Abstract
Literature suggests that the effect of winter birth on vulnerability to schizophrenia might be mediated by increased expression of proinflammatory cytokines due to prenatal infection and its inadequate regulation by anti-inflammatory factors. As the response of the immune system depends on genotype, this study assessed the interaction effects of cytokine genes and season of birth (SOB) on schizotypy measured with the Schizotypal Personality Questionnaire (SPQ-74). We searched for associations of IL1B rs16944, IL4 rs2243250, and IL-1RN VNTR polymorphisms, SOB, and their interactions with the SPQ-74 total score in a sample of 278 healthy individuals. A significant effect of the IL4 X SOB interaction was found, p = 0.007 and η2 = 0.028. We confirmed this effect using an extended sample of 373 individuals. Homozygotes CC born in winter showed the highest SPQ total score and differed significantly from winter-born T allele carriers, p = 0.049. This difference was demonstrated for cognitive-perceptual and disorganized but not interpersonal dimensions. The findings are consistent with the hypothesis that the cytokine genes by SOB interaction can influence variability of schizotypal traits in the general population. The IL4 T allele appeared to have a protective effect against the development of positive and disorganized schizotypal traits in winter-born individuals.
Highlights
Evidence suggests that people born during winter months have an increased risk of developing schizophrenia [1,2,3]
We focused on the proinflammatory cytokine interleukin- (IL-) 1β because of (1) its suggestive role in altered brain development [27] and schizophrenia etiology and pathogenesis [28, 29] and (2) findings indicating its higher concentration in infants born in winter [6]
The full factorial analysis of variance (ANOVA) with all three polymorphisms, season of birth (SOB), and their interactions as between-subjects factors yielded a significant effect of the IL4 X SOB interaction on the SPQ total score, F(1, 262) = 7.45, p = 0.007, and η2 = 0.028
Summary
Evidence suggests that people born during winter months have an increased risk of developing schizophrenia [1,2,3]. One plausible explanation is that the increased risk of schizophrenia in individuals born in winter is caused by deleterious effects of innate immune response-related factors on brain development [2, 4, 5]. Recent findings have demonstrated that SOB may shape neonatal immune function, with winter births correlating with higher levels of most immune cell types in cord blood and airway inflammatory mediators, and this season-related immune profile seems to be an outcome of exposures from the maternal environment [6]. Since prenatal exposure to different types of viral or bacterial infections has similar debilitating effects in later life, it is thought that not pathogen itself but the response of the innate immune system, the increased production of inflammatory cytokines, is the critical mediator in altering fetal brain development [9]
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