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

• Published in: Translational psychiatry Vol. 7; no. 8; p. e1184
• Main Authors: 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, To, Yoshikawa, T, Iwata, N, Nakamura, H, Yamashita, T, Ozaki, N
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2017; Nature Publishing Group
• Subjects: 13; 45; 45/23; 45/41; 631/208/2489; 631/378/340; 96/95; Adolescent; Adult; Aged; Autism; Autism Spectrum Disorder - genetics; Behavioral Sciences; Biological Psychology; Child; Computer Simulation; CX3C Chemokine Receptor 1 - genetics; Exons; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; High-Throughput Nucleotide Sequencing; Humans; Male; Medicine; Medicine & Public Health; Middle Aged; Mutation; Neurodevelopmental disorders; Neurosciences; Original; original-article; Pharmacotherapy; Polymorphism, Single Nucleotide; Psychiatry; Schizophrenia; Schizophrenia - genetics; Signal transduction; Young Adult
• ISSN: 2158-3188; 2158-3188
• DOI: 10.1038/tp.2017.173

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.