Genes may encode for subtle molecular abnormalities rather than directly causing mental illnesses. These abnormalities could alter neurodevelopment or neuronal components, increasing risk for conditions like schizophrenia. A genotype could code for an abnormality linked to abnormal brain activity, a biological endophenotype, which may then relate to psychiatric symptoms. Both genetic and environmental factors like stress, trauma, or lifestyle influence whether symptoms develop.

1. GENES AND SCHIZOPHRENIA
Adapted from Steven Stahl, MD, PHD

2. Subtle Molecular Abnormalities
Theory
• 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.

3. Mental illness may be explained by genes causing
subtle molecular abnormalities

4. The Path From Gene to Behavior

5. Biological Endophenotype
• 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.

7. Stress Diathesis Model
• 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.

8. Stress Diathesis Hypothesis

9. Genetically biased circuit, but no
symptoms
• 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.

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

15. Stress and Personality
• 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 .

17. 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.