title: Reciprocal white matter alterations due to 16p11.2 chromosomal deletions versus duplications.
abstract: Copy number variants at the 16p11.2 chromosomal locus are associated with several neuropsychiatric disorders, including autism, schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder, and speech and language disorders. A gene dosage dependence has been suggested, with 16p11.2 deletion carriers demonstrating higher body mass index and head circumference, and 16p11.2 duplication carriers demonstrating lower body mass index and head circumference. Here, we use diffusion tensor imaging to elucidate this reciprocal relationship in white matter organization, showing widespread increases of fractional anisotropy throughout the supratentorial white matter in pediatric deletion carriers and, in contrast, extensive decreases of white matter fractional anisotropy in pediatric and adult duplication carriers. We find associations of these white matter alterations with cognitive and behavioral impairments. We further demonstrate the value of imaging metrics for characterizing the copy number variant phenotype by employing linear discriminant analysis to predict the gene dosage status of the study subjects. These results show an effect of 16p11.2 gene dosage on white matter microstructure, and further suggest that opposite changes in diffusion tensor imaging metrics can lead to similar cognitive and behavioral deficits. Given the large effect sizes found in this study, our results support the view that specific genetic variations are more strongly associated with specific brain alterations than are shared neuropsychiatric diagnoses. Hum Brain Mapp 37:2833-2848, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, 185 Berry Street, San Francisco, California, 94107.
authors.forename: Yi Shin
authors.initials: YS
authors.lastname: Chang
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, 185 Berry Street, San Francisco, California, 94107.|Program in Bioengineering, University of California, San Francisco, 1700 4th St, San Francisco, California, 94158.
authors.forename: Julia P
authors.initials: JP
authors.lastname: Owen
authors.affiliation: Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, California, 94158.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Pojman
authors.affiliation: Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, California, 94158.
authors.forename: Tony
authors.initials: T
authors.lastname: Thieu
authors.affiliation: Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, California, 94158.
authors.forename: Polina
authors.initials: P
authors.lastname: Bukshpun
authors.affiliation: Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, California, 94158.
authors.forename: Mari L J
authors.initials: ML
authors.lastname: Wakahiro
authors.affiliation: Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, California, 94158.
authors.forename: Elysa J
authors.initials: EJ
authors.lastname: Marco
authors.affiliation: Department of Radiology, Children's Hospital of Philadelphia, Wood Bldg, Suite 2115, Philadelphia, Pennsylvania, 19104.
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Berman
authors.affiliation: Simons Foundation, 160 Fifth Avenue, 7th Floor, New York, New York, 10010.
authors.forename: John E
authors.initials: JE
authors.lastname: Spiro
authors.affiliation: Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, New York, 10032.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.affiliation: Center for Brain Science, Harvard University, 52 Oxford Street, Cambridge, Massachusetts, 02138.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Buckner
authors.affiliation: Department of Radiology, Children's Hospital of Philadelphia, Wood Bldg, Suite 2115, Philadelphia, Pennsylvania, 19104.
authors.forename: Timothy P L
authors.initials: TP
authors.lastname: Roberts
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, 185 Berry Street, San Francisco, California, 94107.|Program in Bioengineering, University of California, San Francisco, 1700 4th St, San Francisco, California, 94158.
authors.forename: Srikantan S
authors.initials: SS
authors.lastname: Nagarajan
authors.affiliation: Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, California, 94158.
authors.forename: Elliott H
authors.initials: EH
authors.lastname: Sherr
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, 185 Berry Street, San Francisco, California, 94107.|Program in Bioengineering, University of California, San Francisco, 1700 4th St, San Francisco, California, 94158.
authors.forename: Pratik
authors.initials: P
authors.lastname: Mukherjee
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000473:pathology*; D002648:Child; D002872:Chromosome Deletion; D058674:Chromosome Duplication; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D056324:Diffusion Tensor Imaging; D005260:Female; D018628:Gene Dosage; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D066127:White Matter / Q000473:pathology*; D055815:Young Adult
keywords: autism; genetics; magnetic resonance imaging; neurodevelopmental disorders; white matter