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“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.”
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.