Contribution of Genetics, Environment, and Inflammation to Development of Severe Mental Illness

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Introduction

Severe and persistent mental illnesses (SPMI) encompass psychiatric conditions including psychotic disorders (eg, schizophrenia), affective and mood disorders (eg, bipolar disorder, major depression), anxiety disorders including posttraumatic stress disorder (PTSD) and trauma-related conditions, and developmental disorders such as autism spectrum disorder (ASD).

Emerging research supports a multifactorial causation model in which polygenic genetic vulnerability interacts dynamically with diverse modifiable environmental factors, notably including postinfectious inflammation and substance use (petty drug abuse), as key pathways affecting illness onset and persistence^1,2,3

Genetic Vulnerability Across Disorders

• Psychotic disorders such as schizophrenia demonstrate heritability estimates up to 80%, mediated by genetic variants affecting neural networks and cognitive endophenotypes.⁴
• Mood and affective disorders show high polygenic risk (40% to 70%) overlapping with psychosis and anxiety disorders.⁵
• Anxiety, obsessive compulsive disorder (OCD), PTSD, and trauma-related disorders share moderate to high heritability (40% to 65%) along with genetic overlap with mood disorders.^6,7
• Autism spectrum disorder is highly heritable (70% to 90%) with broad genetic heterogeneity impacting related developmental and psychiatric vulnerabilities.⁸ The majority of spectrum-disorder patients suffer with neuropsychiatric comorbidities such as depression, epilepsy, anxiety, and psychosis such as schizophrenia.^9,10

Environmental Risk Factors

Key environmental contributors to SPMI include:

1. Parental Communication Deviance: Fragmented, ambiguous family communication patterns elevate risk for schizophrenia spectrum and impact social and emotional development relevant to mood, anxiety, and autistic spectrum conditions.^3,11,12
2. Inadequacy or Deprivation, Maltreatment: Whether intentional or not, caretakers can directly affect physical and psychiatric well-being.^13-17
3. Childhood Lead Exposure: Lead neurotoxicity disrupts brain development and neurotransmission, increasing multifactorial risk for psychiatric and neurodevelopmental disorders.^2,18
4. Head Injury/Traumatic Brain Injury (TBI): Neural damage and neuroinflammation after traumatic injury amplify genetic vulnerability to psychosis, mood, anxiety, and developmental impairments.^5,19
5. Postinfectious Inflammation: Systemic infections trigger cytokine storms and brain neuroinflammation disrupting neurotransmitter systems, neuroendocrine regulation, and sometimes induc autoimmune injury, contributing to diverse psychiatric syndromes.^1,20
6. Petty Drug Abuse: Use of caffeine, tobacco or nicotine, cannabis, alcohol, and energy drinks constitutes a modifiable environmental risk factor interacting with genetic vulnerability, elevating risk and persistence of psychiatric disorders.⁵

Post-Infectious Inflammation as a Distinct Environmental Factor

Infections provoke systemic immune activation with elevated cytokines (IL-6, TNF-α, IL-1β) that signal across the blood-brain barrier activating microglia, causing neuroinflammation, impaired synaptic plasticity, neurotransmitter balance disruption, and sometimes autoimmune neuronal injury.^1,20 These contribute to onset or worsening of depression, psychosis, PTSD, OCD, and neurodevelopmental disorders.

Concluding Thoughts

Severe and persistent mental illnesses arise from the intersection of inherited genetic liability, aberrant communication in the family, and multiple environmental risks including concussion/TBI, environmental toxin exposure, postinfectious inflammation, and petty drug abuse.¹⁷

Together, neuroinflammation, exposures to environmental toxins, brain trauma, family environment, and substance use or abuse synergistically disrupt brain function governing cognition, mood, and behavior. Prevention and treatment must integrate approaches addressing infectious, toxic, psychosocial, and substance-related risks to reduce illness burden and improve outcomes.

Table 1. Integrated Risk Factors and Mechanisms In Severe and Persistent Mental Illness

Table 2. Post-Infectious Neuroinflammatory Pathway to Psychiatric Symptoms

Table 3. Clinical and Public Health Intervention Stratification for Post-Infectious Neuropsychiatric Risks

Dr Best is the director of The Neuroscience Center in Deerfield, Illinois.

References

1. Boldrini M, Canoll PD, Klein RS. How COVID-19 affects the brain. JAMA Psychiatry. 2021;78(6):682-683.

2. McFarland MJ, Reuben A, Hauer M. Contribution of childhood lead exposure to psychopathology in the us population over the past 75 years. J Child Psychol Psychiatry. 2024.

3. Roisko R, Wahlberg KE, Hakko H, et al. Communication deviance in parents of families with adoptees at a high or low risk of schizophrenia-spectrum disorders and its associations with attributes of the adoptee and the adoptive parents. Psych Res. 2011;185(1):66-71.

4. Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry. 2003;60(12):1187-1192.

5. Robinson N, Bergen SE. Environmental risk factors for schizophrenia and bipolar disorder and their relationship to genetic risk: current knowledge and future directions. Front Genet. 2021;12:686666.

6. Burton CL, Park LS, Corfield EC, et al. Heritability of obsessive–compulsive trait dimensions in youth from the general population. Transl Psychiatry. 2018;8:191.

7. Mataix-Cols D, Fernández de la Cruz L, Beucke JC, et al. Heritability of clinically diagnosed obsessive-compulsive disorder among twins. JAMA Psychiatry. 2024;81(6):631-632.

8. Sandin S, Lichtenstein P, Kuja-Halkola R, et al. The heritability of autism spectrum disorder. Am J Psychiatry. 2017;318(12):1182.

9. Hughes JR, Melyn M. EEG and seizures in autistic children and adolescents: further findings with therapeutic implications. Clin EEG Neurosci. 2005;36(1):15-20.

10. Underwood JFG, DelPozo-Banos M. Neurological and psychiatric disorders among autistic adults: a population healthcare record study.Psychological Medicine. 2022;53(12):5663-5673.

11. Levy DL, Coleman MJ, Sung H, et al. (2010). The genetic basis of thought disorder and language and communication disturbances in schizophrenia. J Neurolinguistics. 2010;23(3):176-192.

12. de Sousa P, Varese F, Sellwood W, et al. Parental communication and psychosis: a meta-analysis. Schizophr Bull. 2014;40(4):756-768.

13. Binder EB, Bradley RG, Liu W, et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA. 2008;299(11):1291-1305.

14. McGrath JJ, Eyles DW, Pedersen CB, et al. Neonatal vitamin D status and risk of schizophrenia: a population-based case-control study. Arch Gen Psychiatry. 2010;67(9):889-894.

15. Schulz-Heik RJ, Rhee SH, Silvern LE. Testing genetic and environmental mediation. Behavior Genetics. 2009;40(3), 338-348.

16. South SC, Schafer MH, Ferraro KF. Genetic and environmental overlap between childhood maltreatment and adult physical health. twin research and human genetics. 2015;18(5):533-544.

17. Uher R. Gene–environment interactions in severe mental illness. Frontiers in Psychiatry. 2014;5:48.

18. Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry. 2003;60(12):1187-1192.

19. Orlovska S, Pedersen MS, Benros ME, et al.Head injury as risk factor for psychiatric disorders: a nationwide register-based follow-up study of 113,906 persons with head injury. Am J Psychiatry. 2014;171(4):463-469.

20. Okobi OE, Ayo-Farai O, Tran M, et al. The impact of infectious diseases on psychiatric disorders: a systematic review. Cureus. 2024.