Childhood adversity is associated with increased risk of future psychiatric illness (Croft et al., 2018). Raised levels of markers of inflammation are also associated future psychiatric illness. We have shown that certain lipids (O'Gorman et al,2017 ) and complement and coagulation proteins (English et al, 2018; Focking et al, 2019) are also raised and /or dysregulated in association with future psychotic illness, and we have shown that these lipid and proteins changes are functionally related to each other (Madrid et al, 2019). Changes to these biological markers may reflect these environmental exposures, in addition to representing novel targets for therapeutic intervention. We have also shown that the complement and coagulation pathway proteins are elevated by exposure to stress in an animal model of social defeat (Focking et al, 2019). There are however, important gaps in our knowledge regarding the relationship between psychiatric outcomes, early exposure to adversity, and early biological measures such as blood protein, lipid, and inflammatory markers levels. Our proposal will address these gaps.

This current proposal aims to utilise a longitudinal design involving all subjects within the ALSPAC Cohort who gave blood at age 11 (n=2160) and / or age 17 (n=1776) and who participated in interviews at age 24 . Cytokine, proteomic and lipidomic analyses will be undertaken in plasma samples from all of these subjects. Exposure to childhood adversity will be determined using existing data from ALSPAC children and parents for a range of possible experiences such as bullying, physical abuse, sexual abuse and emotional neglect, as previously described (Croft et al., 2018). The primary outcomes of interest would be subjects at age 24 who report 1) psychotic experiences 2) depressive / affective symptoms 3) anxiety symptoms and 4) fulfill criteria for any psychiatric disorder at age 24. A secondary outcome will be that of global functioning, as determined from available ALSPAC data, at age 24.

Data will be compared and integrated between groups, and examined in relation to the detailed environmental exposure data available within ALSPAC.

Our overarching aim is to investigate the longitudinal relationship between environmental exposures, blood markers and different psychiatric outcomes.

We have the following specific objectives;
1. To investigate the longitudinal pattern of biomarker change in the different disorders.
2. To investigate the relationship between environmental exposures and biomarker expression.
3. To integrate this data with other, already available, genomic, neuroimaging and neuropsychology data in order to build a predictive model of psychiatric disorders generally based on early biological and environmental data.

This proposal represents a unique opportunity to understand the relationship between environmental experiences, longitudinal measures of biological markers and psychiatric outcomes at age 24.

References:

Croft, J., Heron, J., Teufel, C., Cannon, M., Wolke, D., Thompson, A., . . . Zammit, S. (2018). Association of Trauma Type, Age of Exposure, and Frequency in Childhood and Adolescence With Psychotic Experiences in Early Adulthood. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2018.3155. Davison J, O'Gorman A, Brennan L, Cotter DR. A systematic review of metabolite biomarkers of schizophrenia. Schizophr Res. 2018 May;195:32-50. doi: 10.1016/j.schres.2017.09.021. Epub 2017 Sep 22. Review. PMID: 28947341.

Davison J, O'Gorman A, Brennan L, Cotter DR. A systematic review of metabolite biomarkers of schizophrenia. Schizophr Res. 2018 May;195:32-50. doi: 10.1016/j.schres.2017.09.021. Epub 2017 Sep 22. Review. PMID: 28947341.

English JA, Lopez LM, O'Gorman A, Föcking M, Hryniewiecka M, Scaife C, Sabherwal S, Wynne K, Dicker P, Rutten BPF, Lewis G, Zammit S, Cannon M, Cagney G, Cotter DR. Blood-Based Protein Changes in Childhood Are Associated With Increased Risk for Later Psychotic Disorder: Evidence From a Nested Case-Control Study of the ALSPAC Longitudinal Birth Cohort. Schizophr Bull. 2018 Feb 15;44(2):297-306. PMID: 29036721.

Föcking M, Sabherwal S, Cates HM, Scaife C, Dicker P, Hryniewiecka M, Wynne K, Rutten BPF, Lewis G, Cannon M, Nestler EJ, Heurich M, Cagney G, Zammit S, Cotter DR. Complement pathway changes at age 12 are associated with psychotic experiences at age 18 in a longitudinal population-based study: evidence for a role of stress. Mol Psychiatry. 2019 Jan 11. PMID: 30635638.

Madrid-Gambin F, Föcking M, Sabherwal S, Heurich M, English JA, O'Gorman A, Suvitaival T, Ahonen L, Cannon M, Lewis G, Mattila I, Scaife C, Madden S, Hyötyläinen T, Orešič M, Zammit S, Cagney G, Cotter DR, Brennan L. Integrated Lipidomics and Proteomics Point to Early Blood-Based Changes in Childhood Preceding Later Development of Psychotic Experiences: Evidence From the Avon Longitudinal Study of Parents and Children. Biol Psychiatry. 2019 Jan 30. PMID: 30878195.

O'Gorman A, Suvitaival T, Ahonen L, Cannon M, Zammit S, Lewis G, Roche HM, Mattila I, Hyotylainen T, Oresic M, Brennan L, Cotter DR. Identification of a plasma signature of psychotic disorder in children and adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Transl Psychiatry. 2017 Sep 26;7(9):e1240. doi: 10.1038/tp.2017.211. PMID: 28949339