GENES AND SCHIZOPHRENIA

Adapted from Steven Stahl, MD, PHD

• Genes do not encode for mental illnesses, behaviors or personalities. Genes encode for proteins.

• Genes may produce genetically altered proteins that code for subtle molecular abnormalities, which in turn may be linked to the development of psychiatric symptoms.

• According to this theory, genes may code for an abnormality in the neuro-developmental process or in the synthesis or activity of enzymes, transporters, receptors, components of signal transduction, synaptic plasticity machinery and other neuronal components.

• Each subtle molecular abnormality may convey risk for the development of mental illness rather than directly causing a mental illness.

Subtle Molecular Abnormalities Theory

Mental illness may be explained by genes causing subtle molecular abnormalities

The Path From Gene to Behavior

• Abnormal cortical activity in response to stimuli (abnormal information processing) is an example of a biological endophenotype.

• A single symptom of a mental illness associated with a mental illness is an example of a symptom endophenotype.

• In the path from gene to mental illness, a genotype may code for a subtle molecular abnormality that is closely linked to a biological endophenotype (such as abnormal information processing in specific neuronal circuits), which in turn may be linked to a symptom or behavior(symptom endophenotype) associated with mental illness.

Biological Endophenotype

• Development of psychiatric symptoms is often the function of both genetic and environmental influences.

• Environmental stressors such as child abuse, divorce, viruses or toxins can increase the risk of developing a mental illness.

• Individuals with a normal genome and thus normal circuits may experience only normal activation of circuits in response to stressful events = they have a normal biological endophenotype. These individuals would not express a mental illness.

Stress Diathesis Model

Stress Diathesis Hypothesis

• Environmental stress coupled with a risk gene for mental illness may lead to inefficient information processing in the “biased” circuit; however this does not necessarily mean that symptoms will ensue.

• Genetically inefficient information processing may be behaviorally “silent” if it is compensated by overactivation of the back up systems.

• This individual may still have a normal behavioral phenotype despite having an abnormal biological endophenotype.

• Abnormal circuit activation may be detectable with functional brain scanning, but clinical interview would reveal no psychiatric symptoms.

Genetically biased circuit, but no symptoms

Each suspension cable represents a gene and vehicles represent types of environmental

stressors.

• In addition to genetically determined molecular abnormalities and environmental stressors, personality factors such as coping skills and lifestyle can also affect the impact of stressors on an individual’s genome and thus his or her total risk of mental illness.

• Adaptive coping skills and healthy lifestyles may mitigate the effects of stressful life events on genetic risk, so that despite a “biased” circuit, the individual still exhibits a normal phenotype.

• An individual with poor coping skills and unhealthy lifestyle, stressful life events may exacerbate the effects of genetic risk and render the “biased” circuit unable to compensate .

Stress and Personality

Subtle molecular abnormalities and major depressive disorder

• Major depressive disorder may be less robustly biologically determined than schizophrenia, so that minor stressors may be less likely to trigger symptoms even in the presence of multiple genetic risk factors.

• Major stressors coupled with specific genetic risks of depression may have a greater likelihood of leading to symptoms of a major depressive disorder.