Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights

Kushima, Itaru; Aleksić, Branko; Nakatochi, Masahiro; Shimamura, Teppei; Okada, Takashi; Uno, Yuichi; Morikawa, Mako; Ishizuka, Kanako; Shiino, Tomoko; Kimura, Hiroki; Arioka, Yuko; Yoshimi, Akira; Takasaki, Yuto; Yu, Yanjie; Nakamura, Yukako; Yamamoto, Maeri; Iidaka, Tetsuya; Iritani, Shuji; Inada, Toshiya; Ogawa, Noriyuki; Shishido, Emiko; Torii, Youta; Kawano, Naoki; Omura, Yutaka; Yoshikawa, Toru; Uchiyama, Tokio; Yamamoto, Toshimichi; Ikeda, Masashi; Hashimoto, Ryota; Yamamori, Hidenaga; Yasuda, Yuka; Someya, Toshiyuki; Watanabe, Yuichiro; Egawa, Jun; Nunokawa, Ayako; Itokawa, Masanari; Arai, Makoto; Miyashita, Mitsuhiro; Kobori, Akiko; Suzuki, Michio; Takahashi, Tsutomu; Usami, Masahide; Kodaira, Masaki; Watanabe, Kyota; Sasaki, Tsukasa; Kuwabara, Hitoshi; Tochigi, Mamoru; Nishimura, Fumichika; Yamasue, Hidenori; Eriguchi, Yosuke; Benner, Seico; Kojima, Mitsuharu; Yassin, Walid; Munesue, Toshio; Yokoyama, Shigeru; Kimura, Ryo; Funabiki, Yasuko; Kosaka, Hirotaka; Ishitobi, Makoto; Ohmori, Tetsuro; Numata, Shusuke; Yoshikawa, Takeo; Toyota, Tomoko; Yamakawa, Kazuhiro; Suzuki, Toshimitsu; Inoue, Yushi; Nakaoka, Kentaro; Goto, Yu Ichi; Inagaki, Masumi; Hashimoto, Naoki; Kusumi, Ichiro; Son, Shuraku; Murai, Toshiya; Ikegame, Tempei; Okada, Naohiro; Kasai, Kiyoto; Kunimoto, Shohko; Mori, Daisuke; Iwata, Nakao; Ozaki, Norio

doi:10.1016/j.celrep.2018.08.022

Cited by 182 publications

(168 citation statements)

References 46 publications

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“…We were unable to detect a significant association between 16p11.2 deletion and psychotic symptoms. Although this conflicts with reports of SCZ diagnosis in association with 16p11.2 deletion carriers [Marshall et al, 2017;Kushima et al, 2018], we may have been underpowered to detect an association. Only four deletion carriers had psychotic symptoms in our sample, compared with 12 duplication carriers, which is consistent with recent evidence suggesting that psychotic symptoms may be less common in 16p11.2 deletion than duplication carriers [Niarchou et al, 2019].…”

Section: Discussioncontrasting

confidence: 93%

“…Though rare in the general population, it is overrepresented in those with developmental delay or psychiatric illness. In particular, both 16p11.2 deletion and duplication are associated with autism spectrum disorder (ASD; Weiss et al, ) and schizophrenia (SCZ; McCarthy et al, ; Marshall, Howrigan, Merico, et al, ; Kushima et al, ). ASD prevalence is thought to be similar in both groups, with SCZ symptoms more common in duplication than deletion carriers [Niarchou et al, ].…”

Section: Introductionmentioning

confidence: 99%

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Psychotic symptoms in 16p11.2 copy‐number variant carriers

et al. 2019

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16p11.2 copy‐number variation (CNV) is implicated in neurodevelopmental disorders, with the duplication and deletion associated with autism spectrum disorder (ASD) and the duplication associated with schizophrenia (SCZ). The 16p11.2 CNV may therefore provide insight into the relationship between ASD and SCZ, distinct disorders that co‐occur at an elevated rate, and are difficult to distinguish from each other and from common co‐occurring diagnoses such as obsessive compulsive disorder (OCD), itself a potential risk factor for SCZ. As psychotic symptoms are core to SCZ but distinct from ASD, we sought to examine their predictors in a population (n = 546) of 16p11.2 CNV carriers and their noncarrier siblings recruited by the Simons Variation in Individuals Project. We hypothesized that psychotic symptoms would be most common in duplication carriers followed by deletion carriers and noncarriers, that an ASD diagnosis would predict psychotic symptoms among CNV carriers, and that OCD symptoms would predict psychotic symptoms among all participants. Using data collected across multiple measures, we identified 19 participants with psychotic symptoms. Logistic regression models adjusting for biological sex, age, and IQ found that 16p11.2 duplication and ASD diagnosis predicted psychotic symptom presence. Our findings suggest that the association between 16p11.2 duplication and psychotic symptoms is independent of ASD diagnosis and that ASD diagnosis and psychotic symptoms may be associated in 16p11.2 CNV carriers. Autism Res 2020, 13: 187–198. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Either deletion or duplication at chromosome 16p11.2 raises the risk of autism spectrum disorder, and duplication, but not deletion, has been reported in schizophrenia (SCZ). In a sample of 16p11.2 deletion and duplication carriers, we found that having the duplication or having an autism diagnosis may increase the risk of psychosis, a key feature of SCZ.

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Section: Discussioncontrasting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Psychotic symptoms in 16p11.2 copy‐number variant carriers

et al. 2019

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“…Genetic factors also play a substantial role in the etiology of mental disorders . It has been suggested that ASD and schizophrenia share common biological pathways based on the recent genomic studies . Several groups have examined heritability estimates of eye movement phenotypes in patients with schizophrenia .…”

Section: Discussionmentioning

confidence: 99%

“…9,[35][36][37] It has been suggested that ASD and schizophrenia share common biological pathways based on the recent genomic studies. 38 Several groups have examined heritability estimates of eye movement phenotypes in patients with schizophrenia. 8,35 In those studies, two eye movement tasks were associated with moderate to high heritability.…”

Section: Role Of Eye Movements In Social Interactionmentioning

confidence: 99%

Application of eye trackers for understanding mental disorders: Cases for schizophrenia and autism spectrum disorder

Shishido

Ogawa

Miyata

et al. 2019

Neuropsychopharm Rep

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Studies of eye movement have become an essential tool of basic neuroscience research. Measures of eye movement have been applied to higher brain functions such as cognition, social behavior, and higher‐level decision‐making. With the development of eye trackers, a growing body of research has described eye movements in relation to mental disorders, reporting that the basic oculomotor properties of patients with mental disorders differ from those of healthy controls. Using discrimination analysis, several independent research groups have used eye movements to differentiate patients with schizophrenia from a mixed population of patients and controls. Recently, in addition to traditional oculomotor measures, several new techniques have been applied to measure and analyze eye movement data. One research group investigated eye movements in relation to the risk of autism spectrum disorder several years prior to the emergence of verbal‐behavioral abnormalities. Research on eye movement in humans in social communication is therefore considered important, but has not been well explored. Since eye movement patterns vary between patients with mental disorders and healthy controls, it is necessary to collect a large amount of eye movement data from various populations and age groups. The application of eye trackers in the clinical setting could contribute to the early treatment of mental disorders.

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“…In the third study, whole genome sequencing revealed a de novo point mutation in a putative regulatory element upstream of NR3C2 [Turner et al, ]. Lastly, two large deletions in the gene have been reported: a 848 bp deletion encompassing the first two exons of NR3C2 and a 314 kb deletion which span the first four exons, removing all known start sites [Kushima et al, ; Ruzzo et al, ]. In the gnomAD database, NR3C2 is reported to have only eight loss‐of‐function (LoF) variants, giving an observed/expected LoF variants score of 0.19 and a pLI = 0.84 [Lek et al, ].…”

Section: Clinical Features In Three Brothers With Autismmentioning

confidence: 99%

Three Brothers With Autism Carry a Stop‐Gain Mutation in the HPA‐Axis Gene NR3C2

et al. 2020

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Whole exome sequencing and copy‐number variant analysis was performed on a family with three brothers diagnosed with autism. Each of the siblings shares an alteration in the nuclear receptor subfamily 3 group C member 2 (NR3C2) gene that is predicted to result in a stop‐gain mutation (p.Q919X) in the mineralocorticoid receptor (MR) protein. This variant was maternally inherited and provides further evidence for a connection between the NR3C2 and autism. Interestingly, the NR3C2 gene encodes the MR protein, a steroid hormone‐regulated transcription factor that acts in the hypothalamic–pituitary–adrenal axis and has been connected to stress and anxiety, both of which are features often seen in individuals with autism. Autism Res 2020, 13: 523–531. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Given the complexity of the genetics underlying autism, each gene contributes to risk in a relatively small number of individuals, typically less than 1% of all autism cases. Whole exome sequencing of three brothers with autism identified a rare variant in the nuclear receptor subfamily 3 group C member 2 gene that is predicted to strongly interfere with its normal function. This gene encodes the mineralocorticoid receptor protein, which plays a role in how the body responds to stress and anxiety, features that are often elevated in people diagnosed with autism. This study adds further support to the relevance of this gene as a risk factor for autism.

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Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights

Cited by 182 publications

References 46 publications

Psychotic symptoms in 16p11.2 copy‐number variant carriers

Psychotic symptoms in 16p11.2 copy‐number variant carriers

Application of eye trackers for understanding mental disorders: Cases for schizophrenia and autism spectrum disorder

Three Brothers With Autism Carry a Stop‐Gain Mutation in the HPA‐Axis Gene NR3C2

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