Research Paper Volume 12, Issue 3 pp 2169—2225

Identification of 34 genes conferring genetic and pharmacological risk for the comorbidity of schizophrenia and smoking behaviors

Yunlong Ma1, , Jingjing Li1, , Yi Xu1, , Yan Wang1, , Yinghao Yao1, , Qiang Liu1, , Maiqiu Wang1, , Xinyi Zhao1, , Rongli Fan1, , Jiali Chen1, , Bin Zhang1, , Zhen Cai1, , Haijun Han1, , Zhongli Yang1, , Wenji Yuan1, , Yigang Zhong2, , Xiangning Chen3, , Jennie Z. Ma4, , Thomas J. Payne5, , Yizhou Xu2, , Yuping Ning6, , Wenyan Cui1, , Ming D. Li1,7, ,

  • 1 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
  • 2 Department of Cardiology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
  • 3 Institute of Personalized Medicine, University of Nevada at Las Vegas, Las Vegas, NV 89154, USA
  • 4 , Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22904, USA
  • 5 Department of Otolaryngology and Communicative Sciences, University of Mississippi Medical Center, Jackson, MS 39216, USA
  • 6 The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China
  • 7 Research Center for Air Pollution and Health, Zhejiang University, Hangzhou, China

Received: November 11, 2019       Accepted: January 2, 2020       Published: February 3, 2020
How to Cite

Copyright: © 2020 Ma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


The prevalence of smoking is significantly higher in persons with schizophrenia (SCZ) than in the general population. However, the biological mechanisms of the comorbidity of smoking and SCZ are largely unknown. This study aimed to reveal shared biological pathways for the two diseases by analyzing data from two genome-wide association studies with a total sample size of 153,898. With pathway-based analysis, we first discovered 18 significantly enriched pathways shared by SCZ and smoking, which were classified into five groups: postsynaptic density, cadherin binding, dendritic spine, long-term depression, and axon guidance. Then, by using an integrative analysis of genetic, epigenetic, and expression data, we found not only 34 critical genes (e.g., PRKCZ, ARHGEF3, and CDKN1A) but also various risk-associated SNPs in these genes, which convey susceptibility to the comorbidity of the two disorders. Finally, using both in vivo and in vitro data, we demonstrated that the expression profiles of the 34 genes were significantly altered by multiple psychotropic drugs. Together, this multi-omics study not only reveals target genes for new drugs to treat SCZ but also reveals new insights into the shared genetic vulnerabilities of SCZ and smoking behaviors.


SCZ: schizophrenia; ND: nicotine dependence; GWAS: genome-wide association study; CPD: cigarette smoking per day; MDS: multidimensional scaling; PPI: protein-protein interaction; eQTL: expression quantitative trait loci; meQTL: methylation quantitative trait loci; PGC: the psychiatric genomics consortium; TAG: the tobacco and genetics consortium; GEO: Gene Expression Omnibus; hiPSCs: human induced pluripotent stem cells; KEGG: Kyoto Encyclopedia of Genes and Genomes; GO: gene ontology; WGCNA: weighted gene co-expression network analysis; DGIdb: the Drug-Gene Interaction database; LD: linkage disequilibrium.