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Letter   |    
Genetic and Environmental Interactions in Psychiatric Illnesses
Massoud Stephane, M.D.
The Journal of Neuropsychiatry and Clinical Neurosciences 2003;15:386-387. doi:10.1176/appi.neuropsych.15.3.386

Strong evidence supports a genetic basis for many psychiatric illnesses, such as Huntington disease (HD), autism, schizophrenia, and depression. In most of these diseases, environmental factors are implicated. Interactions between environment and genome, however, are unclear.

Although HD, autism, schizophrenia, and depression are genetically determined diseases, they do not inevitably have onset at birth. In fact delayed onset is generally the case. In autism, the peak onset is before 3 years of age and between 20 and 30, 20 and 40, and 35 and 40 years of age in schizophrenia, depression, and HD, respectively. Since detecting the disease depends on the sensitivity of clinical evaluations and the degree of repercussion of the disease on the patients’ ability to function in daily life, a reasonable assumption might be that the disease process precedes the clinical manifestation. In fact, the degeneration process in HD unfolds over a lengthy period prior to clinical manifestation, and appropriate screening for schizophrenia detects prodromes before the first break.5 Granting these factors account for the delay in clinical onset relative to gene expression (or active disease process), they are not sufficient to indicate that the underlying genes are expressed from the very beginning since birth.

In addition to the variation in the age of onset between HD, autism, schizophrenia, and depression, these illnesses vary considerably in their time course. In autism, steady qualities of deficits are present, and learning and adaptation are impaired or facilitated in specific ways. Schizophrenia and depression have episodic courses, with variable degrees of remission between episodes, while the deficits in HD progress steadily. Furthermore, genes have variable roles in these illnesses. Defective genes are sufficient for the development of HD, however, current opinions suggest that genes are necessary but not sufficient for the development of schizophrenia or depression.

The variation in age of onset and time course and the possibility of environment-dependant gene expression leave a number of questions open for discussion: (1) What is the relationship between gene expression and clinical manifestation? (2) Are underlying genes expressed, from the outset since birth (or even before birth) or at different time points during development? (3) Are the exacerbation and remission of schizophrenia and depression associated with corresponding fluctuation in gene expression?

Jacob and Monod6 discovered that genes in prokaryotes could be regulated by environmental factors. They showed that only in the presence of lactose does Escherichia coli greatly synthesize an enzyme that breaks down lactose. Since the Jacob and Monod6 study, the regulation of gene expression in eukaryotes has been investigated extensively and found to take place at multiple levels, such as transcription, translation, and gene rearrangement. The widely accepted view is that genes fall into one of two basic categories: those that express themselves at a steady rate, regardless of environmental conditions (i.e., constitutive genes), and those that are subject to regulation (i.e., inducible genes).

The first category probably subserves the essential constituents of an organism. On the other hand, gene expression regulation has been implicated in a variety of processes, such as learning, memory, adaptation, and development.710 Thus the second category must be the site for environmental and genetic interaction.

We hypothesize that autism is determined by constitutive genes, which would explain the possibility of onset at birth, the stable time course, and the qualities of deficits. According to this view, autism thwarts development; but the pathology itself is not developmental, and environmental factors are of no importance. We also propose that the HD gene is from the constitutive group, which explains the steady progression. The variability of the age of onset could be linked to the variability in the rate of gene expression. In addition, we believe that schizophrenia and depression are linked to genes from the second group (inducible genes). At some point during adaptive and cognitive development, defective genes are called upon, giving rise to psychotic or mood breakdown. The brain dynamic systems could restabilize to some extent, but only for awhile, which accounts for the late onset and the episodic course.

Gusella JF, McDonald ME, Ambroise CM, et al: Molecular genetics of Huntington's disease. Arch of Neurol  1993; 50:1157—63
 
Smalley SL, Asarnow RF, Spence MA: Autism and genetics. A decade of research. Arch Gen Psychiatry 1988; 45(10), 953—61
 
Kendler KS, Diehl SR: The genetics of Schizophrenia: a current genetic-epidemiologic perspective. Schizophr Bull 1993; 19(2), 261—285
 
McGuffin P, Katz R: The genetics of depression and manic depressive disorder. B J Psychiatry  1989; 155:294—304
 
McGlashan TH: Early detection and intervention of schizophrenia: rationale and research. B J Psychiatry Suppl  1998; 172(33):3—6
 
Jacob F, Monod J: Genetic regulatory mechanisms in the synthesis of proteins. J Mol Biol  1961; 3:318—356
[CrossRef] | [PubMed]
 
Bailey CH, Barest D, Candle ER: Toward a molecular definition of long-term memory storage. Proc Natl Acad Sci USA  1996; 93(24):13445—52
[CrossRef] | [PubMed]
 
Dotman CH, van Herp F, Martens GJ, et al: Dynamics of proopiomelanocortin and prohormone convertase 2 gene expression in Xenopus melanotrope cells during long-term background adaptation. J Endocrino  1998; 159(2):281—286
[CrossRef]
 
Kulikova OG, Reikhardt BA, Sapronov NS: Involvement of the genetic apparatus in memory formation mechanisms: the role of the neuronal calcium-regulatory system in rats. Neurosci Behav Physiol  1998; 28(5):583—588
[CrossRef] | [PubMed]
 
McNamara RK, Stumpo DJ, Morel LM, et al: Effect of reduced myristoylated alanine-rich C kinase substrate expression on hippocampal mossy fiber development and spatial learning in mutant mice: transgenic rescue and interactions with gene background. Proc Natl Acad Sci USA  1998; 95(24):14517—222
[CrossRef] | [PubMed]
 
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References

Gusella JF, McDonald ME, Ambroise CM, et al: Molecular genetics of Huntington's disease. Arch of Neurol  1993; 50:1157—63
 
Smalley SL, Asarnow RF, Spence MA: Autism and genetics. A decade of research. Arch Gen Psychiatry 1988; 45(10), 953—61
 
Kendler KS, Diehl SR: The genetics of Schizophrenia: a current genetic-epidemiologic perspective. Schizophr Bull 1993; 19(2), 261—285
 
McGuffin P, Katz R: The genetics of depression and manic depressive disorder. B J Psychiatry  1989; 155:294—304
 
McGlashan TH: Early detection and intervention of schizophrenia: rationale and research. B J Psychiatry Suppl  1998; 172(33):3—6
 
Jacob F, Monod J: Genetic regulatory mechanisms in the synthesis of proteins. J Mol Biol  1961; 3:318—356
[CrossRef] | [PubMed]
 
Bailey CH, Barest D, Candle ER: Toward a molecular definition of long-term memory storage. Proc Natl Acad Sci USA  1996; 93(24):13445—52
[CrossRef] | [PubMed]
 
Dotman CH, van Herp F, Martens GJ, et al: Dynamics of proopiomelanocortin and prohormone convertase 2 gene expression in Xenopus melanotrope cells during long-term background adaptation. J Endocrino  1998; 159(2):281—286
[CrossRef]
 
Kulikova OG, Reikhardt BA, Sapronov NS: Involvement of the genetic apparatus in memory formation mechanisms: the role of the neuronal calcium-regulatory system in rats. Neurosci Behav Physiol  1998; 28(5):583—588
[CrossRef] | [PubMed]
 
McNamara RK, Stumpo DJ, Morel LM, et al: Effect of reduced myristoylated alanine-rich C kinase substrate expression on hippocampal mossy fiber development and spatial learning in mutant mice: transgenic rescue and interactions with gene background. Proc Natl Acad Sci USA  1998; 95(24):14517—222
[CrossRef] | [PubMed]
 
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