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

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

doi:10.1001/jamapsychiatry.2015.2123

Cited by 219 publications

(230 citation statements)

References 32 publications

Supporting

Mentioning

192

Contrasting

Order By: Relevance

“…In imaging genetics, it has often been assumed that genetic variants may have larger effects on imaging phenotypes than on clinical traits or psychiatric risk (45). Our study shows, however, that the effect size of CNVs on brain structure is similar to their effect previously published for cognitive and behavioral traits (13,18). The effect of the deletion is approximately twice that of the duplication for global and regional brain volumes as well as clinical traits (such as IQ loss) (13).…”

Section: Discussionsupporting

confidence: 58%

“…All families participated in a larger phenotyping project, as previously reported (10,13,(20)(21)(22). Trained neuropsychologists performed all cognitive and behavioral assessments, including tests of overall cognitive functioning (nonverbal IQ [NVIQ]) (23)(24)(25)(26)(27) and phonological skills (standard score of the nonword repetition) (28,29).…”

Section: Methods and Materials Participantsmentioning

confidence: 99%

“…There is a similar 10-fold enrichment of deletions and duplications in ASD cohorts (11,12), and both CNVs have large effects on IQ (Z scores of 1.5 and 0.8, respectively) and Social Responsiveness Scale (SRS) (Z scores of 1 and 2, respectively) (10,(13)(14)(15). However, there are phenotypic differences between both CNVs: the 10-fold enrichment in schizophrenia cohorts (16,17) is only observed for duplications, and only deletions affect measures of language by 1.5 Z scores (18).…”

mentioning

confidence: 89%

“…However, there are phenotypic differences between both CNVs: the 10-fold enrichment in schizophrenia cohorts (16,17) is only observed for duplications, and only deletions affect measures of language by 1.5 Z scores (18). Previous studies demonstrated "mirror" effects of both CNVs on head circumference and body mass index (13,19). Neuroimaging studies reported gene-dosage effects on global brain metrics (20,21).…”

mentioning

confidence: 99%

See 3 more Smart Citations

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

Martin

Rodríguez-Herreros

Nielsen

et al. 2018

Biological Psychiatry

Self Cite

View full text Add to dashboard Cite

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 , 21), and the caudate and hippocampus (control . duplication; 20.5 . Cohen's d . 21). 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. Autism spectrum disorder (ASD) and related neurodevelopmental disorders are defined behaviorally and characterized by a significant clinical and etiologic heterogeneity. As a consequence, investigating ASD under the assumption of an underlying homogeneous condition has resulted in controversial findings in the field of neuroimaging (1). Increased brain growth early in development (2-4) and alterations of many regional brain volumes (5) have been implicated in ASD, but results have proven difficult to replicate (1,(6)(7)(8).To mitigate some of these issues, cohorts of individuals with shared genetic risk factors have been assembled to minimize the noise introduced by etiologic and biological heterogeneity (9). Such a "genetic-first" study design provides the opportunity to investigate a given neurodevelopmental risk (and associated mechanism) shared by individuals who carry the same genetic etiology irrespective of the psychiatric diagnosis.Copy number variants (CNVs) at the 16p11.2 (breakpoints 4-5, 29.6-30.2 Mb-hg19) (10) are among the most frequent risk factors for neurodevelopmental and psychiatric conditions.

show abstract

Section: Discussionsupporting

confidence: 58%

Section: Methods and Materials Participantsmentioning

confidence: 99%

mentioning

confidence: 89%

mentioning

confidence: 99%

See 2 more Smart Citations

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

Martin

Rodríguez-Herreros

Nielsen

et al. 2018

Biological Psychiatry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Similar positive effects were reported in other clinical domains and treatment gains were maintained at six-month follow-up. Although it is impossible to determine the differential effects of VRET vs. the psychosocial TMT components, the results from the combination of these approaches in an intensive format are promising, especially in light of recent criticism of prolonged exposure approaches (Steenkamp, 2016). …”

Section: Vret Research Outcomesmentioning

confidence: 99%

Clinical Virtual Reality tools to advance the prevention, assessment, and treatment of PTSD

Rizzo

Shilling

2017

European Journal of Psychotraumatology

152

107

View full text Add to dashboard Cite

Numerous reports indicate that the incidence of posttraumatic stress disorder (PTSD) in Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) military personnel has created a significant behavioural healthcare challenge. These findings have served to motivate research on how to better develop and disseminate evidence-based treatments for PTSD. The current article presents the use of Virtual Reality (VR) as a clinical tool to address the assessment, prevention, and treatment of PTSD, based on the VR projects that were evolved at the University of Southern California Institute for Creative Technologies since 2004. A brief discussion of the definition and rationale for the clinical use of VR is followed by a description of a VR application designed for the delivery of prolonged exposure (PE) for treating Service Members (SMs) and Veterans with combat- and sexual assault-related PTSD. The expansion of the virtual treatment simulations of Iraq and Afghanistan for PTSD assessment and prevention is then presented. This is followed by a forward-looking discussion that details early efforts to develop virtual human agent systems that serve the role of virtual patients for training the next generation of clinical providers, as healthcare guides that can be used to support anonymous access to trauma-relevant behavioural healthcare information, and as clinical interviewers capable of automated behaviour analysis of users to infer psychological state. The paper will conclude with a discussion of VR as a tool for breaking down barriers to care in addition to its direct application in assessment and intervention.

show abstract

The Emerging Clinical Neuroscience of Autism Spectrum Disorder

et al. 2018

View full text Add to dashboard Cite

The advent of next-generation sequencing technology, advanced imaging techniques, and cutting-edge molecular techniques for modeling ASD has allowed researchers to define ASD risk-related biological pathways and circuits that may, for the first time, unify the effects of disparate risk factors into common neurobiological mechanisms. The path from these mechanisms to biological treatments that improve the lives of individuals with autism remains unclear, but the cumulative output of multiple lines of research suggests that subtyping by genetic risk factors may be a particularly tractable way to capitalize on individual differences amenable to specific treatments.

show abstract

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

Cited by 219 publications

References 32 publications

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

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

Clinical Virtual Reality tools to advance the prevention, assessment, and treatment of PTSD

The Emerging Clinical Neuroscience of Autism Spectrum Disorder

Contact Info

Product

Resources

About