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The CHRM3 gene is implicated in abnormal thalamo-orbital frontal cortex functional connectivity in first-episode treatment-naive patients with schizophrenia

Published online by Cambridge University Press:  09 March 2016

Q. Wang ,
W. Cheng ,
M. Li ,
H. Ren ,
X. Hu ,
W. Deng ,
M. Li ,
X. Ma ,
L. Zhao  and
Y. Wang
...Show all authors
Q. Wang
Affiliation:
Mental Health Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China State Key Laboratory of Biotherapy, Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
W. Cheng
Affiliation:
Centre for Computational Systems Biology, Fudan University, Shanghai, People's Republic of China
M. Li
Affiliation:
State Key Laboratory of Brain and Cognitive Sciences, Centre for Genomic Sciences and Department of Psychiatry, University of Hong Kong, Pokfulam, S.A.R. China
H. Ren
Affiliation:
Mental Health Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
X. Hu
Affiliation:
Biobank, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
W. Deng
Affiliation:
Mental Health Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
M. Li
Affiliation:
Mental Health Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
X. Ma
Affiliation:
State Key Laboratory of Biotherapy, Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
L. Zhao
Affiliation:
State Key Laboratory of Biotherapy, Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
Y. Wang
Affiliation:
State Key Laboratory of Biotherapy, Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
B. Xiang
Affiliation:
Mental Health Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
H.-M. Wu
Affiliation:
State Key Laboratory of Brain and Cognitive Sciences, Centre for Genomic Sciences and Department of Psychiatry, University of Hong Kong, Pokfulam, S.A.R. China
P. C. Sham
Affiliation:
State Key Laboratory of Brain and Cognitive Sciences, Centre for Genomic Sciences and Department of Psychiatry, University of Hong Kong, Pokfulam, S.A.R. China
J. Feng*
Affiliation:
Centre for Computational Systems Biology, Fudan University, Shanghai, People's Republic of China
T. Li*
Affiliation:
Mental Health Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China State Key Laboratory of Biotherapy, Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
*
*Address for correspondence: T. Li, The Mental Health Center and the Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China. (Email: xuntao26@hotmail.com)
*Address for correspondence: T. Li, The Mental Health Center and the Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, People's Republic of China. (Email: xuntao26@hotmail.com)
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Abstract

Background

The genetic influences in human brain structure and function and impaired functional connectivities are the hallmarks of the schizophrenic brain. To explore how common genetic variants affect the connectivities in schizophrenia, we applied genome-wide association studies assaying the abnormal neural connectivities in schizophrenia as quantitative traits.

Method

We recruited 161 first-onset and treatment-naive patients with schizophrenia and 150 healthy controls. All the participants underwent scanning with a 3 T-magnetic resonance imaging scanner to acquire structural and functional imaging data and genotyping using the HumanOmniZhongHua-8 BeadChip. The brain-wide association study approach was employed to account for the inherent modular nature of brain connectivities.

Results

We found differences in four abnormal functional connectivities [left rectus to left thalamus (REC.L–THA.L), left rectus to right thalamus (REC.L–THA.R), left superior orbital cortex to left thalamus (ORBsup.L–THA.L) and left superior orbital cortex to right thalamus (ORBsup.L–THA.R)] between the two groups. Univariate single nucleotide polymorphism (SNP)-based association revealed that the SNP rs6800381, located nearest to the CHRM3 (cholinergic receptor, muscarinic 3) gene, reached genomic significance (p = 1.768 × 10−8) using REC.L–THA.R as the phenotype. Multivariate gene-based association revealed that the FAM12A (family with sequence similarity 12, member A) gene nearly reached genomic significance (nominal p = 2.22 × 10–6, corrected p = 0.05).

Conclusions

Overall, we identified the first evidence that the CHRM3 gene plays a role in abnormal thalamo-orbital frontal cortex functional connectivity in first-episode treatment-naive patients with schizophrenia. Identification of these genetic variants using neuroimaging genetics provides insights into the causes of variability in human brain development, and may help us determine the mechanisms of dysfunction in schizophrenia.

Keywords

First-episode patientsfunctional connectivitygenome-wide association studiesschizophrenia
Type
Original Articles
Information
Psychological Medicine , Volume 46 , Issue 7 , May 2016 , pp. 1523 - 1534
Copyright
Copyright © Cambridge University Press 2016 

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