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Genetic study gives insight into schizophrenia

01 February 2016

By Helen Robertson

Appeared in BioNews 837

A gene involved in managing the connections between brain cells appears to be associated with an increased risk of developing schizophrenia.

While previous research had shown that schizophrenia has a genetic component, this is the first time that a specific gene and biological pathway has been identified as contributing to the disease.

'Since schizophrenia was first described over a century ago, its underlying biology has been a black box, in part because it has been virtually impossible to model the disorder in cells or animals,' said Dr Steven McCarroll of Harvard Medical School, senior author on the study, which was published in Nature.

'The human genome is providing a powerful new way in to this disease. Understanding these genetic effects on risk is a way of prying open that black box, peering inside, and starting to see actual biological mechanisms.'

The researchers analysed genetic data from 28,799 schizophrenia cases and 35,986 controls, across 22 countries. Previous genome analysis had identified variation in chromosome 6 as increasing the risk of schizophrenia, but with no further clues as to which of the genes in this region might be a risk factor for the disease.

Basing their study on this chromosomal region, Dr McCarroll and his team focused on an unusual gene called complement component 4 (C4). Unlike most other genes, the type and number of copies of C4 varies between different people.

By using a novel technique to identify the type of C4 present in DNA, the researchers found that they could predict the behaviour of different types of C4 in people with and without schizophrenia. Particular variants, which cause an increased amount of C4 activity, appeared to increase the risk of developing schizophrenia by 27 to 50 percent.

In mice, C4 was found to have an important role in 'pruning' unnecessary synapses – the connections between neurons – in the brain. The greater the amount of C4 in the developing brain, the higher the number of synapses that were eliminated.

In humans, most synaptic pruning happens during adolescence and early adulthood – the same age at which the symptoms of schizophrenia most commonly present. This research proposes that a high level of C4 activity could result in the over-removal of cells in the brain, causing both the thinning of brain tissue and the cognitive symptoms observed in schizophrenia.

Speaking to the MIT Technology Review, Dr Steven Hyman, director of the Stanley Center for Psychiatric Research and a former director of the US National Institute of Mental Health, who was not an author on the study, said: '[This research] begins to suggest potential routes toward therapies.'

However, it is clear that the implications of these findings on future treatments are complex. 'It's not going to be an easy thing to tweak synaptic pruning because underpruning wouldn't be so good either,' said Dr Hyman.

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HAVE YOUR SAY
This is Caused by C4 Not Working Properly: More C4 means More Synapse Loss (jamesmhoward - Updated on 01/02/2016)
I suggest these findings may be explained by low levels of dehydroepiandrosterone (DHEA).  This phenomenon is not disintegration of synapses, rather, it is reduced formation / support of synapses in individuals who carry C4.

It is my hypothesis that evolution selected dehydroepiandrosterone (DHEA) because it optimizes replication and transcription of DNA, that is, genes. Therefore, DHEA levels affect all tissues and all tissues compete for available DHEA, especially the brain. (I think evolutionary selection of DHEA produced Mammalia. “Hormones in Mammalian Evolution,” Rivista di Biologia / Biology Forum 2001; 94: 177-184). DHEA naturally begins to decline around the ages of twenty to twenty-five, reaching very low levels in old age. When DHEA is low or decreasing, all tissues are adversely affected.

Furthermore, I suggest that optimal levels of DHEA positively affect optimally formed genes optimally.  Therefore, it follows that genes that are not optimally formed will be less affected by DHEA levels.  In old age, fewer and fewer genes will be transcribed as the competition for the reduced levels of DHEA of old age occur.

Additionally, mutated / poorly duplicated genes will respond less effectively to optimal levels of DHEA and this will increase with aging.  I have explained this in detail at: “Why There are Two Peaks of Death and Disease in Older Age,” at: http://anthropogeny.com/Death%20Two%20Peaks.htm  .  This explains the occurrence of “early-onset” diseases in early aging vis-à-vis the same disease manifesting in old age.  That is, optimally formed genes begin to fail as DHEA naturally reaches very low levels while malformed / mutated genes fail earlier as DHEA begins to decline.

It is my hypothesis that schizophrenia is caused by low DHEA in utero. This results in poor brain development. Later in life, cortisol and testosterone act to reduce the effects of already low DHEA and adversely affect brain function as well as maintenance of anatomy. DHEA naturally begins to decline in the early twenties. This is why schizophrenia often occurs in the late teens / early twenties (puberty and loss of DHEA) and is often triggered by a stressful event (cortisol). Therefore, at this time, brain function and maintenance is inhibited and, in the case of cortisol, may be reduced. I suggest this reduces prefrontal function and increases lower brain function, the seat of hallucinations. It is known that DHEA is low in schizophrenia and that DHEA acts positively in neuron growth and function. (DHEA has also been found to be high in schizophrenia. I suggest low DHEA may account for negative symptoms and high DHEA may account for positive symptoms of schizophrenia.) DHEA in sufficient levels acts to positively affect growth and development of the brain and, following growth and development, to positively affect neuronal activities. (DHEA, Melatonin, and Schizophrenia, at: http://anthropogeny.com/Schizophrenia.htm )

This regards the findings of Sekar, et al., Nature 2016: “Schizophrenia risk from complex variation of complement component 4,” in this manner:  I disagree with the interpretation of Sekar, et al., that their findings represent an attack on synapse formation.  Based on my foregoing explanation of DHEA and gene function and schizophrenia, I suggest the C4 is a less than optimally formed gene.  Therefore, in an environment of low DHEA, C4 will fail to form synapses.  The more C4 one has, the more likely synapses will fail to form properly.

It is my hypothesis that mammals evolved because of selection for dehydroepiandrosterone (DHEA). (Hormones in Mammalian Evolution, Rivista di Biologia / Biology Forum 2001; 94: 177-184 ) This is based on my hypothesis that evolution selected DHEA because it optimizes replication and transcription of DNA. DHEA affects expression of genes. Therefore DHEA levels affect all tissues and the life span. A case may be made that optimal amounts of DHEA are necessary for conception. Since a mother produces DHEA for herself and her fetus, she must have an optimal level of DHEA for conception and maintenance of a fetus until near birth when fetal production of DHEA combines with the mothers DHEA to signal and initiate birth. DHEA is important to genes producing libido for initiation of conception in order to function in optimal maintenance of pregnancy. Selection pressure within Mammalia for testosterone produced primates and, with exaggeration, humans. I think testosterone increases cellular absorption of DHEA by increasing androgen receptors through which DHEA enters cells. The selection is basically selection for additional cellular DHEA because of testosterone. Estradiol was selected because of the same mechanism, testosterone simply is more effective. (If you, et al., desire more detail of this: DHEA, Estradiol, Testosterone, and the Relevance of Their Ratio The Androgen Receptor and the Secular Trend, at: http://anthropogeny.com/Androgen%20Receptor%20and%20Secular%20Trend.html .)

“Synaptic pruning” is characteristic of adolescence and early adulthood.  As testosterone rises in adolescence and early adulthood, DHEA is directed to different tissues / cells for reproduction.  This induces a competition for DHEA which will adversely affect some tissues at the expense of others.  This will reduce available DHEA and, therefore, reduce support of synapse formation in parts of the brain so that others, used in reproduction, remain or may be enhanced.  (Remember, from above that I suggest the onset of testosterone production in schizophrenia, low DHEA, is part of the cause of schizophrenia following puberty.)

If an individual produces more C4, then the reduction in synaptic formation increases.

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