Leukemia inhibitory factor gene is associated with schizophrenia and working memory function

Leukemia inhibitory factor (LIF), a member of the interleukin-6 cytokine family, regulates the neuronal phenotype and coordinates astrocyte, oligodendrocyte, microglia, and inflammatory cell responses. The LIF gene is located on 22q12.1–q12.2, a hot spot for schizophrenia. Three polymorphisms of the LIF gene (rs929271, rs737812, and rs929273) were examined in a case–control association study of 390 patients with schizophrenia and 410 age- and sex-matched controls. Effects of a risk genotype of LIF on cognitive domains were evaluated by the Wechsler Adult Intelligence Scale—Revised, Wechsler Memory Scale—Revised, and Wisconsin Card Sorting Test (WCST) in 355 healthy volunteers. The LIF gene showed significant associations with schizophrenia at rs929271 and a haplotype consisting of rs929271–rs737812. After stratification by subtype of schizophrenia, the hebephrenic, but not paranoid, type was associated with the LIF gene at rs929271 (allele, P = 0.014) and the haplotype (permutation P = 0.013). Having the T-allele and T-carrier genotypes (TT and TG) of rs929271 were risks for hebephrenic schizophrenia, and the odds ratios were 1.38 (95% CI: 1.21–1.56) and 1.54 (95%CI: 1.19–1.98), respectively. Subjects with T-carrier genotypes made significantly more errors on the WCST compared with those without (P = 0.04). The present study indicated that the LIF gene variant may produce susceptibility to hebephrenic schizophrenia and deterioration of working memory function.