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A joint study of whole exome sequencing and structural MRI analysis in major depressive disorder

Published online by Cambridge University Press:  06 February 2019

Yamin Zhang Open the ORCID record for Yamin Zhang [Opens in a new window] ,
Mingli Li ,
Qiang Wang ,
Jacob Shujui Hsu ,
Wei Deng ,
Xiaohong Ma ,
Peiyan Ni ,
Liansheng Zhao ,
Yang Tian  and
Pak Chung Sham
...Show all authors
Yamin Zhang
Affiliation:
Psychiatric Laboratory and Mental Health Center, The State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
Mingli Li
Affiliation:
Psychiatric Laboratory and Mental Health Center, The State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
Qiang Wang
Affiliation:
Psychiatric Laboratory and Mental Health Center, The State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
Jacob Shujui Hsu
Affiliation:
Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong, China State Key Laboratory for Cognitive and Brain Sciences, The University of Hong Kong, Pokfulam, Hong Kong, China
Wei Deng
Affiliation:
Psychiatric Laboratory and Mental Health Center, The State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
Xiaohong Ma
Affiliation:
Psychiatric Laboratory and Mental Health Center, The State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
Peiyan Ni
Affiliation:
Psychiatric Laboratory and Mental Health Center, The State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
Liansheng Zhao
Affiliation:
Psychiatric Laboratory and Mental Health Center, The State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
Yang Tian
Affiliation:
Psychiatric Laboratory and Mental Health Center, The State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
Pak Chung Sham*
Affiliation:
Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong, China State Key Laboratory for Cognitive and Brain Sciences, The University of Hong Kong, Pokfulam, Hong Kong, China
Tao Li*
Affiliation:
Psychiatric Laboratory and Mental Health Center, The State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, China Huaxi Brain Research Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
*
Author for correspondence: Tao Li; Pak Chung Sham, E-mail: litaohx@scu.edu.cn; pcsham@hku.hk
Author for correspondence: Tao Li; Pak Chung Sham, E-mail: litaohx@scu.edu.cn; pcsham@hku.hk
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Abstract

Background

Major depressive disorder (MDD) is a leading cause of disability worldwide and influenced by both environmental and genetic factors. Genetic studies of MDD have focused on common variants and have been constrained by the heterogeneity of clinical symptoms.

Methods

We sequenced the exome of 77 cases and 245 controls of Han Chinese ancestry and scanned their brain. Burden tests of rare variants were performed first to explore the association between genes/pathways and MDD. Secondly, parallel Independent Component Analysis was conducted to investigate genetic underpinnings of gray matter volume (GMV) changes of MDD.

Results

Two genes (CSMD1, p = 5.32×10−6; CNTNAP5, p = 1.32×10−6) and one pathway (Neuroactive Ligand Receptor Interactive, p = 1.29×10−5) achieved significance in burden test. In addition, we identified one pair of imaging-genetic components of significant correlation (r = 0.38, p = 9.92×10−6). The imaging component reflected decreased GMV in cases and correlated with intelligence quotient (IQ). IQ mediated the effects of GMV on MDD. The genetic component enriched in two gene sets, namely Singling by G-protein coupled receptors [false discovery rate (FDR) q = 3.23×10−4) and Alzheimer Disease Up (FDR q = 6.12×10−4).

Conclusions

Both rare variants analysis and imaging–genetic analysis found evidence corresponding with the neuroinflammation and synaptic plasticity hypotheses of MDD. The mediation of IQ indicates that genetic component may act on MDD through GMV alteration and cognitive impairment.

Keywords

Major depressive disorderMRIparallel ICAwhole exome sequencing
Type
Original Articles
Information
Psychological Medicine , Volume 50 , Issue 3 , February 2020 , pp. 384 - 395
Copyright
Copyright © Cambridge University Press 2019

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