Association between a functional interleukin 6 receptor genetic variant and risk of depression and psychosis in a population-based birth cohort

Brain Behav Immun. 2018 Mar;69:264-272. doi: 10.1016/j.bbi.2017.11.020. Epub 2017 Dec 2.


Objective: Interleukin 6 (IL-6) levels are commonly elevated in patients with depression and psychosis and in people who are at risk of developing these disorders. A common, functional variant in the IL6R gene (IL6R Asp358Ala; rs2228145 A > C) is known to dampen down inflammation by impairing IL6R signaling. We have examined the association of Asp358Ala with diagnosis of depression and psychosis, serum IL-6, CRP levels, and a number of risk factors commonly linked with inflammation, depression or psychosis. We predicted that if IL-6 were related to depression/psychosis risk causally, rather than due to confounding, Asp358Ala would be associated with risk of these disorders, serum IL-6, CRP levels, but not with any of the confounders.

Method: We used data from the population-based ALSPAC birth cohort. Serum IL-6 and CRP levels were measured at age 9 years. Psychotic disorder, ICD-10 diagnosis of severe depressive episode, and total depression score were assessed at age 18 years. IL6R Asp358Ala was genotyped using the Illumina HumanHap550 quad genome-wide SNP genotyping platform. Risk factors assessed include sex, body mass index, social class, ethnicity, maternal education, birth weight, gestational age, maternal post-natal depression, childhood psychological and behavioral problems, and total IQ score.

Results: Asp358Ala was associated with decreased risk of severe depression and/or psychosis; adjusted odds ratio for those with CC, compared with AA, genotype was 0.38 (95% CI, 0.15-0.94). The variant was associated with increased serum IL-6 levels (P = 5.5 × 10-22) but decreased serum CRP levels (P = 3.5 × 10-5), consistent with an anti-inflammatory effect downstream of IL-6. Asp358Ala was not associated with total depression score. Asp358Ala was not associated with any of the other risk factors commonly linked with inflammation, depression or psychosis (all P > 0.20).

Conclusions: The findings provide further evidence that the IL-6/IL6R pathways are involved in pathogenesis of severe depression and psychosis, and may be novel therapeutic targets. Previously reported associations between IL-6, depression and psychosis are unlikely to be fully explained by confounding. Based on a small number of cases, findings from the current study need replication in other samples.

Keywords: ALSPAC birth cohort; Asp358Ala; Depression; IL-6; IL6R; Immunopsychiatry; Inflammation; Interleukin 6; Interleukin 6 receptor; Interleukin 6 receptor gene; Mendelian randomization; Psychosis; rs2228145.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • C-Reactive Protein / metabolism
  • Child
  • Cohort Studies
  • Depressive Disorder / diagnosis
  • Depressive Disorder / genetics*
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Interleukin-6 / blood
  • Male
  • Polymorphism, Single Nucleotide*
  • Psychotic Disorders / diagnosis
  • Psychotic Disorders / genetics*
  • Receptors, Interleukin-6 / genetics*


  • Interleukin-6
  • Receptors, Interleukin-6
  • interleukin-6 receptor alpha
  • C-Reactive Protein