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Showing posts with label Bipolar. Show all posts
Showing posts with label Bipolar. Show all posts

Thursday 13 April 2017

Estradiol/Aromatase Deficiency in Autism, Schizophrenia and Bipolar



There was a rather complicated post in which I was linking some of the odd biological features of autism to something called RORα.

This was one of those posts that appeals to the scientist readers like Tyler.







Happy with his elevated estradiol level

Today’s post is more like the Psychiatrist's take on the same subject, so it is less complicated.

I was thinking that a logical way to treat boys, post puberty, and girls with autism would be to target RORα. In males this would be the treating aromatase deficiency.  You would start by measuring by measuring the level of testosterone and estradiol in both boys and girls.

My assumption is that there will be a substantial group of males who will have high testosterone and low estradiol.  In autism and its big brothers (and sisters) Schizophrenia and Bipolar, there are disturbed levels of these hormones.  One logical therapy would be estradiol, which is much less problematic for girls than boys.

Boys with genetically caused aromatase deficiency lack the female hormone estradiol, but are not treated with transdermal estradiol until after puberty.  Girls are treated with estradiol from a younger age.

Untreated males with aromatase deficiency have retarded bone age, but end up as very tall adults. They also have a problem with low bone density and so have weak bones.



Clinical Features of Aromatase Deficiency

Female
Male
Fetal life:
Masculinization of the mother during pregnancy
Masculinization of the mother during pregnancy
Genitalia at birth:
Severe clitoromegaly and posterior labioscrotal fusion
Normal male
Childhood:
Multi-cystic ovaries
Unremarkable
Puberty:
Absent growth spurt
Absent breast development
Primary amenorrhea
Further enlargement of clitoris
Enlarged cystic ovaries
Normal development of pubic and axillary hair
Absent growth spurt
Normal pubertal development
Adult:
Severe estrogen deficiency
Virilization
Enlarged cystic ovaries
Continued linear bone growth
Tall, eunucoid proportions with continued linear growth into adulthood
Osteoporosis
Genu valgum

Source: AROMATASE DEFICIENCY


I have commented before that I think retarded bone age is a useful marker of some types of autism. You just need an X-ray of your hand and some interpretation that looks at the gaps between the small bones.

We have also seen in the comments section of this blog that numerous readers have low bone density problems in their families.

Extreme aromatase deficiency is very rare and is caused by mutations in the CYP19A1 gene.

We saw that RORα seems to be a hub for where things go wrong in autism (also schizophrenia and bipolar); I am not suggesting a problem with the CYP19A1 gene.

One approach in psychiatry research is to just try things, without bothering too much about the underlying science.  This has been the case with Estradiol, where there have been several very positive studies in schizophrenia and bipolar.  


Estradiol in Clinical Trials

Nobody is going get approval to use Estradiol in young boys, other than those who are promoting gender reassignment. These people want to chemically block puberty and then use high doses of estradiol to feminize the male body.

Estradiol is widely used in post-menopausal women, but also in clinical trials of middle aged women with schizophrenia or bipolar, where it appears to provide a clear improvement.




Many women with schizophrenia remain symptomatic despite optimal use of current therapies. While previous studies suggest that adjunctive oestrogen therapy might be effective, large-scale clinical trials are required before clinical applications are possible. This study is the first large-scale randomized-controlled trial in women with treatment-resistant schizophrenia. This Definitive Oestrogen Patch Trial was an 8-week, three-arm, double-blind, randomized-controlled trial conducted between 2006 and 2011. The 183 female participants were aged between 18 and 45 (mean = 35 years), with schizophrenia or schizoaffective disorder and ongoing symptoms of psychosis (Positive and Negative Syndrome Scale, PANSS score>60) despite a stable dose of antipsychotic medication for at least 4 weeks. Mean duration of illness was more than 10 years. Participants received transdermal estradiol 200 μg, transdermal estradiol 100 μg or an identical placebo patch. For the 180 women who completed the study, the a priori outcome measure was the change in PANSS score measured at baseline and days 7, 14, 28 and 56. Cognition was assessed at baseline and day 56 using the Repeatable Battery of Neuropsychological Status. Data were analysed using latent growth curve modelling. Both estradiol groups had greater decreases in PANSS positive, general and total symptoms compared with the placebo this study shows estradiol is an effective and clinically significant adjunctive therapy for women with treatment-resistant schizophrenia, particularly for positive symptoms.





BACKGROUND:


It appears that the female reproductive events and hormonal treatments may impact the course of bipolar disorder in women. In particular, childbirth is known to be associated with onset of affective episodes in women with bipolar disorder. During the female reproductive events the sex hormones, e.g. estrogen, are fluctuating and particularly postpartum there is a steep fall in the levels of serum estrogen. The role of estrogen in women with bipolar disorder is, however, not fully understood.

AIM:


The main objective of this review is to evaluate the possible relation between serum estrogen levels and women with bipolar disorder including studies of the anti-manic effects of the selective estrogen receptor modulator tamoxifen.

METHOD:


A systematically literature search on PubMed was conducted: two studies regarding the connection between serum estrogen levels and women with bipolar disorder were identified. Furthermore, four studies were found concerning the antimanic effects of tamoxifen.

RESULTS:


Both studies in the estrogen studies showed very low levels of estrogen in women with postpartum psychosis and significant improvement of symptoms after treatment with estrogen. The four tamoxifen studies found that tamoxifen was effective in producing antimanic effects.

CONCLUSION:


These results indicate that estrogen fluctuations may be an important factor in the etiology of bipolar disorder and it is obvious that more research on this topic is needed to clarify the role of estrogen in women with bipolar disorder.



Men also need to have a certain level of estradiol, but as they age, and particularly if they get overweight, they often end up with too much.  So the usual problem is too much estradiol.

In males, estrogen is produced in fat (adipose) tissue by the action of the enzyme aromatase on testosterone.  So it would not be surprising if males with five times more adipose tissue produced more estrogen/estradiol. This would might explain mild feminization of the body and the lack of more aggressive male behaviors.

Many males with schizophrenia and a substantial number with autism are on medication that causes weight gain. While there are is research on how to reduce this weight gain, if the weight gain causes more estradiol, there actually is some potential benefit.





"We found that testosterone alone can improve an aspect of memory known as spatial memory -- the kind of memory needed to drive, get dressed, use a knife and fork -- what you need to learn to navigate three-dimensional space," Asthana says. "But men with both testosterone and estrogen had better verbal memory."

Asthana thinks that new estrogen-like drugs that lack sex-hormone effects such as breast enlargement might be useful to preserve memory in aging men. He says he is planning to test this theory in human trials



An estrogen-like drug, raloxifene, was trialed unsuccessfully in women with Alzheimer’s, but not in men.

Estradiol is a research therapy for males with prostate cancer.


Estradiol in Autism

We saw in the science heavy earlier post that that children with autism do not have sufficient estrogen receptor beta expression to mediate the protective benefits of estrogen.

Estrogen receptor beta agonists, which are already known to improve brain plasticity and memory in animals, have been proposed to help reverse autism's behavioral deficits.

High testosterone, low aromatase and correspondingly low estradiol are features of autism and will compound the effect of reduced estrogen receptor beta expression.



Conclusion

There are far less issues with the use of estradiol in females with autism.  Given there have already been trials in Schizophrenia and Bipolar on females using estradiol, it is about time a psychiatrist made a trial in autism.

I think that via the effect on RORα, there will be numerous positive effects.  The risks and side effects will be exactly the same as in the previous Schizophrenia and Bipolar trials.

Having seen what, if any, positive effects the females with autism experience, it would be time to consider adult males.  Is there a behavioral benefit in small enough doses of estradiol that do not cause feminization?

It would also be useful to measure the level of estradiol in overweight males to get some benchmarks of what is “normal" today in males.

Later on, using bone-age and indeed estradiol levels it might be possible to identify a sub-group of autism who might be likely to benefit from this therapy.  There may even be familial markers, like problems associated with low bone density, which might predispose the person with autism to have low levels of estradiol.

The other issue is the lack of estrogen beta-type receptors in people with autism.








Thursday 23 March 2017

Targeting Angiotensin in Schizophrenia and Some Autism





 A home run? Certainly worth further consideration.

Just when you thought we had run out of hormones to connect to autism and schizophrenia, today we have Angiotensin. 

Angiotensin is a hormone that causes vasoconstriction and a subsequent increase in blood pressure. It is part of the renin-angiotensin system, which is a major target for drugs (ACE inhibitors) that lower blood pressure. Angiotensin also stimulates the release of aldosterone, a hormone that promotes sodium retention which also drives blood pressure up.

Angiotensin I has no biological activity and exists solely as a precursor to angiotensin II.

Angiotensin I is converted to angiotensin II  by the enzyme angiotensin-converting enzyme (ACE).  ACE is a target for inactivation by ACE inhibitor drugs, which decrease the rate of Angiotensin II production.  

It turns out that Angiotensin has some other properties very relevant to schizophrenia, some autism and quite likely many other inflammatory conditions. 

Blocking angiotensin-converting enzyme (ACE) induces those potent regulatory T cells that are lacking in autism and modulates Th1 and Th17 mediated autoimmunity.  See my last post on Th1,Th2 and Th17. 

In addition, Angiotensin II affects the function of the NKCC1/2 chloride cotransporters that are dysfunctional in much autism and at least some schizophrenia.  

Drugs that reduce Angiotensin are very widely prescribed, so they are cheap and well understood. This means that yet another cheap generic has the potential to be repurposed to treat neurological disorders. 

As one paper puts it “modulation of the RAAS (renin-angiotensin-aldosterone system) with inexpensive, safe pharmaceuticals used by millions worldwide is an attractive therapeutic strategy for application to human autoimmune diseases.” 

No big profits then for big pharma. 


IL-17a 

We learnt all about the inflammatory cytokines IL-17 and IL-17a in a recent post. That post was about autism, but not surprisingly, elevated levels of IL-17a are a feature in big brother schizophrenia. Big brothers do tend to get more research attention.

In schizophrenia there is increased plasmatic Angiotensin Converting Enzyme (ACE) activity in patients compared to healthy controls, which is also associated to poor cognitive functioning. The ACE main product angiotensin II has known pro-inflammatory properties. 

So an ACE inhibitor looks an obvious choice for schizophrenia.  Very slowly research is indeed moving in that direction.

Angiotensin receptor blockers have even been proposed for bipolar disorder, autism’s other elder brother.
  

What about ACE and Autism? 

As we have got used to, kid bother autism has not had the same level of research attention as given to schizophrenia, but we do have this:- 



Autism is a disease of complex nature with a significant genetic component. The importance of renin-angiotensin system (RAS) elements in cognition and behavior besides the interaction of angiotensin II (Ang II), the main product of angiotensin-converting enzyme (ACE), with neurotransmitters in CNS, especially dopamine, proposes the involvement of RAS in autism. Since the genetic architecture of autism has remained elusive, here we postulated that genetic variations in RAS are associated with autism. 

Our data suggests the involvement of RAS genetic diversity in increasing the risk of autism.
   

Here is the supporting research:-  



The renin-angiotensin-aldosterone system (RAAS) is a major regulator of blood pressure. The octapeptide angiotensin II (AII) is proteolytically processed from the decapeptide AI by angiotensin-converting enzyme (ACE), and then acts via angiotensin type 1 and type 2 receptors (AT1R and AT2R). Inhibitors of ACE and antagonists of the AT1R are used in the treatment of hypertension, myocardial infarction, and stroke. We now show that the RAAS also plays a major role in autoimmunity, exemplified by multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Using proteomics, we observed that RAAS is up-regulated in brain lesions of MS. AT1R was induced in myelin-specific CD4+ T cells and monocytes during autoimmune neuroinflammation. Blocking AII production with ACE inhibitors or inhibiting AII signaling with AT1R blockers suppressed autoreactive TH1 and TH17 cells and promoted antigen-specific CD4+FoxP3+ regulatory T cells (Treg cells) with inhibition of the canonical NF-κB1 transcription factor complex and activation of the alternative NF-κB2 pathway. Treatment with ACE inhibitors induces abundant CD4+FoxP3+ T cells with sufficient potency to reverse paralytic EAE. Modulation of the RAAS with inexpensive, safe pharmaceuticals used by millions worldwide is an attractive therapeutic strategy for application to human autoimmune diseases.
  

In an effort to find a marker that predicts psychosis, postdoctoral researcher Lindsay Hayes, Ph.D., learned unexpectedly that mice and people with behavior disorders have abnormally low levels of a hormone system tied to blood pressure regulation and inflammation. In the cerebrospinal fluid of patients with first episode psychosis, she noticed abnormally low levels of the enzyme that makes the hormone angiotensin. To see if these results correlated to animals and could be studied in the lab, Hayes, who works in the laboratory of treated brain cells with angiotensin and inflammation activators in their mouse model for behavior disorders, then measured the output of proteins involved in inflammation. Compared to normal mice, the cells from the mouse with behavioral disorders released more inflammation protein when treated with low levels of angiotensin and less when treated with high levels. Next, she looked at gene expression levels of the angiotensin system components in the brain cells of the behavioral disorder mice. The gene expression levels for the receptor that detects angiotensin were abnormally low in a specific type of brain cell. Hayes says these specific cells in the behavior disorder mice seem to be less susceptible to angiotensin’s immunosuppressive properties, because they have less receptor to detect angiotensin than the same brain cells in normal mice. Hayes and Sawa plan to investigate whether targeting angiotensin could control inflammation and perhaps treat psychosis. 

Angiotensin converting enzyme activity is positively associated with IL-17a levels in patients with schizophrenia.

Abstract


Previous studies of our group showed increased plasmatic Angiotensin-I Converting Enzyme (ACE) activity in schizophrenia (SCZ) patients compared to healthy controls, which was also associated to poor cognitive functioning. The ACE main product angiotensin II (Ang-II) has pro-inflammatory properties. Activated immune-inflammatory responses in SCZ and their association with disease progression and cognitive impairments are also well-described. Therefore, we examined here the association of plasma ACE activity and inflammatory mediators in 33 SCZ patients and 92 healthy controls. Non-parametric correlations were used to investigate the association of the enzyme activity and the peripheral levels of immune inflammatory markers as interleukins, tumor necrosis factor (TNF-α), and interferon (IFN-γ). Although no significant correlations could be observed for ACE activity and measured cytokines levels in healthy controls, a significant positive correlation for ACE enzymatic activity and IL-17a levels was observed in SCZ patients. Correcting for gender did not change these results. Moreover, a significant association for ACE activity and IFN-γ levels was also observed. To our knowledge, this is the first study to show a significant association between higher ACE activity and the levels of cytokines, namely IL-17a and IFN-γ, in patients with SCZ. 

Cerebrospinal fluid angiotensin-converting enzyme (ACE) correlates with length of illness in schizophrenia. 

Abstract


The aim of the study was to evaluate a possible progression with time of cerebrospinal fluid (CSF) angiotensin-converting enzyme (ACE) levels in treated schizophrenia patients. CSF ACE was determined in duplicate by a sensitive inhibitor-binding assay (IBA) from morning CSF samples of 56 acute and chronic in-patients with schizophrenic psychoses diagnosed according to DSM-IV. CSF ACE correlated significantly with length of schizophrenic psychosis (r=0.39, p=0.003). There was also a positive significant correlation between CSF ACE and duration of current psychotic episode (r=0.39, p=0.003) as well as duration of current hospitalization (r=0.66, p<0 .001="" span=""> These significances were maintained even when patients who were not treated with antipsychotics at the time of sampling were excluded. The correlations also remained significant when controlling for current neuroleptic dose in chlorpromazine equivalents. Serum ACE did not correlate with any clinical variable. No significant correlations between serum or CSF ACE and age, diagnostic subgroup, gender, serum ACE, CSF to serum albumin ratios, or neuroleptic dose in chlorpromazine equivalents were detected. The elevation of CSF ACE seemed to be confined to a subgroup of chronic patients with few positive symptoms. Elevated CSF ACE may reflect an increased solubilization of ACE from cell membranes in the central nervous system or constitute an increased expression of the ACE gene in response to some stimuli. This may be a function of treatment or a result of the deteriorating schizophrenic process. 



The renin-angiotensin-aldosterone system (RAAS) is a major regulator of blood pressure. The octapeptide angiotensin II (AII) is proteolytically processed from the decapeptide AI by angiotensin-converting enzyme (ACE), and then acts via angiotensin type 1 and type 2 receptors (AT1R and AT2R). Inhibitors of ACE and antagonists of the AT1R are used in the treatment of hypertension, myocardial infarction, and stroke. We now show that the RAAS also plays a major role in autoimmunity, exemplified by multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Using proteomics, we observed that RAAS is up-regulated in brain lesions of MS. AT1R was induced in myelin-specific CD4+ T cells and monocytes during autoimmune neuroinflammation. Blocking AII production with ACE inhibitors or inhibiting AII signaling with AT1R blockers suppressed autoreactive TH1 and TH17 cells and promoted antigen-specific CD4+FoxP3+ regulatory T cells (Treg cells) with inhibition of the canonical NF-κB1 transcription factor complex and activation of the alternative NF-κB2 pathway. Treatment with ACE inhibitors induces abundant CD4+FoxP3+ T cells with sufficient potency to reverse paralytic EAE. Modulation of the RAAS with inexpensive, safe pharmaceuticals used by millions worldwide is an attractive therapeutic strategy for application to human autoimmune diseases.


African Americans have been shown to exhibit lower urinary potassium excretion when compared to Caucasians. Angiotensin II regulates both potassium handling by the kidney and the Na-K-2Cl (NKCC) cotransporter in vitro . However, little is known about the role of the reninangiotensin system (RAS) in human NKCC cotransport regulation in vivo. We hypothesized that regulation of RAS would induce concomitant alterations in NKCC activity in humans. The kidney and erythrocyte express NKCC-1 isoform. Therefore, we measured NKCC-1 activity in freshly isolated ex vivo red cells from 12 healthy blacks and 11 healthy whites in high (200 mmol/d) and low (10 mmol/d) salt balance, followed by a measure 24 h-post candesartan [16 mg] to block angiotensin II type I receptors on low salt diet. Baseline NKCC cotransport activity was significantly lower in Blacks when compared to Whites in balance on a typical high salt diet, and was reduced when the subjects were placed on a low salt diet in whites only. Administration of candesartan reversed the reduction seen with low salt diet in whites, where as in blacks there was no significant effect. These data suggest altered in vivo regulation of NKCC-1 via RAS in Blacks when compared to Whites, and provide a mechanism that may in part explain the altered potassium handling observed among otherwise healthy African Americans.


Conclusion

I think it is likely that some sub-types of autism would likely benefit from an ACE inhibitor. As a secondary benefit, it will also reduce any troubling high levels of leptin.

There are other ways to modulate Th1, Th2 and Th17, but if you have elevated Angiotensin Converting Enzyme (ACE), then an ACE inhibitor would appear the logical choice.

How about a clinical trial in adults with Asperger's?











Friday 3 March 2017

Polygenic Disorders that Overlap – Autism(s), Schizophrenia(s), Bipolar(s) and ADHD(s) – Creativity & Intelligence




Blogs are inevitably rather jumbled up and lack a clear structure; today’s post really should be at the beginning.
One clear message from the more sophisticated research into neuropsychiatric disorders is that they are generally associated with variances in the expression of numerous different genes, making them polygenic.
What I find interesting is that there is a substantial overlap in the genes that are miss-expressed across different neuropsychiatric disorders.  This is further proof, if it was needed, that the observational diagnoses used by psychiatrists are rather primitive.
So individual people will have a near unique set of genetic variances that make their symptoms slightly different to everyone else.  However it is highly likely that discrete biological dysfunctions will exist across the diagnoses.  So for example elevated intracellular chloride will be found in some autism and some schizophrenia. A calcium channelopathy affecting Cav1.2 would be found in some autism and some bipolar.
Eventually you would dispose of the old observational diagnoses like bipolar and give the biological diagnoses.  Then you will have the same drugs being used in a person with “bipolar” and another with “autism”.  When all this will happen is no time soon. 
In the meantime people interested in autism can benefit from the research into the other neuropsychiatric disorders.  These other disorders can be much better researched, partly because they usually concern adults who are fully verbal and have typical IQ.  In many cases there are both hypo and hyper cases in these disorders.   
Also of interest is that the same unusual gene expression in schizophrenia/bipolar is linked to creativity and the autism genes to intelligence. This is put forward as an explanation as to why evolution has conserved rather than erased neuropsychiatric disorders.

Height is polygenic 

Let’s start will a simple example.
There is no single gene that determines your height. Some school books suggest 3 or 4 genes, so let’s assume that is correct for now.
Traits are polygenic when there is wide variation. For example, humans can be many different sizes. Height is a polygenic trait, controlled by at least three genes with six alleles. If you are dominant for all of the alleles for height, then you will be very tall. There is also a wide range of skin colour across people. Skin colour is also a polygenic trait, as are hair and eye colour.

Polygenic inheritance often results in a bell shaped curve when you analyze the population. Most people fall in the middle of the phenotypic range, such as average height, while very few people are at the extremes, such as very tall or very short. At one end of the curve will be individuals who are recessive for all the alleles (for example, aabbcc); at the other end will be individuals who are dominant for all the alleles (for example, AABBCC). Through the middle of the curve will be individuals who have a combination of dominant and recessive alleles (for example, AaBbCc or AaBBcc).



There may be 4 or 6 or more alleles involved in the phenotype. At the left extreme, individuals are completely dominant for all alleles, and at the right extreme, individuals are completely recessive for all alleles. Individuals in the middle have various combinations of recessive and dominant alleles.
Unfortunately the real world is a bit more complex than high school biology. 


“Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.


Genes vs the Environment 
The spectrum of human diseases are caused by a multitude of genetic and environmental factors acting together. In certain conditions such as Down syndrome , genetic factors predominate, while in infections for example, environmental factors predominate. Most chronic non-communicable conditions such as schizophrenia and diabetes as well as congenital malformations are caused by an interaction of both genetic and environmental factors.







The environment and epigenetic change
Some environmental influences, like smoking or pollution, can also become genetic in that heritable epigenetic markers can become tagged to a specific gene.  This impacts whether it is turned on or off.  


Multifactorial vs Polygenic Inheritance 
Multifactorial inheritance diseases that show familial clustering but do not conform to any recognized pattern of single gene inheritance are termed multifactorial disorders. They are determined by the additive effects of many genes at different loci together with the effect of environmental factors.

These conditions show a definite familial tendency but the incidence in close relatives of affected individuals is usually around 2-4%, instead of the much higher figures that would be seen if these conditions were caused by mutations in single genes (25-50%).
Examples of disorders of multifactorial inheritance

·        asthma

·        schizophrenia

·        diabetes mellitus

·        hypertension

Polygenic inheritance involves the inheritance and expression of a phenotype being determined by many genes at different loci, with each gene exerting a small additive effect. Additive implies that the effects of the genes are cumulative, i.e. no one gene is dominant or recessive to another.





According to the liability/threshold model, all of the factors which influence the development of a multifactorial disorder, whether genetic or environmental, can be considered as a single entity known as liability.
The liabilities of all individuals in a population form a continuous variable, which can be exemplified by a bell shaped curve.

Individuals on the right side of the threshold line represent those affected by the disorder. 
In autism the threshold keeps being moved, because the definition of the disease keeps being widened.


Liability curves of affected and their relatives
The liability curve is relevant to the question posed by parents who have autism in the family and want to know whether it will occur again and also to grown up siblings of those with autism.

The curve for relatives of affected will be shifted to the right; so the familial incidence is higher than the general population incidence.



So the biggest future autism risk is likely to be a previous occurance. 
There are ways to actively promote protective factors and shift the curve back to the left; but a risk will remain. 


Evidence that Autism is Polygenic 
This is a paper from 2016 that looks at how the genetic risks are additive.



Autism spectrum disorder (ASD) risk is influenced by both common polygenic and de novo variation. The purpose of this analysis was to clarify the influence of common polygenic risk for ASDs and to identify subgroups of cases, including those with strong acting de novo variants, in which different types of polygenic risk are relevant. To do so, we extend the transmission disequilibrium approach to encompass polygenic risk scores, and introduce with polygenic transmission disequilibrium test. Using data from more than 6,400 children with ASDs and 15,000 of their family members, we show that polygenic risk for ASDs, schizophrenia, and educational attainment is over transmitted to children with ASDs in two independent samples, but not to their unaffected siblings. These findings hold independent of proband IQ. We find that common polygenic variation contributes additively to ASD risk in cases that carry a very strong acting de novo variant. Lastly, we find evidence that elements of polygenic risk are independent and differ in their relationship with proband phenotype. These results confirm that ASDs' genetic influences are highly additive and suggest that they create risk through at least partially distinct etiologic pathways.
  

Summary and Conclusions
Autism and related conditions are highly heritable disorders. Consequently, gene discovery promises to help elucidate the underlying pathophysiology of these syndromes and, it is hoped, eventually improve diagnosis, treatment, and prognosis. The genetic architecture of autism is not yet known. What can be said from the studies to date is that writ large, autism is not a monogenic disorder with Mendelian inheritance. In many, but clearly not all individual cases, it is likely to be a complex genetic disorder that results from simultaneous genetic variations in multiple genes. The CDCV hypothesis predicts that the risk alleles in Autism and other complex disorders will be common in the population. However, recent evidence both with regard to autism and other complex disorders, raises significant questions regarding the overall applicability of the theory and the extent of its usefulness in explaining individual genetic liability. In addition, considerable evidence points to the importance of rare alleles for the overall population of affected individuals as well as their role in providing a foothold into the molecular mechanisms of disease. Finally, there is debate regarding the clinical implications of autism genetic research to date. Most institutional guidelines recommend genetic testing or referral only for idiopathic autism if intellectual disability and dysmorphic features are present. However, recent advances suggest that the combination of several routine tests combined with a low threshold for referral is well-justified in cases of idiopathic autism.


So What is Autism? 
Most people’s autism is of unknown cause (idiopathic) and this is most likely to be polygenic, but highly likely to have some environmental influences making it multifactorial.

What is interesting and potentially relevant to therapy is that the polygenic footprint of autism overlaps with those causing other neuropsychiatric diseases like bipolar, schizophrenia and even ADHD.

As you broaden the definition of autism and so move the threshold you will eventually diagnose everyone as having autism; because we all have some autism genes.


This does then start to be ridiculous, but in some ways we are now at the point where quirky but normal has become quirky autistic.
This same questionable position of where to draw the threshold applies to all such disorders (bipolar, ADHD etc.).  At what point does a difference become a disorder?
Where things currently stand more than 10% of the population have an autism-gene-overlapping diagnosis.  That is a lot and suggests that things are getting a little out of control.  Perhaps better to raise the threshold for where difference become disorder?



 Percent of the population affected by various disorders genetically overlapping to strictly define autism (SDA). Estimates of prevalence vary widely by country and study.

If you raise the threshold for how severe autism has to be, you soon lose the quirky autism. A stricter approach to diagnosing ADHD would mean losing the people that will naturally “grow out of it” and leave a much smaller group that might genuinely benefit from medical intervention. We saw in an earlier post that the percentage of kids with ADHD given drugs varies massively among developed countries, with the US at the top and France at the bottom. Here is another article on this subject.


Autism overlapping with Schizophrenia, Bipolar ADHD etc.
There are now numerous different studies showing how the large number of genes that underlie each observational diagnosis overlap with each other.



One Sentence Summary: Autism, schizophrenia, and bipolar disorder share global gene expression patterns, characterized by astrocyte activation and disrupted synaptic processes.
Recent large-scale studies have identified multiple genetic risk factors for mental illness and indicate a complex, polygenic, and pleiotropic genetic architecture for neuropsychiatric disease. However, little is known about how genetic variants yield brain dysfunction or pathology. We use transcriptomic profiling as an unbiased, quantitative readout of molecular phenotypes across 5 major psychiatric disorders, including autism (ASD), schizophrenia (SCZ), bipolar disorder (BD), depression (MDD), and alcoholism (AAD), compared with carefully matched controls. We identify a clear pattern of shared and distinct gene-expression perturbations across these conditions, identifying neuronal gene co-expression modules downregulated across ASD, SCZ, and BD, and astrocyte related modules most prominently upregulated in ASD and SCZ. Remarkably, the degree of sharing of transcriptional dysregulation was strongly related to polygenic (SNP-based) overlap across disorders, indicating a significant genetic component. These findings provide a systems-level view of the neurobiological architecture of major neuropsychiatric illness and demonstrate pathways of molecular convergence and specificity.


We observe a gradient of synaptic gene down-regulation, with ASD > SZ > BD. BD and SCZ appear most similar in terms of synaptic dysfunction and astroglial activation and are most differentiated by subtle downregulation in microglial and endothelial modules. ASD shows the most pronounced upregulation of a microglia signature, which is minimal in SCZ or BD. Based on these data, we hypothesize that a more severe synaptic phenotype, as well as the presence of microglial activation, is responsible for the earlier onset of symptoms in ASD, compared with the other disorders, consistent with an emerging understanding of the critical non-inflammatory role for microglia in regulation of synaptic connectivity during neurodevelopment (39, 66). MDD shows neither the synaptic nor astroglial pathology observed in SCZ, BD. In contrast, in MDD, a striking dysregulation of HPA-axis and hormonal signalling not seen in the other disorders is observed. These results provide the first systematic, transcriptomic framework for understanding the pathophysiology of neuropsychiatric disease, placing disorder-related alterations in gene expression in the context of shared and distinct genetic effects.



  


Several of the variants lie in regions important for immune function and associated with autism. This suggests that both disorders stem partly from abnormal activation of the immune system, say some researchers.


The study builds on previous work, in which Arking’s team characterized gene expression in postmortem brain tissue from 32 individuals with autism and 40 controls2. In the new analysis, the researchers made use of that dataset as well as one from the Stanley Medical Research Institute that looked at 31 people with schizophrenia, 25 with bipolar disorder and 26 controls3.
They found 106 genes expressed at lower levels in autism and schizophrenia brains than in controls. These genes are involved in the development of neurons, especially the formation of the long projections that carry nerve signals and the development of the junctions, or synapses, between one cell and the next. The results are consistent with those from previous studies indicating a role for genes involved in brain development in both conditions.

“On the one hand, it’s exciting because it tells us that there’s a lot of overlap,” says Jeremy Willsey, assistant professor of psychiatry at the University of California, San Francisco, who was not involved in the work. “On the other hand, these are fairly general things that are overlapping.”
Full paper




Schizophrenia/Bipolar linked to Creativity? Autism linked to Intelligence?





Since we see that neuropsychiatric disorders are substantially polygenic, the question arises why they have been evolutionarily conserved. Over thousands of years why have these traits not just faded away?
That question was raised, and answered again, in a recent autism study at Yale.  The same wide cluster of genes that may lead trigger autism are again seen to be linked to higher intelligence. You may get autism, higher intelligence, both or indeed neither, but people with those genes have a higher likelihood of autism and/or a higher IQ.

Previous studies have linked bipolar/schizophrenia to creativity, so you would expect artists and stage actors to have a higher incidence of those disorders.
In terms of evolutionary selection, clearly creativity and intelligence have been valued and so the associated disorders did not fade away over thousands of years.
  


“It might be difficult to imagine why the large number of gene variants that together give rise to traits like ASD are retained in human populations — why aren’t they just eliminated by evolution?” said Joel Gelernter, the Foundations Fund Professor of Psychiatry, professor of genetics and of neuroscience, and co-author. “The idea is that during evolution these variants that have positive effects on cognitive function were selected, but at a cost — in this case an increased risk of autism spectrum disorders. 


Abstract

Cognitive impairment is common among individuals diagnosed with autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). It has been suggested that some aspects of intelligence are preserved or even superior in people with ASD compared with controls, but consistent evidence is lacking. Few studies have examined the genetic overlap between cognitive ability and ASD/ADHD. The aim of this study was to examine the polygenic overlap between ASD/ADHD and cognitive ability in individuals from the general population. Polygenic risk for ADHD and ASD was calculated from genome-wide association studies of ASD and ADHD conducted by the Psychiatric Genetics Consortium. Risk scores were created in three independent cohorts: Generation Scotland Scottish Family Health Study (GS:SFHS) (n=9863), the Lothian Birth Cohorts 1936 and 1921 (n=1522), and the Brisbane Adolescent Twin Sample (BATS) (n=921). We report that polygenic risk for ASD is positively correlated with general cognitive ability (beta=0.07, P=6 × 10(-7), r(2)=0.003), logical memory and verbal intelligence in GS:SFHS. This was replicated in BATS as a positive association with full-scale intelligent quotient (IQ) (beta=0.07, P=0.03, r(2)=0.005). We did not find consistent evidence that polygenic risk for ADHD was associated with cognitive function; however, a negative correlation with IQ at age 11 years (beta=-0.08, Z=-3.3, P=0.001) was observed in the Lothian Birth Cohorts. These findings are in individuals from the general population, suggesting that the relationship between genetic risk for ASD and intelligence is partly independent of clinical state. These data suggest that common genetic variation relevant for ASD influences general cognitive ability.
  
Conclusion
Given the overlap between so many neuropsychiatric disorders it might be helpful if psychiatrists were more aware of the limitations of their observational diagnoses.
There is no singular schizophrenia like there is no single autism. They are all intertwined.  A mood disturbance in Asperger’s may have plenty in common with one in schizophrenia and respond to the same therapy.  Not surprisingly an off-label treatment in autism may work wonders for someone who is bipolar.
Probably the tighter you define autism the more there will be biological overlaps with bipolar/schizophrenia.
While there are overlaps there are other areas where autism is the opposite of bipolar and/or schizophrenia.
From a therapeutic perspective, since schizophrenia therapies have been more deeply researched than those of autism, it is always well work checking schizophrenia research for evidence.
The multifactorial approach does help explain the increasing incidence of more severe autism as environmental insults increase in modern life and we accumulate epigenetic damage.  The studies linked autism/schizophrenia with immunity genes and there is has been a continuing rise in other auto-immune, disease like asthma.
The ever sliding diagnosis threshold substantially explains much of the great increase in mild autism.
You can also use this framework to work out how to reduce the incidence of autism in future generations, but it seems that human nature continues to work in the opposite way.

Environmental factors are simple to modify, reducing risk factors and increasing protective factors.

If you think like Knut Wittkowski you might look at the tail of autism liability curve and try to identify those future people. Those people are likely to have some of the 700 autism risk genes over/under expressed and might benefit from some preventative therapy to minimize the coming developmental damage.  Knut thinks that Mefanemic acid will do the job. There are numerous other ideas.