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Thursday 9 March 2017

Gene Primer for people interested in Autism


Today’s post is a standalone introduction to genetics, as relevant for lay people interested in autism.
The scientists among you will likely know all this and more, but many more people are talking about genes and genetic testing these days.
Genetics is the domain of some very clever scientists and to fully understand this field would require a great deal of effort.  Often the cleverest people are the least able to explain things to the rest of us. Some equally clever researchers think that there will be so many possible autism genes that it is better to focus on the much smaller number of shared affected pathways.  I stand with the latter group.
Confused? He should be.

As is often the case, even a basic understanding of the principles does allow you to draw meaningful practical conclusions from the ever-expanding pool of research.
In most cases of idiopathic autism there is over/under expression of a very large number of genes.  Most of these genes do their job and produce perfectly functional proteins, just too much or too little. If you ran a test to sequence all those genes, most would come up as normal.  A variation in the expression in one gene can affect the expression of numerous others.
Ultimately what matters is, in each part of the body, which genes are turned on when they should be off and vice versa.
Some well-known syndromes result from missing copies, or extra copies, of certain genes.  These are called CNVs (Copy Number Variants). This is relatively easy to validate with existing tests.
The most common type of genetic variation among people is an SNP (single nucleotide polymorphism) and it represents a difference in a single DNA building block, called a nucleotide.  There are online database that log the effect of individual SNPs, which you can look up.
There are 12,932 known SNPs for the CACNA1C gene, which expresses the calcium ion channel Cav1.2. Ion channels are little gates in your cells that open and close as part of the signaling process that controls your body.  When these gates are faulty they might stay open, or stay shut, or you might just have too many of them; and you end up with a problem called a channelopathy. The Cav1.2 ion channel is known  to go wrong autism, bipolar and schizophrenia. If you want to give that gate a nudge to shut it, you use a channel blocker. A complication is that these same gates appear all over your body and a Cav1.2 blocker will affect them all. This is why some people get side effects.
There can be genetic mutations that result in a variation in the structure of the protein that is expressed.  This can be good (protective), or it can be bad.  This does not seem to underlie autism.
The great majority of research concerns the exome, a tiny part of the wider genome; the exome holds the information needed to express proteins.  The remaining 98% was thought to be “DNA junk”, but this appears not to be the case.  Variations in the 98% do matter, because they include things like silencers and enhancers that affect gene expression.  Only recently have scientists paid attention to the 98%; so much remains unknown.
Until recently, scientists thought that human diseases were caused mainly by changes in DNA sequence, infectious agents such as bacteria and viruses, or environmental agents. Now, researchers have demonstrated that changes in the epigenome also can cause, or result from, disease.
The epigenome consists of a record of the chemical markers attached to your DNA, like bookmarks that turn on or turn off particular genes.  These changes can be passed down via transgenerational epigenetic inheritance.  Changes to the epigenome result in changes to the function of the genome. 
Epigenomics/epigenetics, will become a vital part of efforts to better understand the human body and to improve health. Epigenomic maps may someday enable doctors to determine an individual's health status and predict a patient's response to therapies. 
Genetics can be made to sound bewildering complex:-
An analogy to the human genome stored on DNA is that of instructions stored in a book:
  • The book (genome) would contain 23 chapters (chromosomes);
  • Each chapter contains 48 to 250 million letters (A,C,G,T) without spaces;
  • Hence, the book contains over 3.2 billion letters total;
  • The book fits into a cell nucleus the size of a pinpoint;

 Or you can make it quite simple:-

·        The latest Boing 747 has 6,000,000 parts, and I expect many special extra ones in the new Air Force One variant.
·        Less than 25,000 different genes are needed to make a human and many of these appear not be essential.
·       As with jumbo jet you don't just need all the components, but you have to know where to put them and the correct sequence. Is the human equivalent of these instructions in the exome? or elsewhere in the genome?

I prefer simple.

There are different forms of genetic testing; simple ones test for a specific dysfunction, like Fragile-X.  This is relatively straight forward because the lab knows exactly where to look.
When you start looking for unknown dysfunctions the big risk is that you will find very many variances, the great majority of which have no relevance whatsoever.  You need to only consider the variances that are relevant.  Who decides which are relevant?  Beyond the very well-known risk genes, it becomes hugely subjective.
This interpretation is subjective because no one knows for sure the complete list of genes that could relate to autism.  It is likely to be a sub-set of the so-called "essential genes". The Simons Foundation suggest around 700 genes, but the list keeps growing. The AutsimKB database maintained by Peking University currently contains 3075 genes (99 syndromic autism related genes and 3022 non-syndromic autism related genes), 4964 Copy Number Variations (CNVs).
Some people will learn important things about their autism from today’s  genetic testing, but many will not.
Two things need to change, better data and better analysis.
I did check the analysis from one well-known US testing laboratory.  All I did was look at the genes they highlighted as being relevant to autism and then look at the supplementary list of variance present in one test, but that they considered irrelevant to autism.  Just using google I could find evidence that some of those irrelevant genes were actually potentially relevant.
Even if you find you have a flagged autism gene, this may or may not help you. 
If you have a defect in your mitochondrial DNA then you can say “for sure” that you have a particular type of mitochondrial disease and try and optimize your therapy.
If you have a variance in a gene associated with people with autism who remain non-verbal, you might be better off not knowing.  There is a case often quoted of the mother who made great efforts to get her child to talk, only to find later that a “non-verbal” mutation existed.  She might not have bothered had she made the genetic testing at a younger age.  I actually know a child diagnosed with a supposed “non-verbal” mutation and I think it is a really stupid diagnosis.  


A Future World

In a future time you might analyze the genome and epigenome of both parents and the child. This would be automatically be compared with the results from tens of millions of other people.  This would then reliably predict the possible dysfunctions that might develop in the child.  Having predicted the dysfunctions and the probability of them actually occurring,  a list of personalized therapies, some preventative, would be provided.


Conclusion
The science is not quite there yet. There is much work to be done on the exome, the wider genome, let alone the record of all those tags on it, which is the epigenome.
Current genetic testing can confirm known single gene autism syndromes.
Current genetic testing can identify known single gene metabolic and other disorders that can contribute to autism.
For idiopathic autism current genetic testing may, or may not, tell you anything that leads to a useful therapy.  Given the choice, take the best genetic testing available, just realize its limitations.
Now for the science:-


Understanding Genetics
There are some good introductions to genetics that are available for free.
Wikipedia gets quite complicated
This book is available for free:-


  

DNA

DNA is the hereditary material in humans. Nearly every cell in a person’s body has the same DNA. Most DNA is located in the cell nucleus, where it is called nuclear DNA, but a small amount of DNA can also be found in the mitochondria, where it is called mitochondrial DNA. 

The information in DNA is stored as a code made up of four chemical bases:

adenine (A), guanine (G), cytosine (C), and thymine (T).

Human DNA consists of about 3 billion bases, and more than 99 percent of those bases are the same in all people. The order, or sequence, of these bases determines the information available for building and maintaining an organism, similar to the way in which letters of the alphabet appear in a certain order to form words and sentences. 

DNA bases pair up with each other, A with T and C with G, to form units called base pairs.  Each base is also attached to a sugar molecule and a phosphate molecule. Together, a base, sugar, and phosphate are called a nucleotide. 

Nucleotides are arranged in two long strands that form a spiral called a double helix. The structure of the double helix is somewhat like a ladder, with the base pairs forming the ladder’s rungs and the sugar and phosphate molecules forming the vertical sidepieces of the ladder. 

An important property of DNA is that it can replicate, or make copies of itself. 

Each strand of DNA in the double helix can serve as a pattern for duplicating the sequence of bases. This is critical when cells divide because each new cell needs to have an exact copy of the DNA present in the old cell.





Mitochondrial DNA

Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA. This genetic material is known as mitochondrial DNA. 

Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Each cell contains hundreds to thousands of  mitochondria. 

Mitochondria produce energy through a process called oxidative phosphorylation. This process uses oxygen and simple sugars to create adenosine triphosphate (ATP), the cell’s main energy source. A set of enzyme complexes, designated as complexes I-V, carry out oxidative phosphorylation within mitochondria. 
In addition to energy production, mitochondria play a role in several other cellular activities. For example, mitochondria help regulate the self-destruction of cells (apoptosis). They are also necessary for the production of substances such as  cholesterol and heme (a component of hemoglobin, the molecule that carries oxygen in the blood). 

Mitochondrial DNA contains 37 genes, all of which are essential for normal mitochondrial function. Thirteen of these genes provide instructions for making enzymes involved in oxidative phosphorylation. The remaining genes provide instructions for making molecules called transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), which are chemical cousins of DNA. These types of RNA help assemble protein building blocks (amino acids) into functioning proteins.


Genes
A gene is the basic physical and functional unit of heredity. Genes, which are made up of DNA, act as instructions to make molecules called proteins. In humans, genes vary in size from a few hundred DNA bases to more than 2 million bases. The Human Genome Project has estimated that humans have between 20,000 and 25,000 genes.

Every person has two copies of each gene, one inherited from each parent.

Most genes are the same in all people, but a small number of genes (less than 1 percent of the total) are slightly different between people.

Alleles are forms of the same gene with small differences in their sequence of DNA bases. These small differences contribute to each person’s unique physical features.

Genes are made up of DNA. Each chromosome contains many genes.

Chromosome

In the nucleus of each cell, the DNA molecule is packaged into thread-like structures called chromosomes. Each chromosome is made up of DNA tightly coiled many times around proteins called histones that support its structure.

Chromosomes are not visible in the cell’s nucleus—not even under a microscope - when the cell is not dividing.
In humans, each cell normally contains 23 pairs of chromosomes, for a total of 46.

We inherit 23 of our chromosomes from our mother (in the egg), and the other 23 from our father (in the sperm), so that we have 23 pairs of chromosomes, and therefore two copies of each gene.

Twenty-two of these pairs, called autosomes, look the same in both males and females. The 22 autosomes are numbered by size.

The 23rd pair, the sex chromosomes, differ between males and females. Females have two copies of the X chromosome, while males have one X and one Y chromosome.

Down syndrome is caused by possessing three copies of chromosome 21 instead of the usual two.

Fragile X syndrome is caused by a defect on chromosome 23, typically due to the expansion of the CGG triplet repeat within the Fragile X mental retardation 1 (FMR1) gene on the X chromosome.

Males with a full mutation display virtually complete penetrance and will therefore almost always display symptoms of FXS, while females with a full mutation generally display a penetrance of about 50% as a result of having a second, normal X chromosome. Females with FXS may have symptoms ranging from mild to severe, although they are generally less affected than males.



Do all gene mutations affect health and development?

No; only a small percentage of mutations cause genetic disorders—most have no impact on health or development. For example, some mutations alter a gene's DNA sequence but do not change the function of the protein made by the gene.
Often, gene mutations that could cause a genetic disorder are repaired by certain enzymes before the gene is expressed and an altered protein is produced.
Each cell has a number of pathways through which enzymes recognize and repair mistakes in DNA. Because DNA can be damaged or mutated in many ways, DNA repair is an important process by which the body protects itself from disease.

A very small percentage of all mutations actually have a positive effect. These mutations lead to new versions of proteins that help an individual better adapt to changes in his or her environment. For example, a beneficial mutation could result in a protein that protects an individual and future generations from a new strain of bacteria.

Because a person's genetic code can have a large number of mutations with no effect on health, diagnosing genetic conditions can be difficult. Sometimes, genes thought to be related to a particular genetic condition have mutations, but whether these changes are involved in development of the condition has not been determined; these genetic changes are known as variants of unknown significance (VOUS). Sometimes, no mutations are found in suspected disease related genes, but mutations are found in other genes whose relationship to a particular genetic condition is unknown. It is difficult to know whether these variants are involved in the disease.

The types of possible gene mutations

The DNA sequence of a gene can be altered in a number of ways. Gene mutations have varying effects on health, depending on where they occur and whether they alter the function of essential proteins. The types of mutations include:


Missense mutation

This type of mutation is a change in one DNA base pair that results in the substitution of one amino acid for another in the protein made by a gene.


Nonsense mutation

A nonsense mutation is also a change in one DNA base pair. Instead of substituting one amino acid for another, however, the altered DNA sequence prematurely signals the cell to stop building a protein. This type of mutation results in a shortened protein that may function improperly or not at all.


Insertion

An insertion changes the number of DNA bases in a gene by adding a piece of DNA. As a result, the protein made by the gene may not function properly.


Deletion

A deletion changes the number of DNA bases by removing a piece of DNA. Small deletions may remove one or a few base pairs within a gene, while larger deletions can remove an entire gene or several neighboring genes.

The deleted DNA may alter the function of the resulting protein(s).


Duplication

A duplication consists of a piece of DNA that is abnormally copied one or more times. This type of mutation may alter the function of the resulting protein.


Frameshift mutation

This type of mutation occurs when the addition or loss of DNA bases changes a gene's reading frame. A reading frame consists of groups of 3 bases that each code for one amino acid. A frameshift mutation shifts the grouping of these bases and changes the code for amino acids.

The resulting protein is usually nonfunctional. Insertions, deletions, and duplications can all be frameshift mutations.


Repeat expansion

Nucleotide repeats are short DNA sequences that are repeated a number of times in a row. For example, a trinucleotide repeat is made up of 3-base-pair sequences, and a tetranucleotide repeat is made up of 4-base-pair sequences. A repeat expansion is a mutation that increases the number of times that the short DNA sequence is repeated. This type of mutation can cause the resulting protein to function improperly.






Change in the number of genes (CNVs)

People have two copies of most genes, one copy inherited from each parent. In some cases, however, the number of copies varies—meaning that a person can be born with one, three, or more copies of particular genes. Less commonly, one or more genes may be entirely missing. This type of genetic difference is known as copy number variation (CNV).

Copy number variation results from insertions, deletions, and duplications of large segments of DNA. These segments are big enough to include whole genes. Variation in gene copy number can influence the activity of genes and ultimately affect many body functions.

Copy number variation accounts for a significant amount of genetic difference between people. More than 10 percent of human DNA appears to contain these differences in gene copy number. While much of this variation does not affect health or development, some differences likely influence a person’s risk of disease and response to certain drugs.

Changes in the number of chromosomes

Human cells normally contain 23 pairs of chromosomes, for a total of 46 chromosomes in each cell. A change in the number of chromosomes can cause problems with growth, development, and function of the body's systems. These changes can occur during the formation of reproductive cells (eggs and sperm), in early fetal development, or in any cell after birth. A gain or loss of chromosomes from the normal 46 is called aneuploidy.

A common form of aneuploidy is trisomy, or the presence of an extra chromosome in cells. People with trisomy have three copies of a particular chromosome in cells instead of the normal two copies.

Down syndrome is an example of a condition caused by trisomy. People with Down syndrome typically have three copies of chromosome 21 in each cell, for a total of 47 chromosomes per cell.

Monosomy, or the loss of one chromosome in cells, is another kind of aneuploidy. People with monosomy have one copy of a particular chromosome in cells instead of the normal two copies. Turner syndrome is a condition caused by monosomy.  Women with Turner syndrome usually have only one copy of the X chromosome in every cell, for a total of 45 chromosomes per cell.

Rarely, some cells end up with complete extra sets of chromosomes. Cells with one additional set of chromosomes, for a total of 69 chromosomes, are called triploid. Cells with two additional sets of chromosomes, for a total of 92 chromosomes, are called tetraploid. A condition in which every cell in the body has an extra set of chromosomes is not compatible with life.


Changes in the structure of chromosomes

This type of change is usually associated with cancer.

Changes that affect the structure of chromosomes can cause problems with growth, development, and function of the body's systems. These changes can affect many genes along the chromosome and disrupt the proteins made from those genes.

Structural changes can occur during the formation of egg or sperm cells, in early fetal development, or in any cell after birth. Pieces of DNA can be rearranged within one chromosome or transferred between two or more chromosomes. The effects of structural changes depend on their size and location, and whether any genetic material is gained or lost. Some changes cause medical problems, while others may have no effect on a person's health.

Changes in chromosome structure include:


Translocations

A translocation occurs when a piece of one chromosome breaks off and attaches to another chromosome. This type of rearrangement is described as balanced if no genetic material is gained or lost in the cell. If there is a gain or loss of genetic material, the translocation is described as unbalanced.


Deletions

Deletions occur when a chromosome breaks and some genetic material is lost. Deletions can be large or small, and can occur anywhere along a chromosome.


Duplications

Duplications occur when part of a chromosome is copied (duplicated) too many times. This type of chromosomal change results in extra copies of genetic material from the duplicated segment.


Inversion

An inversion involves the breakage of a chromosome in two places; the resulting piece of DNA is reversed and re-inserted into the chromosome.
Genetic material may or may not be lost as a result of the chromosome breaks. An inversion that involves the chromosome's constriction point (centromere) is called a pericentric inversion. An inversion that occurs in the long (q) arm or short (p) arm and does not involve the centromere is called a paracentric inversion.





Isochromosomes

An isochromosome is a chromosome with two identical arms. Instead of one long (q) arm and one short (p) arm, an isochromosome has two long arms or two short arms. As a result, these abnormal chromosomes have an extra copy of some genes and are missing copies of other genes.


Dicentric chromosomes

Unlike normal chromosomes, which have a single constriction point (centromere), a dicentric chromosome contains two centromeres. Dicentric chromosomes result from the abnormal fusion of two chromosome pieces, each of which includes a centromere. These structures are unstable and often involve a loss of some genetic material.


Ring chromosomes

Ring chromosomes usually occur when a chromosome breaks in two places and the ends of the chromosome arms fuse together to form a circular structure. The ring may or may not include the chromosome's constriction point (centromere). In many cases, genetic material near the ends of the chromosome is lost.

Many cancer cells also have changes in their chromosome structure. These changes are not inherited; they occur in somatic cells (cells other than eggs or sperm) during the formation or progression of a cancerous tumor.


Changes in mitochondrial DNA

Mitochondria  are structures within cells that convert the energy from food into a form that cells can use. Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA (known as mitochondrial DNA or mtDNA). In some cases, inherited changes in mitochondrial DNA can cause problems with growth, development, and function of the body’s systems. These mutations disrupt the mitochondria’s ability to generate energy efficiently for the cell.

Conditions caused by mutations in mitochondrial DNA often involve multiple organ systems. The effects of these conditions are most pronounced in organs and tissues that require a lot of energy (such as the heart, brain, and muscles).

Although the health consequences of inherited mitochondrial DNA mutations vary widely, frequently observed features include muscle weakness and wasting, problems with movement, diabetes, kidney failure, heart disease, loss of intellectual functions (dementia), hearing loss, and abnormalities involving the eyes and vision.

Mitochondrial DNA is also prone to somatic mutations, which are not inherited. somatic mutations occur in the DNA of certain cells during a person’s lifetime and typically are not passed to future generations. Because mitochondrial DNA has a limited ability to repair itself when it is damaged, these mutations tend to build up over time. A buildup of somatic mutations in mitochondrial DNA has been associated with some forms of cancer and an increased risk of certain age-related disorders such as heart disease, Alzheimer disease, and Parkinson disease. Additionally, research suggests that the progressive accumulation of these mutations over a person’s lifetime may play a role in the normal process of aging.

What does it mean to have a genetic predisposition to a disease?

A genetic predisposition (sometimes also called genetic susceptibility) is an increased likelihood of developing a particular disease based on a person's genetic makeup. A genetic predisposition results from specific genetic variations that are often inherited from a parent. These genetic changes contribute to the development of a disease but do not directly cause it. Some people with a predisposing genetic variation will never get the disease while others will, even within the same family.

Genetic variations can have large or small effects on the likelihood of developing a particular disease. For example, certain mutations in the BRCA1 or BRCA2 genes greatly increase a person's risk of developing breast cancer and ovarian cancer. Variations in other genes, such as BARD1 and BRIP1, also increase breast cancer risk, but the contribution of these genetic changes to a person's overall risk appears to be much smaller.

Current research is focused on identifying genetic changes that have a small effect on disease risk but are common in the general population. Although each of these variations only slightly increases a person's risk, having changes in several different genes may combine to increase disease risk significantly.

Changes in many genes, each with a small effect, may underlie susceptibility to many common diseases, including cancer, obesity, diabetes, heart disease, and mental illness.

In people with a genetic predisposition, the risk of disease can depend on multiple factors in addition to an identified genetic change. These include other genetic factors (sometimes called modifiers) as well as lifestyle and environmental factors.  Although a person's genetic makeup cannot be altered, some lifestyle and environmental  modifications (such as having more frequent disease screenings and maintaining a healthy weight) may be able to reduce disease risk in people with a genetic predisposition.


Genes direct the production of proteins

Most genes contain the information needed to make functional molecules called proteins. (A few genes produce other molecules that help the cell assemble proteins.)

The journey from gene to protein is complex and tightly controlled within each cell. It consists of two major steps: transcription and translation. Together, transcription and translation are known as gene expression. During the process of transcription, the information stored in a gene's DNA is transferred to a similar molecule called RNA (ribonucleic acid) in the cell nucleus.

Both RNA and DNA are made up of a chain of nucleotide bases, but they have slightly different chemical properties. The type of RNA that contains the information for making a protein is called messenger RNA (mRNA) because it carries the information, or message, from the DNA out of the nucleus into the cytoplasm.

Translation, the second step in getting from a gene to a protein, takes place in the cytoplasm. The mRNA interacts with a specialized complex called a ribosome, which "reads" the sequence of mRNA bases. Each sequence of three bases, called a codon, usually codes for one particular amino acid. (Amino acids are the building blocks of proteins.) A type of RNA called transfer RNA (tRNA) assembles the protein, one amino acid at a time. Protein assembly continues until the ribosome encounters a “stop” codon (a sequence of three bases that does not code for an amino acid).
The flow of information from DNA to RNA to proteins is one of the fundamental principles of molecular biology. It is so important that it is sometimes called the "central dogma.”


Genes turn on and off in cells

Each cell expresses, or turns on, only a fraction of its genes. The rest of the genes are repressed, or turned off. The process of turning genes on and off is known as gene regulation. Gene regulation is an important part of normal development. Genes are turned on and off in different patterns during development to make a brain cell look and act different from a liver cell or a muscle cell, for example. Gene regulation also allows cells to react quickly to changes in their environments. Although we know that the regulation of genes is critical for life, this complex process is not yet fully understood.

Gene regulation can occur at any point during gene expression, but most commonly occurs at the level of transcription (when the information in a gene’s DNA is transferred to mRNA). Signals from the environment or from other cells activate proteins called transcription factors. These proteins bind to regulatory regions of a gene and increase or decrease the level of transcription. By controlling the level of transcription, this process can determine the amount of protein product that is made by a gene at any given time.


The epigenome

DNA modifications that do not change the DNA sequence can affect gene activity. Chemical compounds that are added to single genes can regulate their activity; these modifications are known as epigenetic changes. The epigenome comprises all of the chemical compounds that have been added to the entirety of one’s DNA (genome) as a way to regulate the activity (expression) of all the genes within the genome. The chemical compounds of the epigenome are not part of the DNA sequence, but are on or attached to DNA (“epi-“ means above in Greek). Epigenomic modifications remain as cells divide and in some cases can be inherited through the generations. Environmental influences, such as a person’s diet and exposure to pollutants, can also impact the epigenome.

Epigenetic changes can help determine whether genes are turned on or off and can influence the production of proteins in certain cells, ensuring that only necessary proteins are produced. For example, proteins that promote bone growth are not produced in muscle cells. Patterns of epigenome modification vary among individuals, different tissues within an individual, and even different cells.

A common type of epigenomic modification is called methylation. Methylation involves attaching small molecules called methyl groups, each consisting of one
carbon atom and three hydrogen atoms, to segments of DNA. When methyl groups are added to a particular gene, that gene is turned off or silenced, and no protein is produced from that gene.

Because errors in the epigenetic process, such as modifying the wrong gene or failing to add a compound to a gene, can lead to abnormal gene activity or inactivity, they can cause genetic disorders. Conditions including cancers, metabolic disorders, and degenerative disorders have all been found to be related to epigenetic errors.

Scientists continue to explore the relationship between the genome and the
chemical compounds that modify it. In particular, they are studying what effect
the modifications have on gene function, protein production, and human health.




How geneticists indicate the location of a gene
Geneticists use maps to describe the location of a particular gene on a chromosome. One type of map uses the cytogenetic location to describe a gene’s position. The cytogenetic location is based on a distinctive pattern of bands created when chromosomes are stained with certain chemicals. Another type of map uses the molecular location, a precise description of a gene's position on a chromosome. The molecular location is based on the sequence of DNA building blocks (base pairs) that make up the chromosome.


Cytogenetic location

Geneticists use a standardized way of describing a gene's cytogenetic location.
In most cases, the location describes the position of a particular band on a stained chromosome:

        17q12

It can also be written as a range of bands, if less is known about the exact location:

        17q12-q21

The combination of numbers and letters provide a gene's “address” on a chromosome. This address is made up of several parts:


  • The chromosome on which the gene can be found. The first number or letter used to describe a gene's location represents the chromosome. Chromosomes 1 through 22 (the autosomes) are designated by their chromosome number. The sex chromosomes are designated by X or Y.
  • The arm of the chromosome. Each chromosome is divided into two sections (arms) based on the location of a narrowing (constriction) called the centromere. By convention, the shorter arm is called p, and the longer arm is called q. The chromosome arm is the second part of the gene's address. For example, 5q is the long arm of chromosome 5, and Xp is the short arm of the X chromosome.
  • The position of the gene on the p or q arm. The position of a gene is based on a distinctive pattern of light and dark bands that appear when the chromosome is stained in a certain way. The position is usually designated by two digits (representing a region and a band), which are sometimes followed by a decimal point and one or more additional digits (representing sub-bands within a light or dark area). The number indicating the gene position increases with distance from  the centromere. For example: 14q21 represents position 21 on the long arm of chromosome 14. 14q21 is closer to the centromere than 14q22. Sometimes, the abbreviations “cen” or “ter” are also used to describe a gene's cytogenetic location. “Cen” indicates that the gene is very close to the  centromere. For example, 16pcen refers to the short arm of chromosome 16 near the centromere. “Ter” stands for terminus, which indicates that the gene is very close to the end of the p or q arm. For example, 14qter refers to the tip of the long arm of chromosome 14. (“Tel” is also sometimes used to describe a gene's location. “Tel” stands for telomeres, which are at the ends of each chromosome. The abbreviations “tel” and “ter” refer to the same location.)



The different ways in which a genetic condition can be inherited?

Some genetic conditions are caused by mutations in a single gene. These conditions are usually inherited in one of several patterns, depending on the gene involved:



Patterns of inheritance



Inheritance                   Description                                                                       Examples
pattern



Autosomal                     One mutated copy of the gene in each                      Huntington disease
Dominant                       cell is sufficient for a person to be affected               Marfan syndrome
by an autosomal dominant disorder. In
some cases, an affected person inherits the
condition from an affected parent.
                                   In others, the condition may result from a new
                                      mutation in the geneand occur in people with
                                      no history of the disorder in their family



Autosomal                In autosomal recessive inheritance,                           Both cystic fibrosis
Recessive                copies of the gene in each cell have                          sickle
mutations. The parents of an individual with
an autosomal recessive condition each carry
one copy of the mutated gene, but they typically
do not show signs and symptoms of the condition.

Autosomal recessive disorders are typically
not seen in every generation of an affected
family.



X-linked                    X-linked dominant disorders are caused by               Fragile X
Dominant                  mutations in genes on the X chromosome,                syndrome
one of the two sex chromosomes in
each cell. In females (who have two X
chromosomes), a mutation in one of the two
copies of the gene in each cell is sufficient
to cause the disorder. In males (who have
only one X chromosome), a mutation in the
only copy of the gene in each cell causes
the disorder. In most cases, males experience
more severe symptoms of the disorder than
females. A characteristic of X-linked inheritance
is that fathers cannot pass X-linked traits to their
sons (no male-to-male transmission).



X-linked                    X-linked recessive disorders are also                         Hemophilia,
Recessive                caused by mutations in genes on the X                      Fabry disease
chromosome. In males (who have only
one X chromosome), one altered copy of
the gene in each cell is sufficient to cause
the condition. In females (who have two
X chromosomes), a mutation would have
to occur in both copies of the gene to
cause the disorder.
Because it is unlikely that females will have
two altered copies of this gene, males are
affected by X-linked recessive disorders
much more frequently than females. A
characteristic of X-linked inheritance is that
fathers cannot pass X-linked traits to their
sons (no male-to-male transmission).



Y-linked                   A condition is considered Y-linked if the                     Y chromosome
mutated gene that causes the disorder                      infertility, someis             located on the Y chromosome, one of                         cases of Swyer
the two sex chromosomes in each of a                     syndrome
male's cells. Because only males have a
Y chromosome, in Y-linked inheritance, a
mutation can only be passed from father to
son.

Codominant             In codominant inheritance, two different                    ABO blood group
versions (alleles) of a gene are expressed,
and each version makes a slightly different
protein. Both alleles influence the genetic trait
or determine the characteristics of the genetic
condition.



Mitochondrial            Mitochondrial inheritance, also known as                  Leber hereditary
maternal inheritance, applies to genes in                   optic neuropathy
mitochondrial DNA. Mitochondria, which                   (LHON)
are structures in each cell that convert
molecules into energy, each contain a
small amount of DNA. Because only
egg cells contribute mitochondria to the
developing embryo, only females can pass
on mitochondrial mutations to their children
Conditions resulting from mutations in
mitochondrial DNA can appear in every
generation of a family and can affect both
males and females, but fathers do not pass
these disorders to their daughters or sons.


Many health conditions are caused by the combined effects of multiple genes or by interactions between genes and the environment. Such disorders usually do not follow the patterns of inheritance described above. Examples of conditions caused by multiple genes or gene/environment interactions include heart disease, diabetes, schizophrenia, and certain types of cancer.
Disorders caused by changes in the number or structure of chromosomes also do not follow the straightforward patterns of inheritance listed above.
Other genetic factors sometimes influence how a disorder is inherited.

Reduced penetrance and variable expressivity
Reduced penetrance and variable expressivity are factors that influence the effects of particular genetic changes. These factors usually affect disorders that have an autosomal dominant pattern of inheritance, although they are occasionally seen in disorders with an autosomal recessive inheritance pattern.

Reduced penetrance

Penetrance refers to the proportion of people with a particular genetic change (such as a mutation in a specific gene) who exhibit signs and symptoms of a genetic disorder. If some people with the mutation do not develop features of the disorder, the condition is said to have reduced (or incomplete) penetrance.

Reduced penetrance often occurs with familial cancer syndromes. For example, many people with a mutation in the BRCA1 or BRCA2 gene will develop cancer during their lifetime, but some people will not. Doctors cannot predict which people with these mutations will develop cancer or when the tumors will develop.

Reduced penetrance probably results from a combination of genetic, environmental, and lifestyle factors, many of which are unknown. This phenomenon can make it challenging for genetics professionals to interpret a person’s family medical history and predict the risk of passing a genetic condition to future generations.


Variable expressivity

Although some genetic disorders exhibit little variation, most have signs and symptoms that differ among affected individuals. Variable expressivity refers to the range of signs and symptoms that can occur in different people with the same genetic condition. For example, the features of Marfan syndrome vary widely— some people have only mild symptoms (such as being tall and thin with long, slender fingers), while others also experience life-threatening complications involving the heart and blood vessels. Although the features are highly variable, most people with this disorder have a mutation in the same gene (FBN1).

As with reduced penetrance, variable expressivity is probably caused by a combination of genetic, environmental, and lifestyle factors, most of which have not been identified. If a genetic condition has highly variable signs and symptoms, it may be challenging to diagnose.


Gene therapy

Gene therapy is an experimental technique that uses genes to treat or prevent disease. In the future, this technique may allow doctors to treat a disorder by inserting a gene into a patient’s cells instead of using drugs or surgery. Researchers are testing several approaches to gene therapy, including:

  • Replacing a mutated gene that causes disease with a healthy copy of the gene.
  • Inactivating, or “knocking out,” a mutated gene that is functioning improperly.
  • Introducing a new gene into the body to help fight a disease.

Although gene therapy is a promising treatment option for a number of diseases (including inherited disorders, some types of cancer, and certain viral infections), the technique remains risky and is still under study to make sure that it will be safe and effective. Gene therapy is currently only being tested for the treatment of diseases that have no other cures.


How does gene therapy work?

Gene therapy is designed to introduce genetic material into cells to compensate for abnormal genes or to make a beneficial protein. If a mutated gene causes a necessary protein to be faulty or missing, gene therapy may be able to introduce a normal copy of the gene to restore the function of the protein.

A gene that is inserted directly into a cell usually does not function. Instead, a carrier called a vector is genetically engineered to deliver the gene. Certain viruses are often used as vectors because they can deliver the new gene by infecting the cell. The viruses are modified so they can't cause disease when used in people. Some types of virus, such as retroviruses, integrate their genetic material (including the new gene) into a chromosome in the human cell. Other viruses, such as adenoviruses, introduce their DNA into the nucleus of the cell, but the DNA is not integrated into a chromosome.

The vector can be injected or given intravenously (by IV) directly into a specific tissue in the body, where it is taken up by individual cells. Alternately, a sample of the patient's cells can be removed and exposed to the vector in a laboratory setting. The cells containing the vector are then returned to the patient. If the treatment is successful, the new gene delivered by the vector will make a functioning protein.

Researchers must overcome many technical challenges before gene therapy will be a practical approach to treating disease. For example, scientists must find better ways to deliver genes and target them to particular cells. They must also ensure that new genes are precisely controlled by the body













Genetic Testing Methods

If you made it through the above information you may be interested in how it is possible to detect these genetic variances.
We are looking for two distinct types of variances, SNPs (Single-Nucleotide Polymorphism) and CNVs (Copy Number variants).


Microarray-based genotyping vs Whole Exome/Genome Sequencing
There are three general types of testing that you might encounter in trying to achieve a biological diagnosis of a person’s autism.

The simplest and cheapest is microarray genotyping, also known as chromosomal microarray CMA .  This tests the prevalence of a very large number of known suspect DNA sequences that have been programed into the machine.  CMA is often suggested as the first tier test for individuals with developmental disabilities, intellectual disabilities, autism spectrum disorders, or multiple congenital anomalies.  This is a good method if you know what variances you are looking for.

Whole Exome Sequencing (WES) established the exact nucleotide sequences of DNA at the thousands of exon loci tested.  This test used to be very expensive, but is now quite widely available in the United States, both for research and commercially.

Whole Genome Sequencing (WGS) looks at the entire genome, rather than the much smaller exome.  This test is available, but normally with the caveat “for research purposes”. This should be the holly grail of genetic testing.

The cost of all types of genetic testing continues to fall.

The tests are only as good as the interpretation of their results.

If you live in the US, you can join SPARK for free. This is another initiative of the Simons Foundation, this time to collect genetic material from people affected by autism. They aim to collect saliva samples from 50,000 people with autism, and the their families.  They will then conduct Whole Exome Sequencing (WES).

                          https://sparkforautism.org/portal/page/about-spark/



A more ambitious project is MSSNG, which Google backed project to analyse the entire genome in 10,000 people with autism.

https://www.mss.ng/#










Wednesday 8 March 2017

Take your Bumetanide Studies with a Pinch of Salt



This blog does try to be based on evidence, but sometimes you do have to question the validity of what appears in peer reviewed journals.  It might concern what does, or does not cross the blood brain barrier, or what works in vivo versus in vitro.

Two interesting papers were recently brought to my attention regarding Bumetanide.


With a pinch of salt is an English idiom which means
to view something with skepticism 



In Tyler’s paper it was rats with epilepsy showing big improvements when taking Bumetanide. 

In Agnieszka’s paper, involving mice and Chinese hamsters, researchers are making the point that so little Bumetanide crosses into the brain that its therapeutic value is limited. 

So which is true? 

Well it seems that in some humans with autism enough bumetanide crosses the blood brain barrier (BBB) to show a positive effect.  Perhaps if a more penetrative analogue of Bumetanide was developed, it would show even greater effect, otherwise adjunct therapies may be needed (Acetazolamide, potassium bromide, estradiol etc) to gain the full benefit of lowering intracellular chloride. 

In the past I have made the case for bumetanide possibly reducing the incidence of epilepsy developing in autism and that this really would be important. This does not mean that one person with autism might not develop epilepsy around the same time he started taking bumetanide. In the study below the rats with seizures seemed to be protected by bumetanide and the number of harmful neural connections detected in the brain was significantly reduced. 




Abstract

There is accumulating evidence that bumetanide, which has been used over decades as a potent loop diuretic, also exerts effects on brain disorders, including autism, neonatal seizures, and epilepsy, which are not related to its effects on the kidney but rather mediated by inhibition of the neuronal Na-K-Cl cotransporter isoform NKCC1. However, following systemic administration, brain levels of bumetanide are typically below those needed to inhibit NKCC1, which critically limits its clinical use for treating brain disorders. Recently, active efflux transport at the blood-brain barrier (BBB) has been suggested as a process involved in the low brain:plasma ratio of bumetanide, but it is presently not clear which transporters are involved. Understanding the processes explaining the poor brain penetration of bumetanide is needed for developing strategies to improve the brain delivery of this drug. In the present study, we administered probenecid and more selective inhibitors of active transport carriers at the BBB directly into the brain of mice to minimize the contribution of peripheral effects on the brain penetration of bumetanide. Furthermore, in vitro experiments with mouse organic anion transporter 3 (Oat3)-overexpressing Chinese hamster ovary cells were performed to study the interaction of bumetanide, bumetanide derivatives, and several known inhibitors of Oats on Oat3-mediated transport. The in vivo experiments demonstrated that the uptake and efflux of bumetanide at the BBB is much more complex than previously thought. It seems that both restricted passive diffusion and active efflux transport, mediated by Oat3 but also organic anion-transporting polypeptide (Oatp) Oatp1a4 and multidrug resistance protein 4 explain the extremely low brain concentrations that are achieved after systemic administration of bumetanide, limiting the use of this drug for targeting abnormal expression of neuronal NKCC1 in brain diseases.
  

Prolonged epileptic seizures may cause serious problems that will continue for the rest of a patient's life. As a result of a seizure, neural connections of the brain may be rewired in an incorrect way. This may result in seizures that are difficult to control with medication. Mechanisms underlying this phenomenon are not entirely known, which makes current therapies ineffective in some patients.
A study conducted with a rat epilepsy model at the Neuroscience Center of the University of Helsinki showed that a change in the function of gamma-aminobutyric acid (GABA), a main neurotransmitter in the brain, is an underlying cause in the creation of harmful neural connections.
After a prolonged convulsive seizure, instead of the usual inhibitory effect of the transmitter, GABA accelerates brain activity. This, in turn, creates new, harmful neural connections, says Research Director Claudio Rivera.
The accelerating effect of GABA was blocked for three days with a drug called bumetanide given soon after a seizure. Two months after the seizure, the number of harmful connections detected in the brain was significantly lower.
"Most importantly, the number of convulsive seizures diminished markedly," says Claudio Rivera.
In this study, new indications may be found for bumetanide in the treatment of epilepsy. Bumetanide is a diuretic already in clinical use. Extensive clinical studies have already been conducted with bumetanide regarding its ability to reduce the amount of convulsions or prevent them entirely in the acute phase of seizures. This, however, is the first time that bumetanide has been found to have a long-term effect on the neural network structure of the brain.
Further study of the newly found mechanism may eventually help limit the exacerbation of epilepsy and prevent the onset of permanent epilepsy after an individual serious seizure. It may also be possible that a similar mechanism is responsible for the onset of epilepsy after a traumatic brain injury.
"The next step is to study bumetanide both by itself and in combination with other clinically used drugs. We want to find out the ways in which it may offer additional benefits in the treatment of epilepsy in combination with and even in place of currently used antiepileptic drugs," says Claudio Rivera.



Vitamin D and Autism

Two medical readers of this blog highlighted this recent paper showing an apparent universal benefit of vitamin D supplementation in autism.

Is it too good to be true?  Time for the pinch of salt?

One important point to note is that this study was in Egypt and, although sunny, are children there eating food that has already been fortified with vitamin D, like it is in Western countries?

Randomized controlled trial of vitamin D supplementation in children with autism spectrum disorder

Abstract

BACKGROUND:



Autism spectrum disorder (ASD) is a frequent developmental disorder characterized by pervasive deficits in social interaction, impairment in verbal and nonverbal communication, and stereotyped patterns of interests and activities. It has been previously reported that there is vitamin D deficiency in autistic children; however, there is a lack of randomized controlled trials of vitamin D supplementation in ASD children.

METHODS:



This study is a double-blinded, randomized clinical trial (RCT) that was conducted on 109 children with ASD (85 boys and 24 girls; aged 3-10 years). The aim of this study was to assess the effects of vitamin D supplementation on the core symptoms of autism in children. ASD patients were randomized to receive vitamin D3 or placebo for 4 months. The serum levels of 25-hydroxycholecalciferol (25 (OH)D) were measured at the beginning and at the end of the study. The autism severity and social maturity of the children were assessed by the Childhood Autism Rating Scale (CARS), Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and the Autism Treatment Evaluation Checklist (ATEC).

RESULTS:



Supplementation of vitamin D was well tolerated by the ASD children. The daily doses used in the therapy group was 300 IU vitamin D3/kg/day, not to exceed 5,000 IU/day. The autism symptoms of the children improved significantly, following 4-month vitamin D3 supplementation, but not in the placebo group. This study demonstrates the efficacy and tolerability of high doses of vitamin D3 in children with ASD.

CONCLUSIONS:



This study is the first double-blinded RCT proving the efficacy of vitamin D3 in ASD patients. Depending on the parameters measured in the study, oral vitamin D supplementation may safely improve signs and symptoms of ASD and could be recommended for children with ASD. At this stage, this study is a single RCT with a small number of patients, and a great deal of additional wide-scale studies are needed to critically validate the efficacy of vitamin D in ASD.

Conclusion
Take your research with a pinch of salt.




Monday 6 March 2017

Time to update the Autism Polypill?


It has been a long time since I added anything new to my autism Polypill. This is the combination of therapies that consistently, and materially reduce the symptoms of autism in Monty, now aged 13 with ASD.

As regular readers will be aware, due to the heterogeneous nature of autism, what works wonders for one person with autism may be totally ineffective, or even make matters worse, in another person with a different type of autism.
However, once you have found one therapy that is effective you have an opportunity to identify the underlying biological dysfunction that you have stumbled upon, without the need for any fancy genetic or metabolic testing.  Then you can look for other therapies for that dysfunction and other people who fall into that sub-group of autism and see what else works for them.
I am surprised how many people do respond to some of the therapies I am highlighting in this blog. 

Time to update?

I had been expecting to add the Biogaia Protectis probiotic bacteria to the Polypill.  It does indeed work in Monty and in other readers, but prolonged use does have a problem, at least in some people.  The behavioral effects fade and, in our case, it switches from suppressing allergy to promoting allergy.
The person who originally told us about Biogaia for autism uses the more potent Biogaia Gastrus, which contains the Protectis bacteria and a second one.  She uses a high dosage and uses it three weeks on and one week off.
Like some other readers found, Monty had an immediate negative reaction to the second bacteria in Biogaia Gastrus.  We are users of Biogaia Protectis, but not every day.
A long time ago I proposed the flavonoid Tangeritin/Sytrinol as a safe PPAR gamma agonist that is also a P2Y2 receptor antagonist. Research studies have shown that the flavonoids Tangeritin and kaempferol are antagonists at P2Y2 receptors and may be of interest as potential anti-inflammatory drugs.  Robert Naviaux, from the University of California at San Diego, believes that antipurinergic therapy is a key potential strategy to treat autism and also chronic fatigue syndrome and fibromyalgia.
The broccoli sprout powder already in the Polypill is a rich source of kaempferol.
Tangeritin/Sytrinol has been shown to have sufficient bioavailability to reduce the level of cholesterol in people with high cholesterol.   

KBr

The most likely contender to enter the Polypill for everyday use is potassium bromide (KBr), it does seem to tick all the boxes. 

·        It works

·        It continues to work after longer term use

·        Mode of action is understood

·        Safety record is very well understood

·        Effective at a low dosage

·        Not expensive, about 30 cents a day.  Much less if you use bulk KBr.

KBr should be effective in people who respond to bumetanide, since they both reduce intra-cellular chloride levels, but by different mechanisms.
In people who stop responding to bumetanide, I think KBr might be a good choice.  In responders to bumetanide, increasing inflammation due to an unrelated condition, may further reduce the expression of the KCC2 transporter that lets chloride exit neurons. So the inflammation increases the level of intracellular chloride and wipes out the benefit that was being produced by the bumetanide.  The effect of the KBr will be to reduce chloride again, this time by substitution with the relatively inert bromide.
It is also possible that some people with severe autism do not respond to bumetanide because their chloride level is so high that bumetanide is not sufficiently potent.  In those people the additive effect of KBr might just tip the balance.
In some countries bumetanide tablets include potassium chloride (KCl) to compensate for potassium lost in diuresis.  The cleverer thing in autism would be to add KBr, since you benefit from the K+ and the Br-.
Due to the very long half-life, you need to take a low dosage of KBr for 4 to 6 weeks until you reach the peak level of Br- in your body.  Only then can you judge whether you are a responder or not. 
What I am considering the autism dose (8mg/Kg) is far lower than the dose used for intractable pediatric epilepsy (30-50mg/Kg), specifically to avoid the known side effects.  The main side effect at high doses is bromo-acne. Children with intractable epilepsy opt for some facial spots over seizures.
Quite possibly a higher KBr dosage would be even more effective in autism, but then you will for sure be dealing with bromo-acne.


Summertime Add-ons

One conclusion from the gene studies is that often in autism and schizophrenia there are variances in the genes linked to the immune system. So the immune–related therapies that help Monty a great deal during spring and summer may indeed be applicable to a substantial sub-group of autism. For others they are likely to be ineffective.
I am hopeful of yet another step forward this summer using the amino acid L-histidine.  Histidine is very closely related to histamine and you might think that would be the last thing that could help in those prone to allergy-driven autism flare-ups.  However in an earlier post we saw that there is a paradoxical effect when raising the level of histidine, inhibits the release of histamine from mast cells.  We also saw that histidine has an inhibitory effect on mTOR, one of the suggested common core autism pathways that was highlighted yet again in the gene studies.
L-histidine, is an essential amino acid that is not synthesized in humans.  You have to eat it.





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.