The goal of this project application is to enable a PhD student to use data requested in previous applications.
We and others have identified numerous risk factors that influence mental health in young adults and early adulthood. These include adversity, cannabis use, population density, immigrant status (PMID: 29352556, 31563981), exposure to infections such as COVID (PMID: 35987197), obstetric and delivery complications (PMID: 12091183), and maternal characteristics and behaviours during pregnancy. Evidence for example suggests that offspring of mothers who smoked during pregnancy have an increased risk (38%) of developing schizophrenia (PMID: 27216261). Furthermore, infection during pregnancy is associated with an increased the risk of psychosis in offspring (PMID: 26303935). Additionally, in the ALSPAC cohort, we recently identified that suicidal ideation at age 17 is associated with 7-fold increased odds of psychotic disorder, and with depressive disorder and generalised anxiety disorder at age 24. Indeed, over 40% of those with psychotic disorder in early adulthood had experienced this symptom in late adolescence (Mongan et al, 2022).
We and others have also identified evidence for inflammatory marker dysregulation both preceding and in association with psychiatric disorders including psychosis, depression and recently, long COVID (PMID: 36085284, 35472304). Dysregulation of acute inflammatory markers [such as Interleukin (IL)-6 and C-Reactive Protein] and complement proteins has been reported prior to and in association with these outcomes (PMID: 25133871, PMID: 32857162).

Using ALSPAC data we identified for the first time the cross-sectional association of suPAR (soluble urokinase plasminogen activator receptor- an established marker of chronic inflammation) and IL-6 (an established marker of primarily acute inflammation) with psychotic disorder in young adults (PMID: 37004760). We previously found an inverse association between the anti-inflammatory marker n-3 fatty acid docosahexaenoic acid (DHA) at age 17 and psychotic disorder at age 24 in the ALSPAC cohort (PMID 34059620). Using ALSPAC data, we have also shown for the first time that elevated suPAR is associated cross-sectionally with cannabis exposure, itself a marker for mental ill health (Power et al., 2022 (under review)).
We now seek to expand our knowledge to mental health outcomes in early adulthood (using data collected at age 24 and age 30). We wish to examine cross-sectional and longitudinal associations between early life, childhood and later life risk factors with inflammation in relation to clinical thresholds of psychiatric disorders, as well as in relation to specific symptoms and symptom severity. In light of recent findings, (PMID: 34390805; PMID: 26033244), we are particularly interested in the relationship between adverse childhood events including physical, sexual and emotional abuse, bullying or victimisation, and inflammatory dysregulation in the development of psychiatric disorders. Elevated inflammatory levels (supar) for example have been reported in adolescents that have experienced persistent parent-child separation in childhood (PMID: 34454061).

Additionally, sexual minority groups can experience increased exposure to victimization and discrimination, as well as higher rates of anxiety, depression, suicidal thoughts and antisocial behaviour (PMID: 35572280). Recent evidence suggests the presence of increased inflammatory marker levels in such groups (PMID: 32930919).
Additionally, emerging evidence also suggests that exposure to adversity such as high stress across lifetime (PMID: 26673150) or exposure to sexual abuse (PMID: 29365106) influences epigenetic aging in adulthood. One recent meta-analysis quantified this age acceleration, showing that any exposure to childhood trauma was associated with an epigenetic “outpace” of as much as 6 months (PMID: 29452766).
We hypothesise that exposure to environmental risk factors and early-life adversity is associated with chronic inflammatory dysregulation, in line with recent evidence (PMID: 31682707, 26033244, 34990745). We also hypothesise that inflammatory dysregulation will be more common in those who go on to report mental disorders in adulthood (PMID: 25133871, PMID: 32857162). Crucially, we hypothesise that inflammatory dysregulation mediates the relationship between environmental exposures and adult mental disorders, which could provide evidence for a biological mechanism by which environmental exposures influences the risk of adult mental disorder. Alternatively, environmental exposures and biological risk factors may operate independently, but have a cumulative effect on the risk of mental disorders. We propose to investigate this using a combination of existing ALSPAC data, and new data derived from assays undertaken by us which assessed levels of the robust marker of chronic inflammation, suPAR, in age 24 plasma samples donated by ALSPAC participants.

Additionally, we would like to request data relating to general medical conditions and previous infections as accounting for these factors will be important to avoid potential confounding of our findings. For example, there are reports of associations between childhood infection, in particular viral CNS infections and increased risk for psychosis in adulthood (PMID: 29450471; PMID: 22704639). Regarding suPAR itself, there is also evidence of associations between elevated suPAR levels with the development of cancer, CVD, T2D and mortality in the general and psychiatric populations (PMID: 20561148).

We are interested in investigating the longitudinal associations between biological and environmental risk factors with subsequent mental ill-health at age 24 and age 30 (when available). In order to explain any potential relationships appropriately, we will need to include particular demographic variables (such as ethnicity) as co-varying factors.
Previous research has shown that the incidence of psychotic disorders is elevated in various ethnic groups (PMID: 28642258). Evidence has also indicated an association between ethnicity and inflammation, with Caucasian populations often having lower CRP or IL-6 levels compared to other ethnic groups (PMID: 15205215; PMID: 16123316). Based on such findings, we feel that it is important to determine the extent of the relationship between ethnicity, inflammation and later psychiatric outcomes.
Evidence has also shown that lifestyle factors including low physical activity can contribute to a higher suPAR levels (PMID: 30679937), as well as altered levels of acute inflammatory biomarkers (CRP) in healthy populations (PMID: 12038947). Physical activity was also shown to act as a potential protective mechanism against oxidative stress in first-episode psychosis patients (PMID: 32709912). Based on such findings, we would like to investigate how physical activity might influence the relationship between inflammation (as measured by suPAR, and/or CRP & IL-6) and later psychiatric outcome.

An earlier project, B4168 aims to investigate longitudinal associations between environmental risk factors and subsequent mental ill-health, and then if possible, to investigate whether inflammation mediates the relationship between these environmental risk factors and mental health outcomes. One such risk factor is childhood trauma.
There is some evidence that trauma exposure is associated with elevated inflammatory levels (PMID: 29741788) and with poor mental health outcomes (PMID: 23592532).
We aim to explore if these relationships exist in relation to age 24 chronic inflammatory marker - suPAR - and if inflammation (as measured by suPAR) mediates the relationship between trauma and poor mental health.
Recently, emerging evidence suggests that while trauma might be related to elevated inflammation levels, certain positive experiences in childhood are associated with lower levels of inflammation (PMID: 36420372). Therefore, we feel that in order to fully understand the relationship between trauma exposure, inflammation and later mental health outcomes, we must investigate and account for positive childhood experiences as an important confounder/contributor in the relationship.

No new data is requested - Only data from B4168 will be used.