Complement Component C4 and Schizophrenia


Copyright 2016, James Michael Howard, Fayetteville, Arkansas, U.S.A.


An alternative explanation of “Schizophrenia risk from complex variation of complement component 4, Nature 2016, Sekar, et al.


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. 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. This could explain the effects of “null” C4.