Rare Genetic Mutations and Schizophrenia
March 28, 2008 by Kristina Chew, PhD
Filed under Genetics, Neuroscience, Psychiatry
In a new study, scientists at the University of Washington and Cold Spring Harbor Laboratories have found that rates of genetic deletions and duplications are three to four times higher in people with schizophrenia. These genetic mutations are more likely to disrupt that brain’s signaling genes, which affect brain development. Further, researchers found that “most patients have different mutations” which cause them to have schizophrenia. (While autism was once referred to as child schizophrenia, they are different diagnoses; here’s an interesting note about this at Left Brain/Right Brain.)
As today’s Science Daily reports:
Some deletions and duplications are common and found in all humans. The researchers studied such mutations that were found only in individuals with the illness, and compared them to mutations found only in healthy persons. They theorized that rare mutations found only in schizophrenic patients would be more likely to disrupt genes related to brain functioning and thus may cause schizophrenia.
The study was conducted using DNA from 150 people with schizophrenia and 268 healthy individuals. The investigators found rare deletions and duplications of genes present in 15 percent of those with schizophrenia, versus only 5 percent in the healthy controls. The rate was even higher in patients whose schizophrenia first presented at a younger age, with 20 percent of those patients having a rare mutation.
…..
The findings suggest that schizophrenia is caused by many different mutations in many different genes, with each mutation leading to a disruption in key pathways important to a developing brain. Once a disease-causing mutation is identified, other different disease-causing mutations may be found in the same gene in different people with the illness.Thus, for most cases of schizophrenia, the genetic causes may be different.
Jonathan Sebat, assistant professor of genetics at Cold Spring Harbor Laboratory, also theorized that “some mutations probably overlap with other brain disorders, such as autism, depression and bipolarism,” as noted in PsychPort.com. Many of the DNA variants found in the study are, like those in an autism study under Michael Wigler, another Cold Spring geneticist, occur spontaneously.
The study was published on March 27th in the online version of the journal Science. PsychCentral casts a more critical eye on the study and points out that these gene mutations do not occur “in the vast majority” of people with schizophrenia (80-85% of people with schizophrenia do not have the mutations.)
Jeff Stimpson
Jill Cornfield
The technology used by Cold Spring Harbor is relatively primitive to what is now available. The first most detailed examing of a single healthy middle aged man was published last year. The study took years and cost millions of dollars and should give pause to any tudies published by Cold Spring Harbor.
The study reported:
“His newly released genome, published today in the journal PLoS Biology, differs from both of the previous versions of the human genome (one from Celera, the other from the Human Genome Project) in that it details all of the DNA inherited from both mother and father. Known as a diploid genome, this allows scientists to better estimate the variability in the genetic code. (In a genome sequence generated from a conglomerate of different individuals, some variations are lost in the averaging.) Within the genome of 2.810 billion base pairs, scientists found 4.1 million variations among the chromosomes; 1.2 million of these were previously unknown. Of the variations, 3.2 million were single nucleotide polymorphisms, or SNPs, the most well-characterized type of variation, while nearly one million were other kinds of variants, including insertions, deletions, and duplications”.
Over four million variants genetic variants including a million that included insertions, deletions and duplications…. in a single healthy middle aged man.
It will take many years before this technology can be used in genetic studies, until then everything should be taken with a grain of salt.
Like all multifactorial conditions the puzzle is what do these variations do to ’cause’ a disorder. The only known evidence for how a copy number variation causes a condition comes from AIDS research. It was discovered that copy number variations found in a specific single gene can increase susceptability to contracted HIV after an exposure.
We are all genetic mutants.
Here is a review of the study:
http://www.technologyreview.com/Biotech/19328/
RAJ
Thank you for that very informative comment. Can you meant by “It was discovered that copy number variations found in a specific single gene can increase susceptability to contracted HIV after an exposure.”
Are you suggesting that environmental factors might also, in interaction, with genetic factors, cause conditions like autism, or in the example you used HIV?
It’s the spontaneous (de novo) aspect that seems to be arousing particular interest. Here’s evolutionary biologist Olivia Judson on mutants.
Harold Doherty asked:
“Are you suggesting that environmental factors might also, in interaction, with genetic factors, cause conditions like autism, or in the example you used HIV”?
The most informative condition where gene-environment interactions are well described is in Leprosy research. What I find to be most illuminating is the interaction between a strong genetic component and a strong environmental component reported in decades of genetic research in leprosy compared to decades of genetic research in autism.
The genetic research in these two unrelated conditions are a mirror image of each other:
http://www.nature.com/ng/journal/v27/n4/full/ng0401_439.html
The casue of Leprosy, exposure to myobacterium laprae has been known for over a hundred years, but what has come to light more recently is just how strong the genetic component in leprosy actually is.
Like autism, in leprosy there are high concordance rates in MZ twin ( 60 -85%) and a dramatic decline in concordance rates in DZ twin pairs ( 5-20%), indicating the presence of a strong genetic factor .
Since Biblical times leprosy is known to cluster within families, like autism, and the sib risk ratio is the same as has been reported in autism. Heritability estimates or leprosy have been reported to be as high as 80% (again like autism).
The etiology of leprosy can be considered the Gold Standard for a gene-environment interaction model and the mirror image of ecades of genetic in research in leprosy and autism should give any rational person pause in the interpretations given by autism genetic theorists about what twin studies, familial clustering and heritability estimates are telling us.
Here is the article that explains how copy number variations in a single specific gene increases susceptability to infection after exposure to HIV:
http://stke.sciencemag.org/cgi/content/abstract/sci;307/5714/1434
Schizophrenia and genetics? I am note sure that there is more than some particular ’sensibility’ in the persons who become schizophrenic, maybe they are more ‘affect-and-attention-pretending-persons’. I myself suffered before 1999 for 3 and a half years a ‘delirious paranoid schizophrenia’, but with the help of several years of an individual, more psychoanalytic and less cognitive psychotherapy I completely recovered now. Since half 2002 I don’t take psychofarmakon any more. Since april ‘08 on the european WMHO-site ther has been made a very short article about my recovery under: http//www.euro.who.int/mentalhealth/topics/20080415_1 (= Lia’s story), where under dr. Matt Muijen’s commentary there are also the key factors in my recovery process.
Within the end of 2008 my autobiographic story will also be publicated in the Netherlands.