In a separate, genome-wide association study funded by the Wellcome Trust and
Medical Research Council, a team at Cardiff University - led by Professor
Michael O'Donovan - has identified a number of potential genetic candidates. The
most strongly associated of these is a common variant near the gene ZNF804A,
which regulates expression of other genes.
"[Our study] means that all of us or virtually all of us have some genes for
schizophrenia and there are probably hundreds of them," says Professor
O'Donovan. "Those of us that don't have the disease probably don't have enough
of the genes or possibly have not been exposed to the right environment."
In this case, the consortium found three deletions: one on chromosome 1 and two on chromosome 15, which were seen multiple times in people with schizophrenia. Two of the deletions had never been recognized before. "That triples the number of specific DNA areas that may be responsible for schizophrenia," Sklar said. "All of these together were found in about 1 percent of patients." But they conferred a very large risk, multiplying the odds of getting schizophrenia by a factor of more than 10, Stefansson said.
The Nature Genetics paper identified three "single-nucleotide polymorphisms" (changes) or SNPs that were associated with schizophrenia and appear to be risk factors for the disease. The strongest association was with a variant near the gene ZNF804A, whose function may be to regulate other genes.
According to O'Donovan, other researchers have looked at what are called "whole chapters" in the genome. In contrast, his team honed in on what he described as tiny spelling differences.
The variations identified are much more common than those reported in the previous two papers.
"In addition to rare variants, we were able to convincingly show that common variants are involved in schizophrenia. But we don't know how much of a role they play compared with rare variants," O'Donovan said. "It means that virtually all of us have genes for schizophrenia, but probably those of us who don't have schizophrenia don't have enough of the genes or possibly have not been exposed to [an environmental stimulus]."
"Schizophrenia is the ultimate human disease, affecting the things that characterize us as individuals," Stefansson added. "Perhaps with a little bit of luck, we will gain insight into the pathogenesis of schizophrenia . . . and will discover enough of the variants to put together meaningful diagnostic instruments for this very difficult disease."a HREF="https://www.biologicalpsychiatryjournal.com/article/S0006-3223(17)31905-4/fulltext">twin study
Schizophrenia and Bipolar Disorder Share Genetic Roots
Schizophrenia and Bipolar Disorder Share Genetic Roots
three studies highlight genes found on Chromosome 6 in area known as the Major Histocompatibility Complex, which plays a role in the immune system, and in controlling when other genes are switched on and off.
The researchers believe this might help explain why environmental factors also seem to affect risk for schizophrenia.
For example, there is evidence that children whose mothers contract flu while pregnant have a higher risk.
In total the researchers identified 30,000 tiny genetic variants more common in people with schizophrenia.
A similar pattern was found in people with bipolar disorder - indicating a previously unrecognised overlap between the two conditions.
Dr Thomas Insel, of the US National Institute of Mental Health, said: "These new results recommend a fresh look at our diagnostic categories.
"If some of the same genetic risks underlie schizophrenia and bipolar disorder, perhaps these disorders originate from some common vulnerability in brain development."
The three research teams, who shared their data, were the International Schizophrenia Consortium, the Molecular Genetics of Schizophrenia consortium and SGENE.
In total, they analysed genetic data from 8,014 people with schizophrenia, comparing them to samples from 19,090 people who did not have the condition.
Paul Corry, of the mental health charity Rethink, said: "This exciting research brings us one step closer to understanding the causes of schizophrenia, but we are still a long way from a full explanation.
"Most of the genetic contribution to this illness is still unknown and it is crucial to realise that genes are only part of the picture - environmental and social factors, such as drug use or trauma, can exacerbate or even trigger schizophrenia."
Disc1 [ Disrupted In SChizophrenia1 ] keeps coming up as a fault in schizophrenia.
DISC2 is thought to specify a noncoding RNA molecule antisense to DISC1 (MIM 605210). Both genes
were found to be disrupted by a translocation in a large schizophrenia sample of
The protein DISC1, encoded by a gene implicated in schizophrenia susceptibility, regulates the development of postmitotic neurons.
Mao et al. (2009) now report that DISC1 also regulates the proliferation of embryonic and adult neural progenitor cells through the GSK3?/?-catenin pathway,
providing new insights into how susceptibility genes may contribute to the etiology of psychiatric disorders.
It looks now [ to me ! ] as though DISC1 is a weakening processor for neuron maturity and connection maintenance, which requires some other brain difference to bring out a particular 'disease'.
Maybe ... Disc 1 + x = autism and aspergers; Disc1 + y = schizophrenia; Disc1 + z = affective illness. It could even be that Disc1 + introvert personality brain connections - gives the spectrum obsessional, anancastic, autistic, asperger spread depending on when an additional factor comes in.
Disc1 + extrovert personality = bipolar.
Disc1 + father introvert/mother extrovert = schizophrenia.
I do not understand how it is that that people being different in their enduring personalities are not considered to be the product of different hardwiring in their brains, and that way show it in their mental behaviour. The outcome effect of Disc1 on one kind of personality will be disruptive in one respect, but the outcome differently in a different personality.
How parents with different hard wired brains merge their genes in their offspring has to be taken into consideration when looking a gene expresion and releasing.
The DISC1 gene was first discovered as the casualty of a chromosomal translocation in a large Scottish family
with a high incidence of schizophrenia, bipolar disorder, and major depression.
As much as catastrophic genetic mistakes like the DISC1 translocation offer researchers a window into disease pathophysiology,
it can be challenging (!) to get a clear picture of mechanism.
Work over the past decade has linked DISC1 mutations to aberrant neuronal development ( Kamiya et al., 2005 )
, and the protein also appears to play a role in adult neurogenesis and differentiation .
The Disc1 protein takes part in the functions of mature neurons as well, and how these different facets of its physiology contribute to psychiatric disease remains unclear.
In mice xpression of DISC1 peaks at the height of neurogenesis at embryonic days 14-15 and in adult brain regions associated with active neuron production
In vivo, blocking the the delivery of DISC1by siRNA through electroporation into embryonic brain resulted in a loss of proliferative cells, premature differentiation and an overall reduction of the progenitor pool.
In adult mice, Injection of DISC1 siRNA into the dentate gyrus of the hippocampus decreased the proliferation of adult progenitor cells. The loss of progenitors had behavioral consequences: the siRNA-treated mice showed hyperactivity in response to novel environment, a model for positive symptoms of schizophrenia.
This is not the first time that GSK3? has been implicated in schizophrenia or behavior (see SRF related news story).
The kinase sits downstream of the dopamine D2 receptor, the target for antipsychotic drugs.
The schizophrenia risk genes neuregulin-1 and Akt (the latter activated by D2 signaling, in fact) both regulate GSK3?.
Likewise, defects in neurogenesis have been implicated in schizophrenia and in depression.
The new findings that DISC1 occupies a critical regulatory position in neurogenesis pulls together a lot of these previous observations
and makes a strong argument for GSK3? as a potential target for new therapies
If, however, GSK3 regulation turns out to be part of the mechanism of schizophrenia or bipolar disorder, then identifying which of the substrates
and which of the many activities of GSK3, including on plasticity and hence cognition (Peineau et al., 2007; Hooper et al., 2007), are important in disease will become the critical task
cerebellum is quite high in DISC1. And also has D2 receptors.
My hunch is that itís doing basically the same thing in different brain regions.
well, Data suggest that DISC1 may do different things in the hippocampus vs. PFC in development
cAMP does different things in the prefrontal cortex than it does in hippocampus; therefore, DISC1 may be having an overall different function by region. And remember that the cerebellum has an extensive noradrenergic input that likely acts via ? receptors.
Regarding the cerebellum, the network of PFC-thalamus-cerebellum is functionally very important, and may be involved in schizophrenia.
Akira, I agree. Aren't smooth eye tracking movements controlled by the cerebellum and disrupted in schizophrenia?
keep in mind that pyramidal neurons and more notably interneurons continue maturing through adolescence, so it should not be unexpected to see expression changes or modulation differences in adult vs. adolescent or pre-adolescent mice.
cAMP impairs prefrontal working memory function, so loss of DISC1 may worsen prefrontal functions. We are trying to test this now. If we think DISC1 genetics is important for schizophrenia, a dysfunction in this system would be expected to provide behavioral anomalies after adolescence.
And PFC excitation-inhibition balance does mature during that age.
So, one can have a dysfunctional circuit due to DISC1-dependent anomalies,
but the deficits wonít be expressed until the circuits mature.
Brain structure and functional changes emerge long before psychosis in schizophrenia
while positive symptoms emerge during adolescence, the working memory and LTM deficits are there earlier
and are predictive of future psychosis in those at risk.
Gray matter [ cells ]decreases more steeply in those prodromal patients who convert compared with those who do not, particularly in dorsal prefrontal.
preclinical data with Rolipram [ weird - it's an anti inflammatory drug leads to elevated cyclic AMP (above) is pretty good with both antipsychotic and procognitive effects
more gene news
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Schizophrenia liability in relatives