Potential involvement of the interleukin-18 pathway in schizophrenia

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• 作者：Yong Xu^a ; ¹ ; Weihua Yue^b ; ^c ; ¹ ; Yin Yao Shugart^d ; ¹ ; Jianmin Yuan^e ; Guoqiang Wang^e ; Harold Z. Wang^d ; Benjamin Lehrman^d ; Fuquan Zhang^e ; ^{zhangfq@njmu.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Dai Zhang^b ; ^c ; ^f
• 关键词：Schizophrenia ; IL18 ; IL18R1
• 刊名：Journal of Psychiatric Research
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：74
• 期：Complete
• 页码：10-16
• 全文大小：1242 K

文摘

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.

Conclusion

Our findings suggest the alteration of IL18 pathway may contribute to the psychopathology of SZ.