A complicated blog entry about genes causing neuropsychiatric disorders

Summary  of a Molecular Psychiatry (#1 psychiatry journal) article .

Topic: CNV (copy number variants) and genotype and phenotype

Translation:  Gene deletions or repeats in the DNA change the DNA sequence (genotype) and result in different manifestations (traits) in people (phenotype)

The current state of affairs/ 2013

It looks like there are several theories why and how genes cause neuropsychiatric developmental disorders, and this close study of the 22q11.2 CNV lights the way forward.  In this case it is the deletion of this section of DNA (22q11) that causes schizophrenia or autism.    The former studies on 22q11 are not as elegant as this one:  this one can account for six different hypothetical models for the relationship between genome and phenotype.

The region of  22q11.21-.23, which is 200kD long,  is replete with neurobehavioral genes  linked to neurobehavioural traits.  It has important genes like COMT, Sept5, Tbx1 within it.  Prior individual studies link these individual genes to anxiety, pre-pulse inhibition (schizophrenia trait), social interaction, working memory, and this current study showed that large deletions within 22q11 (across dozens of genes) are linked to these same symptoms.  The study proceeded to understand how a different deletions within dozens of genes create different patterns of genotype and phenotype.

They concluded that genes can express a phenotype in six ways.  It can relate to 1) total stochastic load (a trait emerges when a total amount of DNA is changed) , 2) based on gene context ( a given gene changes or is deleted in the setting of certain other gene patterns and manifests a trait), 3) in a dose-phenotype linear or nonlinear curve (a trait emerges based on a number of genes , like a dosage), 4) as a part of a developmental arc in which timing determines effect ( gene change emerges a certain times in development) , 5) as a relation of noncontiguous genes within the region and nearby areas (a gene makes a trait depending on other key genes in a functional web), or 6) inherent pleotropy in genes (a trait requires a whole bunch of select genes to change in a given pattern).

They proposed a hypothetical 3D graph with the x,y, z axes as  gene, trait z-score (how likely is the trait) , and  trait.  Specifically, the trait‘s z-score (significance) varies by each change (or deletion) of a gene.  The gave an example of a grid with eight genes, eight traits, and eight z-scores.  In that grid, some genes made all the traits present, some genes a few, and some genes make all the traits not present. The 3D graph was then altered– by the environment or  gene context–so a either a single z-score was changed to significant or insignificant,  or a particular gene x trait relationship was be canceled or created, or a total shift of z-scores made all the particular gene x trait patterns either more or less significant.

They concluded the DSM-5 diagnostic manual is not helpful for clinicians, particularly when read “chapter by chapter”. The situation of diagnosis and psychiatric manifestion is more like reading the index at back of the book–there is a list of neurobehavioral traits, which do not cluster or bunch like the DSM suggestions–each individual has their own selection of symptoms,   based on gene penetrance,  gene x environment interaction, and gene x gene interaction.

Note: they point out that, as opposed to CNV deletions,  SNPs (single nucleotide polymorphisms, which are single base pair change in a complex gene) are not likely associated with autism or schizophrenia.  Other researchers are unlikely to agree with this, since many studies are finding dozens of candidate SNPs for schizophrenia or autism.  Admittedly, no particular gene variant has been shown to cause schizophrenia or autism.  In contrast, the 22q11 deletion is a well established cause.  The article concluded that the 22q11 CNV is the guiding light for future research, and should be the foundation of future research, given that it is currently the most well studied genetic cause of schizophrenia or autism.

I added a current high-browed debate going on this week between Richard Dawkins and David Dobbs about genes and evolution.


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