachel Earl, James Edgar, Jenna Elgin, Jennifer Endre Olson, Yolanda L. Evans, Anne Findlay, Gerald D. Fischbach, Charlie Fisk, Brieana Fregeau, Bill Gaetz, Leah Gaetz, Silvia Garza, Jennifer Gerdts, Orit Glenn, Sarah E. Gobuty, Rachel Golembski, Marion Greenup, Kory Heiken, Katherine Hines, Leighton Hinkley, Frank I. Jackson, Julian Jenkins, Rita J. Jeremy, Kelly Johnson, Stephen M. Kanne, Sudha Kessler, Sarah Y. Khan, Matthew Ku, Emily Kuschner, Anna L. Laakman, Peter Lam, Morgan W. Lasala, Hana Lee, Kevin LaGuerre, Susan Levy, Alyss Lian Cavanagh, Ashlie V. Llorens, Katherine Loftus Campe, Tracy L. Luks, Elysa J. Marco, Stephen Martin, Alastair J. Martin, Gabriela Marzano, Christina Masson, Kathleen E. McGovern, Rebecca McNally Keehn, David T. Miller, Fiona K. Miller, Timothy J. Moss, Rebecca Murray, Srikantan S. Nagarajan, Kerri P. Nowell, Julia Owen, Andrea M. Paal, Alan Packer, Patricia Z. Page, Brianna M. Paul, Alana Peters, Danica Peterson, Annapurna Poduri, Nicholas J. Pojman, Ken Porche, Monica B. Proud, Saba Qasmieh, Melissa B. Ramocki, Beau Reilly, Timothy P.L. Roberts, Dennis Shaw, Tuhin Sinha, Bethanny Smith-Packard, Anne Snow Gallagher, Vivek Swarnakar, Tony Thieu, Christina Triantafallou, Roger Vaughan, Mari Wakahiro, Arianne Wallace, Tracey Ward, Julia Wenegrat, Anne Wolken, 16p11.2 European Consortium, Simons Variation in Individuals Project (VIP) Consortium, CSIR-Institute of Microbial Technology [Chandigarh] (IMTech), Council of Scientific and Industrial Research [India] (CSIR), Service Hospitalier Frédéric Joliot (SHFJ), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Human Genetics, Gillberg Neuropsychiatry Centre [Göteborg, Sueden], Institute of Neuroscience and Physiology [Göteborg]-University of Gothenburg (GU), The Wellcome Trust Sanger Institute [Cambridge], Department of Psychiatry [Boston], Massachusetts General Hospital [Boston], Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Laboratoire de Génétique Clinique, Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Génétique Humaine, Développement et Cancer, Université Bordeaux Segalen - Bordeaux 2, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Guglielmo Marconi University [Roma], Laboratoire de biomécanique (LBM), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13), Systèmes de Référence Temps Espace (SYRTE), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Medical Sciences, Università degli studi di Torino (UNITO), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Liège (CHU-Liège), Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Department of Clinical Genetics, Vejle Hospital, Institute of Child Health, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Génétique Médicale, Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA)-Hôpital Chubert, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Génétique Chromosomique, Bâtiment Hôtel Dieu - Centre Hospitalier de Chambéry, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Service de génétique, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne, CHU Bordeaux [Bordeaux], Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Department of Genomics of Common Disease, Imperial College London, Regional Hospital, Department of Psychiatry and Behavioral Sciences! (UW psychiatry), University of Washington [Seattle], University of California, San Francisco (UCSF), UCSF, Unité de Recherches Zootechniques (URZ), Institut National de la Recherche Agronomique (INRA), University of California [San Francisco] (UCSF), University of California, UCL Institute of Neurology, Biomagnetic Imaging Laboratory - University of California, SFARI219193, Simons Foundation, 31003A160203, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Roger De Spoelberch, Partridge Foundations, Jeanne et Jean Louis Levesque Foundation, 604102, Seventh Framework Programme, Canada Research Chairs, CRSII33-133044, SNSF Sinergia, 32003B_159780, SNSF National Centre of Competence in Research Synapsy, Foundation Parkinson Switzerland, Foundation Synapsis, Université de Lausanne = University of Lausanne (UNIL), CHU Sainte Justine [Montréal], Harvard University [Cambridge], Odense University Hospital (OUH), Department of radiology (Massachusetts General Hospital), Department of Psychiatry Massachusetts General Hospital (MGH), Columbia University [New York], Simons Foundation, University of California [San Francisco] (UC San Francisco), University of California (UC), University of Gothenburg (GU), Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Torino = University of Turin (UNITO), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vejle Hospital [Danemark], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Harvard University, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), University of Lausanne (UNIL), Centre de recherche du CHU Sainte-Justine [Montreal], Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Human genetics, Institute of Microbial Technology (IMTECH), Intitute of Microbial Technology, Gillberg Neuropsychiatry Centre, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], PSL Research University (PSL)-PSL Research University (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Bretagne Atlantique-Hôpital Chubert, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Pitié-Salpêtrière [APHP], Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Addor, M.C., Andrieux, J., Arveiler, B., Baujat, G., Sloan-Béna, F., Belfiore, M., Bonneau, D., Bouquillon, S., Boute, O., Brusco, A., Busa, T., Caberg, J.H., Campion, D., Colombert, V., Cordier, M.P., David, A., Debray, F.G., Delrue, M.A., Doco-Fenzy, M., Dunkhase-Heinl, U., Edery, P., Fagerberg, C., Faivre, L., Forzano, F., Genevieve, D., Gérard, M., Giachino, D., Guichet, A., Guillin, O., Héron, D., Isidor, B., Jacquette, A., Jaillard, S., Journel, H., Keren, B., Lacombe, D., Lebon, S., Le Caignec, C., Lemaître, M.P., Lespinasse, J., Mathieu-Dramart, M., Mercier, S., Mignot, C., Missirian, C., Petit, F., Pilekær Sørensen, K., Pinson, L., Plessis, G., Prieur, F., Rooryck-Thambo, C., Rossi, M., Sanlaville, D., Schlott Kristiansen, B., Schluth-Bolard, C., Till, M., Van Haelst, M., Van Maldergem, L., Alupay, H., Aaronson, B., Ackerman, S., Ankenman, K., Anwar, A., Atwell, C., Bowe, A., Beaudet, A.L., Benedetti, M., Berg, J., Berman, J., Berry, L.N., Bibb, A.L., Blaskey, L., Brennan, J., Brewton, C.M., Buckner, R., Bukshpun, P., Burko, J., Cali, P., Cerban, B., Chang, Y., Cheong, M., Chow, V., Chu, Z., Chudnovskaya, D., Cornew, L., Dale, C., Dell, J., Dempsey, A.G., Deschamps, T., Earl, R., Edgar, J., Elgin, J., Olson, J.E., Evans, Y.L., Findlay, A., Fischbach, G.D., Fisk, C., Fregeau, B., Gaetz, B., Gaetz, L., Garza, S., Gerdts, J., Glenn, O., Gobuty, S.E., Golembski, R., Greenup, M., Heiken, K., Hines, K., Hinkley, L., Jackson, F.I., Jenkins, J., Jeremy, R.J., Johnson, K., Kanne, S.M., Kessler, S., Khan, S.Y., Ku, M., Kuschner, E., Laakman, A.L., Lam, P., Lasala, M.W., Lee, H., LaGuerre, K., Levy, S., Cavanagh, A.L., Llorens, A.V., Campe, K.L., Luks, T.L., Marco, E.J., Martin, S., Martin, A.J., Marzano, G., Masson, C., McGovern, K.E., McNally Keehn, R., Miller, D.T., Miller, F.K., Moss, T.J., Murray, R., Nagarajan, S.S., Nowell, K.P., Owen, J., Paal, A.M., Packer, A., Page, P.Z., Paul, B.M., Peters, A., Peterson, D., Poduri, A., Pojman, N.J., Porche, K., Proud, M.B., Qasmieh, S., Ramocki, M.B., Reilly, B., Roberts, TPL, Shaw, D., Sinha, T., Smith-Packard, B., Gallagher, A.S., Swarnakar, V., Thieu, T., Triantafallou, C., Vaughan, R., Wakahiro, M., Wallace, A., Ward, T., Wenegrat, J., and Wolken, A.

Subjects
Adult, Male, 0301 basic medicine, Adolescent, DNA Copy Number Variations, [SDV]Life Sciences [q-bio], Autism Spectrum Disorder/diagnostic imaging, Autism Spectrum Disorder/genetics, Brain/pathology, Child, Chromosome Deletion, Chromosome Duplication, Chromosomes, Human, Pair 16/genetics, Cognitive Dysfunction/diagnostic imaging, Cognitive Dysfunction/genetics, Female, Humans, Intellectual Disability/diagnostic imaging, Intellectual Disability/genetics, Language, Magnetic Resonance Imaging, Middle Aged, Neurodevelopmental Disorders/diagnostic imaging, Neurodevelopmental Disorders/genetics, Schizophrenia/diagnostic imaging, Schizophrenia/genetics, Young Adult, 16p11.2, Autism spectrum disorder, Copy number variant, Genetics, Imaging, Neurodevelopmental disorders, Biology, Biological Psychiatry, 03 medical and health sciences, 0302 clinical medicine, Transverse temporal gyrus, Neuroimaging, Intellectual Disability, medicine, Cognitive Dysfunction, Copy-number variation, ComputingMilieux_MISCELLANEOUS, Brain morphometry, Brain, medicine.disease, 16p112, 030104 developmental biology, Schizophrenia, Williams syndrome, Neuroscience, Insula, Chromosomes, Human, Pair 16, 030217 neurology & neurosurgery
Abstract

BACKGROUND: 16p11.2 breakpoint 4 to 5 copy number variants (CNVs) increase the risk for developing autism spectrum disorder, schizophrenia, and language and cognitive impairment. In this multisite study, we aimed to quantify the effect of 16p11.2 CNVs on brain structure.METHODS: Using voxel- and surface-based brain morphometric methods, we analyzed structural magnetic resonance imaging collected at seven sites from 78 individuals with a deletion, 71 individuals with a duplication, and 212 individuals without a CNV.RESULTS: Beyond the 16p11.2-related mirror effect on global brain morphometry, we observe regional mirror differences in the insula (deletion > control > duplication). Other regions are preferentially affected by either the deletion or the duplication: the calcarine cortex and transverse temporal gyrus (deletion > control; Cohen's d > 1), the superior and middle temporal gyri (deletion < control; Cohen's d < -1), and the caudate and hippocampus (control > duplication; -0.5 > Cohen's d > -1). Measures of cognition, language, and social responsiveness and the presence of psychiatric diagnoses do not influence these results.CONCLUSIONS: The global and regional effects on brain morphometry due to 16p11.2 CNVs generalize across site, computational method, age, and sex. Effect sizes on neuroimaging and cognitive traits are comparable. Findings partially overlap with results of meta-analyses performed across psychiatric disorders. However, the lack of correlation between morphometric and clinical measures suggests that CNV-associated brain changes contribute to clinical manifestations but require additional factors for the development of the disorder. These findings highlight the power of genetic risk factors as a complement to studying groups defined by behavioral criteria.

Published
2018

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