A Schizophrenia-Related Genetic-Brain-Cognition Pathway Revealed in a Large Chinese Population

Na Luo; Jing Sui; Jiayu Chen; Fuquan Zhang; Lin Tian; Dongdong Lin; Ming Song; Vince D Calhoun; Yue Cui; Victor M Vergara; Fanfan Zheng; Jingyu Liu; Zhenyi Yang; Nianming Zuo; Lingzhong Fan; Kaibin Xu; Shengfeng Liu; Jian Li; Yong Xu; Sha Liu; Luxian Lv; Jun Chen; Yunchun Chen; Hua Guo; Peng Li; Lin Lu; Ping Wan; Huaning Wang; Huiling Wang; Hao Yan; Jun Yan; Yongfeng Yang; Hongxing Zhang; Dai Zhang; Tianzi Jiang

doi:10.1016/j.ebiom.2018.10.009

A Schizophrenia-Related Genetic-Brain-Cognition Pathway Revealed in a Large Chinese Population

EBioMedicine. 2018 Nov:37:471-482. doi: 10.1016/j.ebiom.2018.10.009. Epub 2018 Oct 16.

Authors

Na Luo¹, Jing Sui², Jiayu Chen³, Fuquan Zhang⁴, Lin Tian⁴, Dongdong Lin³, Ming Song¹, Vince D Calhoun⁵, Yue Cui¹, Victor M Vergara³, Fanfan Zheng¹, Jingyu Liu³, Zhenyi Yang¹, Nianming Zuo¹, Lingzhong Fan¹, Kaibin Xu¹, Shengfeng Liu¹, Jian Li¹, Yong Xu⁶, Sha Liu⁶, Luxian Lv⁷, Jun Chen⁸, Yunchun Chen⁹, Hua Guo¹⁰, Peng Li¹¹, Lin Lu¹¹, Ping Wan¹⁰, Huaning Wang⁹, Huiling Wang⁸, Hao Yan¹¹, Jun Yan¹¹, Yongfeng Yang¹², Hongxing Zhang¹³, Dai Zhang¹⁴, Tianzi Jiang¹⁵

Affiliations

¹ Brainnetome Center and National Laboratory of Pattern Recognition, Chinese Academy of Sciences, Institute of Automation, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China.
² Brainnetome Center and National Laboratory of Pattern Recognition, Chinese Academy of Sciences, Institute of Automation, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China; The Mind Research Network & LBERI, Albuquerque, NM 87106, USA; CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Institute of Automation, Beijing 100190, China. Electronic address: jing.sui@nlpr.ia.ac.cn.
³ The Mind Research Network & LBERI, Albuquerque, NM 87106, USA.
⁴ Wuxi Mental Health Center, Wuxi 214000, China.
⁵ The Mind Research Network & LBERI, Albuquerque, NM 87106, USA; Department of Electrical and Computer Engineer, The University of New, Albuquerque, NM 87131, USA.
⁶ Department of Psychiatry, First Clinical Medical College, First Hospital of Shanxi Medical University, Taiyuan 030000, China.
⁷ Department of Psychiatry, Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang 453002, China; Henan Key Lab of Biological Psychiatry, Xinxiang Medical University, Xinxiang 453002, China.
⁸ Department of Radiology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
⁹ Department of Psychiatry, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
¹⁰ Zhumadian Psychiatric Hospital, Zhumadian 463000, China.
¹¹ Institute of Mental Health, Peking University Sixth Hospital, Beijing 100191, China; Key Laboratory of Mental Health, Ministry of Health, Peking University, Beijing 100191, China.
¹² Department of Psychiatry, Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang 453002, China; Henan Key Lab of Biological Psychiatry, Xinxiang Medical University, Xinxiang 453002, China,; Key Laboratory for NeuroInformation of Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China.
¹³ Department of Psychiatry, Henan Mental Hospital, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang 453002, China; Department of Psychology, Xinxiang Medical University, Xinxiang 453002, China.
¹⁴ Institute of Mental Health, Peking University Sixth Hospital, Beijing 100191, China; Key Laboratory of Mental Health, Ministry of Health, Peking University, Beijing 100191, China; Center for Life Sciences, PKU-IDG, McGovern Institute for Brain Research, Peking University, Beijing 100871, China.
¹⁵ Brainnetome Center and National Laboratory of Pattern Recognition, Chinese Academy of Sciences, Institute of Automation, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory for NeuroInformation of Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China; Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia; CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Institute of Automation, Beijing 100190, China. Electronic address: jiangtz@nlpr.ia.ac.cn.

Abstract

Background: In the past decades, substantial effort has been made to explore the genetic influence on brain structural/functional abnormalities in schizophrenia, as well as cognitive impairments. In this work, we aimed to extend previous studies to explore the internal mediation pathway among genetic factor, brain features and cognitive scores in a large Chinese dataset.

Methods: Gray matter (GM) volume, fractional amplitude of low-frequency fluctuations (fALFF), and 4522 schizophrenia-susceptible single nucleotide polymorphisms (SNP) from 905 Chinese subjects were jointly analyzed, to investigate the multimodal association. Based on the identified imaging-genetic pattern, correlations with cognition and mediation analysis were then conducted to reveal the potential mediation pathways.

Findings: One linked imaging-genetic pattern was identified to be group discriminative, which was also associated with working memory performance. Particularly, GM reduction in thalamus, putamen and bilateral temporal gyrus in schizophrenia was associated with fALFF decrease in medial prefrontal cortex, both were also associated with genetic factors enriched in neuron development, synapse organization and axon pathways, highlighting genes including CSMD1, CNTNAP2, DCC, GABBR2 etc. This linked pattern was also replicated in an independent cohort (166 subjects), which although showed certain age and clinical differences with the discovery cohort. A further mediation analysis suggested that GM alterations significantly mediated the association from SNP to fALFF, while fALFF mediated the association from SNP and GM to working memory performance.

Interpretation: This study has not only verified the impaired imaging-genetic association in schizophrenia, but also initially revealed a potential genetic-brain-cognition mediation pathway, indicating that polygenic risk factors could exert impact on phenotypic measures from brain structure to function, thus could further affect cognition in schizophrenia.

Keywords: Genetic-brain-cognition pathway; Mediation analysis; Multimodal fusion; Schizophrenia; Working memory.

MeSH terms

Adult
Asian People
Brain / diagnostic imaging*
China
Cognition*
Humans
Male
Memory, Short-Term*
Middle Aged
Polymorphism, Single Nucleotide*
Schizophrenia* / diagnostic imaging
Schizophrenia* / genetics

Grants and funding

R56 MH117107/MH/NIMH NIH HHS/United States