Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders

K. Ishizuka, Y. Fujita, T. Kawabata, H. Kimura, Y. Iwayama, T. Inada, Y. Okahisa, J. Egawa, M. Usami, I. Kushima, Y. Uno, T. Okada, Masashi Ikeda, B. Aleksic, D. Mori, To Someya, T. Yoshikawa, Nakao Iwata, H. Nakamura, T. YamashitaN. Ozaki

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

CX3CR1, a G protein-coupled receptor solely expressed by microglia in the brain, has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in transcriptomic and animal studies but not in genetic studies. To address the impacts of variants in CX3CR1 on neurodevelopmental disorders, we conducted coding exon-targeted resequencing of CX3CR1 in 370 Japanese SCZ and 192 ASD patients using next-generation sequencing technology, followed by a genetic association study in a sample comprising 7054 unrelated individuals (2653 SCZ, 574 ASD and 3827 controls). We then performed in silico three-dimensional (3D) structural modeling and in vivo disruption of Akt phosphorylation to determine the impact of the detected variant on CX3CR1-dependent signal transduction. We detected a statistically significant association between the variant Ala55Thr in CX3CR1 with SCZ and ASD phenotypes (odds ratio=8.3, P=0.020). A 3D structural model indicated that Ala55Thr could destabilize the conformation of the CX3CR1 helix 8 and affect its interaction with a heterotrimeric G protein. In vitro functional analysis showed that the CX3CR1-Ala55Thr mutation inhibited cell signaling induced by fractalkine, the ligand for CX3CR1. The combined data suggested that the variant Ala55Thr in CX3CR1 might result in the disruption of CX3CR1 signaling. Our results strengthen the association between microglia-specific genes and neurodevelopmental disorders.

Original languageEnglish
Article numbere1184
JournalTranslational psychiatry
Volume7
Issue number8
DOIs
Publication statusPublished - 01-08-2017

Fingerprint

Schizophrenia
Microglia
Chemokine CX3CL1
Heterotrimeric GTP-Binding Proteins
Structural Models
Genetic Association Studies
G-Protein-Coupled Receptors
Computer Simulation
Exons
Signal Transduction
Odds Ratio
Phosphorylation
Ligands
Technology
Phenotype
Mutation
Autism Spectrum Disorder
Brain
Genes
Neurodevelopmental Disorders

All Science Journal Classification (ASJC) codes

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry

Cite this

Ishizuka, K. ; Fujita, Y. ; Kawabata, T. ; Kimura, H. ; Iwayama, Y. ; Inada, T. ; Okahisa, Y. ; Egawa, J. ; Usami, M. ; Kushima, I. ; Uno, Y. ; Okada, T. ; Ikeda, Masashi ; Aleksic, B. ; Mori, D. ; Someya, To ; Yoshikawa, T. ; Iwata, Nakao ; Nakamura, H. ; Yamashita, T. ; Ozaki, N. / Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders. In: Translational psychiatry. 2017 ; Vol. 7, No. 8.
@article{200b04f7b8b64b22b4869d590b1755ea,
title = "Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders",
abstract = "CX3CR1, a G protein-coupled receptor solely expressed by microglia in the brain, has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in transcriptomic and animal studies but not in genetic studies. To address the impacts of variants in CX3CR1 on neurodevelopmental disorders, we conducted coding exon-targeted resequencing of CX3CR1 in 370 Japanese SCZ and 192 ASD patients using next-generation sequencing technology, followed by a genetic association study in a sample comprising 7054 unrelated individuals (2653 SCZ, 574 ASD and 3827 controls). We then performed in silico three-dimensional (3D) structural modeling and in vivo disruption of Akt phosphorylation to determine the impact of the detected variant on CX3CR1-dependent signal transduction. We detected a statistically significant association between the variant Ala55Thr in CX3CR1 with SCZ and ASD phenotypes (odds ratio=8.3, P=0.020). A 3D structural model indicated that Ala55Thr could destabilize the conformation of the CX3CR1 helix 8 and affect its interaction with a heterotrimeric G protein. In vitro functional analysis showed that the CX3CR1-Ala55Thr mutation inhibited cell signaling induced by fractalkine, the ligand for CX3CR1. The combined data suggested that the variant Ala55Thr in CX3CR1 might result in the disruption of CX3CR1 signaling. Our results strengthen the association between microglia-specific genes and neurodevelopmental disorders.",
author = "K. Ishizuka and Y. Fujita and T. Kawabata and H. Kimura and Y. Iwayama and T. Inada and Y. Okahisa and J. Egawa and M. Usami and I. Kushima and Y. Uno and T. Okada and Masashi Ikeda and B. Aleksic and D. Mori and To Someya and T. Yoshikawa and Nakao Iwata and H. Nakamura and T. Yamashita and N. Ozaki",
year = "2017",
month = "8",
day = "1",
doi = "10.1038/tp.2017.173",
language = "English",
volume = "7",
journal = "Translational Psychiatry",
issn = "2158-3188",
publisher = "Nature Publishing Group",
number = "8",

}

Ishizuka, K, Fujita, Y, Kawabata, T, Kimura, H, Iwayama, Y, Inada, T, Okahisa, Y, Egawa, J, Usami, M, Kushima, I, Uno, Y, Okada, T, Ikeda, M, Aleksic, B, Mori, D, Someya, T, Yoshikawa, T, Iwata, N, Nakamura, H, Yamashita, T & Ozaki, N 2017, 'Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders', Translational psychiatry, vol. 7, no. 8, e1184. https://doi.org/10.1038/tp.2017.173

Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders. / Ishizuka, K.; Fujita, Y.; Kawabata, T.; Kimura, H.; Iwayama, Y.; Inada, T.; Okahisa, Y.; Egawa, J.; Usami, M.; Kushima, I.; Uno, Y.; Okada, T.; Ikeda, Masashi; Aleksic, B.; Mori, D.; Someya, To; Yoshikawa, T.; Iwata, Nakao; Nakamura, H.; Yamashita, T.; Ozaki, N.

In: Translational psychiatry, Vol. 7, No. 8, e1184, 01.08.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders

AU - Ishizuka, K.

AU - Fujita, Y.

AU - Kawabata, T.

AU - Kimura, H.

AU - Iwayama, Y.

AU - Inada, T.

AU - Okahisa, Y.

AU - Egawa, J.

AU - Usami, M.

AU - Kushima, I.

AU - Uno, Y.

AU - Okada, T.

AU - Ikeda, Masashi

AU - Aleksic, B.

AU - Mori, D.

AU - Someya, To

AU - Yoshikawa, T.

AU - Iwata, Nakao

AU - Nakamura, H.

AU - Yamashita, T.

AU - Ozaki, N.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - CX3CR1, a G protein-coupled receptor solely expressed by microglia in the brain, has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in transcriptomic and animal studies but not in genetic studies. To address the impacts of variants in CX3CR1 on neurodevelopmental disorders, we conducted coding exon-targeted resequencing of CX3CR1 in 370 Japanese SCZ and 192 ASD patients using next-generation sequencing technology, followed by a genetic association study in a sample comprising 7054 unrelated individuals (2653 SCZ, 574 ASD and 3827 controls). We then performed in silico three-dimensional (3D) structural modeling and in vivo disruption of Akt phosphorylation to determine the impact of the detected variant on CX3CR1-dependent signal transduction. We detected a statistically significant association between the variant Ala55Thr in CX3CR1 with SCZ and ASD phenotypes (odds ratio=8.3, P=0.020). A 3D structural model indicated that Ala55Thr could destabilize the conformation of the CX3CR1 helix 8 and affect its interaction with a heterotrimeric G protein. In vitro functional analysis showed that the CX3CR1-Ala55Thr mutation inhibited cell signaling induced by fractalkine, the ligand for CX3CR1. The combined data suggested that the variant Ala55Thr in CX3CR1 might result in the disruption of CX3CR1 signaling. Our results strengthen the association between microglia-specific genes and neurodevelopmental disorders.

AB - CX3CR1, a G protein-coupled receptor solely expressed by microglia in the brain, has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in transcriptomic and animal studies but not in genetic studies. To address the impacts of variants in CX3CR1 on neurodevelopmental disorders, we conducted coding exon-targeted resequencing of CX3CR1 in 370 Japanese SCZ and 192 ASD patients using next-generation sequencing technology, followed by a genetic association study in a sample comprising 7054 unrelated individuals (2653 SCZ, 574 ASD and 3827 controls). We then performed in silico three-dimensional (3D) structural modeling and in vivo disruption of Akt phosphorylation to determine the impact of the detected variant on CX3CR1-dependent signal transduction. We detected a statistically significant association between the variant Ala55Thr in CX3CR1 with SCZ and ASD phenotypes (odds ratio=8.3, P=0.020). A 3D structural model indicated that Ala55Thr could destabilize the conformation of the CX3CR1 helix 8 and affect its interaction with a heterotrimeric G protein. In vitro functional analysis showed that the CX3CR1-Ala55Thr mutation inhibited cell signaling induced by fractalkine, the ligand for CX3CR1. The combined data suggested that the variant Ala55Thr in CX3CR1 might result in the disruption of CX3CR1 signaling. Our results strengthen the association between microglia-specific genes and neurodevelopmental disorders.

UR - http://www.scopus.com/inward/record.url?scp=85026727164&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85026727164&partnerID=8YFLogxK

U2 - 10.1038/tp.2017.173

DO - 10.1038/tp.2017.173

M3 - Article

C2 - 28763059

AN - SCOPUS:85026727164

VL - 7

JO - Translational Psychiatry

JF - Translational Psychiatry

SN - 2158-3188

IS - 8

M1 - e1184

ER -