title: Potential involvement of the interleukin-18 pathway in schizophrenia.
abstract: OBJECTIVE
  Accumulating evidence implicates inflammatory cytokines in the development of psychiatric disorders, including schizophrenia (SZ). IL-18 is one of cytokines that plays a crucial role in immune response and neurodevelopment. We aimed to investigate potential genetic alterations of the cytokine system underpinning SZ.
  
  
  METHODS
  We tested the association of genetic variants within the cytokine-cytokine receptor interaction (CCRI) pathway with SZ, using GWAS-derived data involving 768 adult SZ patients and 1348 controls, and replicated the association of IL18R1 rs1035130 with SZ in an independent sample of 1957 adult patients and 1509 controls. We compared expression levels of IL18, IL18R1 and IL18RAP in peripheral blood of a cohort of adolescent participants (<18 years), including 14 early-onset SZ patients and 13 healthy controls. Furthermore, we carried out a cis-eQTL (expression Quantitative Trait Loci) and a cis-mQTL (Methylation Quantitative Trait Loci) analysis for IL18R1 rs1035130.
  
  
  RESULTS
  In the discovery stage, we detected association signals within two IL18 pathway genes, IL18R1 and IL18RAP, with the most significant marker being IL18R1 rs1035130 (P = 1.84E-7, OR = 0.70). In the validation stage, we found rs1035130 was associated with SZ (P = 0.028, OR = 0.89). Expressions of IL18 and IL18R1 were altered in blood of SZ patients compared with 13 controls. Furthermore, cis-QTL analyses indicated that rs1035130 was associated with an eQTL and 5 mQTLs.
  
  
  CONCLUSIONS
  Our findings suggest the alteration of IL18 pathway may contribute to the psychopathology of SZ.
authors.affiliation: Department of Psychiatry, First Clinical Medical College/First Hospital of Shanxi Medical University, Taiyuan, 030000, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Institute of Mental Health, Sixth Hospital, Peking University, Beijing, China; Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders (Peking University), Beijing, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Yue
authors.affiliation: Unit on Statistical Genomics, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Yin Yao
authors.initials: YY
authors.lastname: Shugart
authors.affiliation: Wuxi Mental Health Center of Nanjing Medical University, Wuxi, 214151, China.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Wuxi Mental Health Center of Nanjing Medical University, Wuxi, 214151, China.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Unit on Statistical Genomics, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Harold Z
authors.initials: HZ
authors.lastname: Wang
authors.affiliation: Unit on Statistical Genomics, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lehrman
authors.affiliation: Wuxi Mental Health Center of Nanjing Medical University, Wuxi, 214151, China. Electronic address: zhangfq@njmu.edu.cn.
authors.forename: Fuquan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Institute of Mental Health, Sixth Hospital, Peking University, Beijing, China; Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders (Peking University), Beijing, China; Peking-Tsinghua Center for Life Sciences/PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China.
authors.forename: Dai
authors.initials: D
authors.lastname: Zhang
mesh_terms: D000293:Adolescent; D002648:Child; D002681:China; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D020382:Interleukin-18 / Q000097:blood*; D053727:Interleukin-18 Receptor alpha Subunit / Q000097:blood* / Q000235:genetics*; D053728:Interleukin-18 Receptor beta Subunit / Q000097:blood; D008297:Male; D040641:Quantitative Trait Loci; D012559:Schizophrenia
chemical_list: C508572:IL18R1 protein, human; C115629:IL18RAP protein, human; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D053728:Interleukin-18 Receptor beta Subunit
keywords: IL18; IL18R1; Schizophrenia