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, 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. 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.
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.
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.
Authors: Clara A Moreau; Christopher Rk Ching; Kuldeep Kumar; Sebastien Jacquemont; Carrie E Bearden Journal: Curr Opin Genet Dev Date: 2021-03-31 Impact factor: 4.665
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Authors: Danijela Drakulic; Srdjan Djurovic; Yasir Ahmed Syed; Sebastiano Trattaro; Nicolò Caporale; Anna Falk; Rivka Ofir; Vivi M Heine; Samuel J R A Chawner; Antonio Rodriguez-Moreno; Marianne B M van den Bree; Giuseppe Testa; Spyros Petrakis; Adrian J Harwood Journal: Mol Autism Date: 2020-06-01 Impact factor: 7.509