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Crow TJ. How and why genetic linkage has not solved the problem of psychosis: review and hypothesis. Am J Psychiatry. 2007 Jan 1 ; 164(1):13-21. Pubmed Abstract

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Primary Papers: How and why genetic linkage has not solved the problem of psychosis: review and hypothesis.

Comment by:  Karl-Ludvig Reichelt (Disclosure)
Submitted 8 March 2007
Posted 8 March 2007
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Genetics in Schizophrenia
It is reasonably certain that the genetic disposition must be polygenomic and on different chromosomes (Craddock et al., 2005). It is, however, proteins and fragments of proteins (peptides) that usually are the active or inactivated chemical compound in genetic disorders. Thus, enzymes, enzyme-binding proteins, membrane transporters and receptors, and modifying peptides are the active executive compounds of the genetic disposition (Parker and Steitz, 1997; Cooper and Stevens, 1995). Since DNA exons are differentially expressed, crossing over and deletions occur, and siRNA and methylation regulate transcription also in an epigenetic way, it is critical to find the proteins/peptides involved. mRNA is extensively edited and even proteins undergo splicing (see Cooper and Stevens, 1995), which also points to this critical necessity. Furthermore, all genes have mutations and the chance of finding mutations, not necessarily of consequence, is large, even with the finding of a high LOD score, etc. Changed chaperones or failed binding can further select/modify enzyme activity (Ashkenas and Byers, 1997). How multiple expressions of a single genome is possible has been reviewed (Graveley, 2001).

Decreased enzyme or transport ability will usually cause metabolite increase proximal to the insufficient enzyme in the metabolic pathway and decrease distally. Hence, increases and decreases in metabolites should act as pointers to meaningful genomic hunts. We have found peptide increase of exorphines (Reichelt et al., 1996), and this has been confirmed (Hole et al., 1979; Cade et al., 2000; Idet et al., 1982; Drysdale et al., 1982). Similarly for depression (in press), peptides point to a reasonable area of search, namely peptidases and peptidase binding proteins. In depression, peptidase decrease has been found in precisely those peptidases that would cause exorphins to accumulate (Maes et al., 1991; Maes et al., 1992; Maes et al., 1994; Maes et al., 1997; Elgun et al., 1999). Since neuroleptics increase peptidase activity by induction (Davis et al., 1983; Davis and Culling-Berglund, 1987), this strengthens this view.

In short, any relevant DNA change must cause protein changes and metabolic changes. Proteins and peptides are the actors, and the consequence that follows is metabolic change. Like in phenylketonuria, treatment would entail a decrease in the pre-lesion input and supplying post-lesion deficiencies. Low-activity polymorphic enzymes can also be stimulated by cofactor (vitamins) increase and mass action (Ames et al., 2002).

References:

Cade RJ , Privette M, Fregly M , Rowland N, Sun Z , Zele V, Wagemaker H and Edelstein C. Autism and schizophrenia : Intestinal disorders. Nutritional Neuroscience. 2000; 3: 57-72.

Idet M, Grof J, Menyhart J and Pajor A. Elevated opioid activity in sera of chronic schizophrenics .Acta Physiol Acad Hung. 1982;60:121-127.

Drysdale A, Deacon R, Lewis P, Olly S, Electricwala A and Sherwood R. A peptide containing fraction of plasma of schizophrenic patients which binds to opiate receptors and induces hyperactivity in rats. Neuroscience. 1982; 7:1567-1574.

Maes, M, Demeester I, Vanhoof G, Scharpe S, Bosmans E, Vandervorst C, Verkerk R, Minner B, Suy E, Raus J: Decreased serum dipeptidyl-peptidase IV activity in major depression. Biol Psychiat. 1991;30:577-586.

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