Multicenter Study

. 2018 Aug 15;84(4):253-264.

doi: 10.1016/j.biopsych.2018.02.1176. Epub 2018 Mar 27.

Quantifying the Effects of 16p11.2 Copy Number Variants on Brain Structure: A Multisite Genetic-First Study

Sandra Martin-Brevet¹, Borja Rodríguez-Herreros², Jared A Nielsen³, Clara Moreau⁴, Claudia Modenato¹, Anne M Maillard⁵, Aurélie Pain⁵, Sonia Richetin⁶, Aia E Jønch⁷, Abid Y Qureshi⁸, Nicole R Zürcher⁹, Philippe Conus¹⁰; 16p11.2 European Consortium; Simons Variation in Individuals Project (VIP) Consortium; Wendy K Chung¹¹, Elliott H Sherr¹², John E Spiro¹³, Ferath Kherif¹⁴, Jacques S Beckmann⁶, Nouchine Hadjikhani¹⁵, Alexandre Reymond¹⁶, Randy L Buckner¹⁷, Bogdan Draganski¹⁸, Sébastien Jacquemont¹⁹

Collaborators, Affiliations

Collaborators

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 3rd, 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

Affiliations

¹ Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; Laboratoire de Recherche en Neuroimagerie, Département des neurosciences cliniques, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
² Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; CHU Sainte-Justine Research Center, Université de Montréal, Montréal, Quebec, Canada.
³ Department of Psychology, Harvard University, Cambridge, Massachusetts; Center for Brain Science, Harvard University, Cambridge, Massachusetts; Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts.
⁴ CHU Sainte-Justine Research Center, Université de Montréal, Montréal, Quebec, Canada.
⁵ Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; Centre Cantonal Autisme, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
⁶ Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
⁷ CHU Sainte-Justine Research Center, Université de Montréal, Montréal, Quebec, Canada; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark; Human Genetics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
⁸ Center for Brain Science, Harvard University, Cambridge, Massachusetts; Department of Neurology, University of Kansas Medical Center, Kansas City, KS.
⁹ Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
¹⁰ Service of General Psychiatry, Department of Psychiatry, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
¹¹ Simons Foundation, New York, New York; Departments of Pediatrics and Medicine, Columbia University, New York, New York.
¹² Department of Neurology, Department of Pediatrics, and Weill Institute for Neurosciences, University of California, San Francisco, California.
¹³ Simons Foundation, New York, New York.
¹⁴ Laboratoire de Recherche en Neuroimagerie, Département des neurosciences cliniques, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
¹⁵ Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden.
¹⁶ Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
¹⁷ Department of Psychology, Harvard University, Cambridge, Massachusetts; Center for Brain Science, Harvard University, Cambridge, Massachusetts; Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
¹⁸ Laboratoire de Recherche en Neuroimagerie, Département des neurosciences cliniques, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
¹⁹ Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; CHU Sainte-Justine Research Center, Université de Montréal, Montréal, Quebec, Canada. Electronic address: sebastien.jacquemont@umontreal.ca.

PMID: 29778275
DOI: 10.1016/j.biopsych.2018.02.1176

Free article

Multicenter Study

Quantifying the Effects of 16p11.2 Copy Number Variants on Brain Structure: A Multisite Genetic-First Study

Sandra Martin-Brevet et al. Biol Psychiatry. 2018.

Free article

. 2018 Aug 15;84(4):253-264.

doi: 10.1016/j.biopsych.2018.02.1176. Epub 2018 Mar 27.

Authors

Collaborators

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 3rd, 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

Affiliations

¹ Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; Laboratoire de Recherche en Neuroimagerie, Département des neurosciences cliniques, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
² Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; CHU Sainte-Justine Research Center, Université de Montréal, Montréal, Quebec, Canada.
³ Department of Psychology, Harvard University, Cambridge, Massachusetts; Center for Brain Science, Harvard University, Cambridge, Massachusetts; Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts.
⁴ CHU Sainte-Justine Research Center, Université de Montréal, Montréal, Quebec, Canada.
⁵ Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; Centre Cantonal Autisme, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
⁶ Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
⁷ CHU Sainte-Justine Research Center, Université de Montréal, Montréal, Quebec, Canada; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark; Human Genetics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
⁸ Center for Brain Science, Harvard University, Cambridge, Massachusetts; Department of Neurology, University of Kansas Medical Center, Kansas City, KS.
⁹ Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
¹⁰ Service of General Psychiatry, Department of Psychiatry, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
¹¹ Simons Foundation, New York, New York; Departments of Pediatrics and Medicine, Columbia University, New York, New York.
¹² Department of Neurology, Department of Pediatrics, and Weill Institute for Neurosciences, University of California, San Francisco, California.
¹³ Simons Foundation, New York, New York.
¹⁴ Laboratoire de Recherche en Neuroimagerie, Département des neurosciences cliniques, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
¹⁵ Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden.
¹⁶ Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
¹⁷ Department of Psychology, Harvard University, Cambridge, Massachusetts; Center for Brain Science, Harvard University, Cambridge, Massachusetts; Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts; Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
¹⁸ Laboratoire de Recherche en Neuroimagerie, Département des neurosciences cliniques, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany.
¹⁹ Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; CHU Sainte-Justine Research Center, Université de Montréal, Montréal, Quebec, Canada. Electronic address: sebastien.jacquemont@umontreal.ca.

PMID: 29778275
DOI: 10.1016/j.biopsych.2018.02.1176

Erratum in

Erratum.
[No authors listed] [No authors listed] Biol Psychiatry. 2020 Jun 15;87(12):1084. doi: 10.1016/j.biopsych.2020.04.020. Biol Psychiatry. 2020. PMID: 32498790 No abstract available.

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.

Keywords: 16p11.2; Autism spectrum disorder; Copy number variant; Genetics; Imaging; Neurodevelopmental disorders.

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Comment in

Genetics-First Approaches in Biological Psychiatry.
Raznahan A. Raznahan A. Biol Psychiatry. 2018 Aug 15;84(4):234-235. doi: 10.1016/j.biopsych.2018.06.008. Biol Psychiatry. 2018. PMID: 30071946 No abstract available.

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Quantifying the Effects of 16p11.2 Copy Number Variants on Brain Structure: A Multisite Genetic-First Study

Collaborators

Affiliations

Quantifying the Effects of 16p11.2 Copy Number Variants on Brain Structure: A Multisite Genetic-First Study

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Collaborators

Affiliations

Erratum in

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