The role of cytokines and inflammatory markers in depression in adolescents

Mills, Natalie Therese (2016). The role of cytokines and inflammatory markers in depression in adolescents PhD Thesis, School of Medicine, The University of Queensland. doi:10.14264/uql.2016.1085

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Author Mills, Natalie Therese
Thesis Title The role of cytokines and inflammatory markers in depression in adolescents
School, Centre or Institute School of Medicine
Institution The University of Queensland
DOI 10.14264/uql.2016.1085
Publication date 2016-11-18
Thesis type PhD Thesis
Supervisor Naomi Wray
James Scott
Gerard Byrne
Nick Martin
Margie Wright
Total pages 186
Language eng
Subjects 1103 Clinical Sciences
110319 Psychiatry (incl. Psychotherapy)
060412 Quantitative Genetics (incl. Disease and Trait Mapping Genetics)
Formatted abstract
Aims: The overarching hypothesis is that circulating levels of pro-inflammatory cytokines and other inflammatory markers are genetically associated with depression in adolescents. Specifically, it is hypothesised that there will be a correlation between variation in genetic risk of depression and genetic variation of circulating pro-inflammatory cytokines and inflammatory markers.

Methods: A systematic review of the literature was conducted to establish the current understanding of the relationship between inflammatory markers and depression in adolescents and to inform study design. Multiple approaches (including different types of genetic analyses and multiple data sets) were used to address the overarching hypothesis. A pilot study measuring cytokines, inflammatory markers, and other biomarkers involved in immune regulation (including Vitamin D, antibodies to infectious agents, and gliadin antibodies (found in coeliac disease)) was conducted in 107 monozygotic (MZ) and 160 dizygotic (DZ) twin pairs (mean age 16.2 years, standard deviation (SD) 0.25 years) from the Brisbane Adolescent Twin Study. A clinical study was undertaken to collect biological samples and clinical data from an in-patient adolescent mental health unit. Investigation of the relationship between iron measures (altered in inflammatory states) and measures of depression was undertaken in community cohorts of twins and their parents (3,416 adolescents from 1,688 families, and 9,035 adults from 4,533 families). In the adolescent cohort, depressive measures were assessed through the Somatic and Psychological Health Report (SPHERE) (mean age 15.1 years (SD 3.2 years)). In the adult cohort, a quantitative score of depression was measured by the Delusions Symptoms State Inventory (DSSI) (mean age 23.2 years (SD 2.2 years)). Heritabilities of, and phenotypic and genetic correlations between, traits were estimated. Association analyses, genetic profile risk score analyses, and LD score analyses were also used to investigate the genetic relationship between the iron and depression measures. The phenotypic and genetic relationship between the inflammatory marker C-reactive protein (CRP) and depression and anxiety was investigated in a community sample from the Australian Twin Registry. Mean age at CRP measurement was 45.3 years (SD 10.1 years), with 14,750 individuals with CRP measures; 8,234 individuals with DSM-IV MDD data; 8,679 individuals with DSM-IV anxiety disorders data; 8,847 individuals with genome-wide SNP data. Analyses were stratified based on experience of childhood trauma. Genetic profile risk score analyses were used to explore the genetic relationship between these variables.

Results: In the pilot study, cytokines that were successfully measured in plasma were found to be moderately heritable (transforming growth factor- β1 (TGFβ1), 0.57 (95% CI 0.26 – 0.80) and tumour necrosis factor-receptor type 1 (TNFR1), 0.50 (95% CI 0.11- 0.63)). A negative correlation between Vitamin D and the cytokine IL-18 (-0.14) was not statistically significant (p=0.054). However, major difficulties were encountered in measuring cytokines, in particular due to the low levels of circulating cytokines in healthy adolescents. Challenges were also encountered in the cytokines study of the clinical sample of adolescents, which were able to be broadly divided into patient factors, blood collection factors, and other data collection factors.

Iron measures were found to be highly heritable in both adolescents and adults: Adolescents: iron 0.46 (95% CI 0.15-0.66), transferrin 0.64 (95% CI 0.42-0.81), transferrin saturation 0.61 (95% CI 0.39-0.70), and log10 ferritin 0.56 (95% CI 0.28-0.72); Adults: iron 0.35 (95% CI 0.25-0.41), transferrin 0.52 (95% CI 0.38-0.56), transferrin saturation 0.50 (95% CI 0.44-0.55), and log10 ferritin 0.42 (95% CI 0.27-0.49). Heritabilities calculated for depressive measures were 0.46 (95% CI 0.29-0.52) and 0.30 (95% CI 0.11-0.40) for adolescents and adults respectively. In adolescents, depression measures were significantly higher in those in the middle 10th percentile versus top 10th percentile of transferrin saturation measures (p=0.002). No evidence was found for a genetic contribution to the relationship between measures of iron and depression in adolescents or adults.

The relationship between CRP and Major Depressive Disorder (MDD) appears to be moderated by age, sex, and body mass index (BMI). No evidence was found that this relationship reflected genetic differences between individuals in CRP. Rather, BMI is likely to be the key factor mediating the relationship between circulating CRP, MDD and anxiety disorders.

Conclusion:

• Cytokines measured in plasma were found to be moderately heritable implying that there is a genetic contribution to variation between individuals in circulating levels of these inflammatory markers.

• Collection of blood inflammatory markers in an in-patient adolescent mental health unit is challenging.

• We found no evidence for a genetic relationship between blood inflammatory markers and measures of depression in community samples.

• Recommendations for future research are:

o Longitudinal study designs are likely to improve the understanding of the role of cytokines / inflammatory markers in adolescent mental illness in relation to genetics, stress, early childhood adversity, and neurodevelopment.

o A less invasive way is needed to accurately measure cytokines in low concentrations

o Additional treatment options of adolescent mental illness are needed, particularly for those individuals who have associated raised pro-inflammatory markers.
Keyword Cytokines
Inflammation
Immune system
Depression
Genes
Stress
Anxiety
Adolescents

Document type: Thesis
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Created: Wed, 09 Nov 2016, 08:06:03 EST by Natalie Mills on behalf of Learning and Research Services (UQ Library)