Tag Archives: Schizophrenia

Gotterdamerung — The Twilight of the GWAS

Life may be like a well, but cellular biochemistry and gene function is like a mattress.  Push on it anywhere and everything changes, because it’s all hooked together.  That’s the only conclusion possible if a review of genome wide association studies (GWAS) is correct [ Cell vol. 169 pp. 1177 – 1186 ’17 ].

 It’s been a scandal for years that GWAS studies as they grow larger and larger are still missing large amounts of the heritability of known very heritable conditions (e.g. schizophrenia, height).  It’s been called the dark matter of the genome (e.g. we know it’s there, but we don’t know what it is).

If you’re a little shaky about how GWAS works have a look at https://luysii.wordpress.com/2014/08/24/tolstoy-rides-again-schizophrenia/ — it will come up again later in this post.

We do know that less than 10% of the SNPs found by GWAS lie in protein coding genes — this means either that they are randomly distributed, or that they are in regions controlling gene expression.  Arguing for randomness — the review states that the heritability contributed by each chromosome tends to be closely proportional to chromosome length.  Schizophrenia is known to be quite heritable, and monozygotic twins have a concordance rate of 40%.  Yet an amazing study (which is quoted but which I have not read) estimates that nearly 100% of all 1 megabase windows in the human genome contribute to schizophrenia heritability (Nature Genet. vol. 47 pp. 1385 – 1392 ’15). Given the 3.2 gigaBase size of our genome that’s 3,200 loci.

Another example is the GIANT study about the heritability of height.  The study was based on 250,000 people and some 697 gene wide significant loci were found.  In aggregate they explain a mere SIXTEEN PERCENT.

So what is going on?

It gets back to the link posted earlier. The title —  “Tolstoy rides again”  isn’t a joke.  It refers to the opening sentence of Anna Karenina — “Happy families are all alike; every unhappy family is unhappy in its own way”.  So there are many routes to schizophrenia (and they are spread all over the genome).

The authors of the review think that larger and larger GWAS studies (some are planned with over a million participants) are not going to help and are probably a waste of money.  Whether the review is Gotterdamerung for GWAS isn’t clear, but the review is provocative.The review is new and it will be interesting to see the response by the GWAS people.

So what do they think is going on?  Namely that everything in organismal and cellular biochemistry, genetics and physiology is related to everything else.  Push on it in one place and like a box spring mattress, everything changes.  The SNPs found outside the DNA coding for proteins are probably changing the control of protein synthesis of all the genes.

The dark matter of the genome is ‘the plan’ which makes the difference between animate and inanimate matter.   For more on this please see — https://luysii.wordpress.com/2015/12/15/it-aint-the-bricks-its-the-plan-take-ii/

Fascinating and enjoyable to be alive at such a time in genetics, biochemistry and molecular biology.

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What is schizophrenia really like ?

The recent tragic death of John Nash and his wife warrants reposting the following written 11 October 2009

“I feel that writing to you there I am writing to the source of a ray of light from within a pit of semi-darkness. It is a strange place where you live, where administration is heaped upon administration, and all tremble with fear or abhorrence (in spite of pious phrases) at symptoms of actual non-local thinking. Up the river, slightly better, but still very strange in a certain area with which we are both familiar. And yet, to see this strangeness, the viewer must be strange.”

“I observed the local Romans show a considerable interest in getting into telephone booths and talking on the telephone and one of their favorite words was pronto. So it’s like ping-pong, pinging back again the bell pinged to me.”

Could you paraphrase this? Neither can I, and when, as a neurologist I had occasion to see schizophrenics, the only way to capture their speech was to transcribe it verbatim. It can’t be paraphrased, because it makes no sense, even though it’s reasonably gramatical.

What is a neurologist doing seeing schizophrenics? That’s for shrinks isn’t it? Sometimes in the early stages, the symptoms suggest something neurological. Epilepsy for example. One lady with funny spells was sent to me with her husband. Family history is important in just about all neurological disorders, particularly epilepsy. I asked if anyone in her family had epilepsy. She thought her nephew might have it. Her husband looked puzzled and asked her why. She said she thought so because they had the same birthday.

It’s time for a little history. The board which certifies neurologists, is called the American Board of Psychiatry and Neurology. This is not an accident as the two fields are joined at the hip. Freud himself started out as a neurologist, wrote papers on cerebral palsy, and studied with a great neurologist of the time, Charcot at la Salpetriere in Paris. 6 months of my 3 year residency were spent in Psychiatry, just as psychiatrists spend time learning neurology (and are tested on it when they take their Boards).

Once a month, a psychiatrist friend and I would go to lunch, discussing cases that were neither psychiatric nor neurologic but a mixture of both. We never lacked for new material.

Mental illness is scary as hell. Society deals with it the same way that kids deal with their fears, by romanticizing it, making it somehow more human and less horrible in the process. My kids were always talking about good monsters and bad monsters when they were little. Look at Sesame street. There are some fairly horrible looking characters on it which turn out actually to be pretty nice. Adults have books like “One flew over the Cuckoo’s nest” etc. etc.

The first quote above is from a letter John Nash wrote to Norbert Weiner in 1959. All this, and much much more, can be found in “A Beatiful Mind” by Sylvia Nasar. It is absolutely the best description of schizophrenia I’ve ever come across. No, I haven’t seen the movie, but there’s no way it can be more accurate than the book.

Unfortunately, the book is about a mathematician, which immediately turns off 95% of the populace. But that is exactly its strength. Nash became ill much later than most schizophrenics — around 30 when he had already done great work. So people saved what he wrote, and could describe what went on decades later. Even better, the mathematicians had no theoretical axe to grind (Freudian or otherwise). So there’s no ego, id, superego or penis envy in the book, just page after page of description from well over 100 people interviewed for the book, who just talked about what they saw. The description of Nash at his sickest covers 120 pages or so in the middle of the book. It’s extremely depressing reading, but you’ll never find a better description of what schizophrenia is actually like — e.g. (p. 242) She recalled that “he kept shifting from station to station. We thought he was just being pesky. But he thought that they were broadcasting messages to him. The things he did were mad, but we didn’t really know it.”

Because of his previous mathematical achievments, people saved what he wrote — the second quote above being from a letter written in 1971 and kept by the recipient for decades, the first quote from a letter written in 12 years before that.

There are a few heartening aspects of the book. His wife Alicia is a true saint, and stood by him and tried to help as best she could. The mathematicians also come off very well, in their attempts to shelter him and to get him treatment (they even took up a collection for this at one point).

I was also very pleased to see rather sympathetic portraits of the docs who took care of him. No 20/20 hindsight is to be found. They are described as doing the best for him that they could given the limited knowledge (and therapies) of the time. This is the way medicine has been and always will be practiced — we never really know enough about the diseases we’re treating, and the therapies are almost never optimal. We just try to do our best with what we know and what we have.

I actually ran into Nash shortly after the book came out. The Princeton University Store had a fabulous collection of math books back then — several hundred at least, most of them over $50, so it was a great place to browse, which I did whenever I was in the area. Afterwards, I stopped in a coffee shop in Nassau Square and there he was, carrying a large disheveled bunch of papers with what appeared to be scribbling on them. I couldn’t bring myself to speak to him. He had the eyes of a hunted animal.

Tolstoy rides again — Schizophrenia

“A field plagued by inconsistency, and perhaps even a degree of charlatanism” — strong stuff indeed [ Neuron vol. 83 pp. 760 – 763 ’14 ]. They are talking about studies attempting to find the genetic causes of schizophrenia.

This was the state of play four and a half years ago (in a post of April 2010)

Happy families are all alike.; every unhappy family is unhappy in its own way”. Thus beginneth Anna Karenina. That wasn’t supposed to happen with hereditary disease. The examples we had before large scale DNA sequencing became cheap were basically one gene causing one disease. Two of the best known cases were sickle cell anemia and cystic fibrosis. In the former, a change in a single position (nucleotide) of DNA caused a switch of one amino acid (valine for glutamic) acid at position #6 in beta hemoglobin. In the latter, all mutations have been found in a single gene called CFTR. 85% of known mutations involve the loss of 1 amino acids. But by 2003 over 600 different mutations accounted for only part of the other 15%. There is plenty of room for mutation as CFTR has 1480 amino acids. The kids I took care of in the muscular dystrophy clinic all turned out to have mutations in the genes for proteins found in muscle.

Why not look for the gene causing schizophrenia? It’s a terrible disease (the post “What is Schizophrenia really Like?” is included after the **** ) with a strong hereditary component. There was an awful era in psychiatry when it was thought to be environmental (e.g. the family was blamed). Deciding what is hereditary and what is environmental can be tricky. TB was thought to be hereditary (for a time) because it also ran in families. So why couldn’t schizophrenia be environmental? Well, if you are an identical twin and the other twin has it, your chances of having schizophrenia are 45%. If you are a fraternal twin your chance of having it are 3 times less (15%). This couldn’t be due to the environment.

It’s time to speak of SNPs (single nucleotide polymorphisms). Our genome has 3.2 gigaBases of DNA. With sequencing being what it is, each position has a standard nucleotide at each position (one of A, T, G, or C). If 5% of the population have one of the other 3 at this position you have a SNP. By 2004 some 7 MILLION SNPs had been found and mapped to the human genome. So to find ‘the gene’ for schizophrenia, just take schizophrenics as a group (there are lots of them — about 1% of the population) look at their SNPs, and see if they have any SNPs in common.

Study after study found suspect SNPs (which can be localized exactly in the genome) for schizophrenia. The area of the genome containing the SNP was then searched for protein coding genes to find the cause of the disease. Unfortunately each study implicated a different bunch of SNPs (in different areas of the genome). A study of 750 schizophrenics and an equal number of controls from North Carolina used 500,000 SNPs. None of the previous candidate genes held up. Not a single one [ Nature vol. 454 pp., 154 – 157 ’08 ]

As of 2009 here are 3,000 diseases showing simple inheritance in which a causative gene hasn’t been found. This is the ‘dark matter’ of the genome. We are sure it exists (because the diseases are hereditary) but we simply can’t see it.

There is presently a large (and expensive) industry called GWAS (Genome Wide Association Studies) which uses SNPs to look for genetic causes of diseases with a known hereditary component. One study on coronary heart disease had 23,000 participants. In 2007 the Wellcome Trust committed 45 million (pounds? dollars?) for studies of 27 diseases in 120,000 people. This is big time science. GWAS studies have found areas of the genome associated with various disorders. However, in all GWAS studies so far, what they’ve picked up explains less than 5% of the heritability. An example is height (not a disease). Its heritability is 80% yet the top 20 candidate genetic variants identified explain only 3% of the variance. People have called for larger and larger samples to improve matters.

What’s going on?

It’s time for you to read “Genetic Heterogeneity in Human Disease” [ Cell vol. 141 pp. 210 – 217 ’10 ]. It may destroy GWAS. Basically, they argue that most SNPs are irrelevant, don’t produce any functional change, and have arisen by random mutation. They are evolutionary chaff if you will. A 12 year followup study of 19,000 women looked at the 101 SNPs found by GWAS as risk variants for cardiovascular disease — not one of them predicted outcome [ J. Am. Med. Assoc. vol. 303 pp. 631 – 637 ’10 ]. The SNPs haven’t been eliminated by natural selection, because they aren’t causing trouble and because the human population has grown exponentially.

There’s a lot more in this article, which is worth reading carefully. It looks like what we’re calling a given disease with a known hereditary component (schizophrenia for example) is the result of a large number of different (and rather rare) mutations. A given SNP study may pick up one or two rare mutations, but they won’t be found in the next. It certainly has been disheartening to follow this literature over the years, in the hopes that the cause of disease X, Y or Z would finally be found, and that we would have a logical point of attack (but see an old post titled “Some Humility is in Order”).

Is there an analogy?

200 years ago (before Pasteur) physicians classified a variety of diseases called fevers. They knew they were somewhat different from each other (quotidian fever, puerperal fever, etc. etc.). But fever was the common denominator and clinically they looked pretty much the same (just as dogs look pretty much the same). Now we know that infectious fever has hundreds of different causes. The Cell article argues that, given what GWAS has turned up so far, this is likely to be the case for many hereditary disorders.

Tolstoy was right.

Fast forward to the present [ Nature vol. 511 pp. 412 – 413, 421 – 427 ’14 ] This is a paper from the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC) which analyzed some 36,989 and 113,075 controls. They found 128 independent associations spanning 108 conservatively defined loci, meeting genome-wide significance. 83/128 hadn’t been previously reported. The associations were enriched among genes expressed in brain. Prior to this work, some 30 schizophrenia associated loci had been found through genome wide association studies (GWAS).

Interestingly 3/4 of the 108 loci include protein coding genes (of which 40% represent a single gene and another 8% are within 20 kiloBases of a gene).

The editorial noted that there have been 800 associations ‘of dubious value’

The present risk variants are common, and contribute in most (if not all) cases. One such association is with the D2 dopamine receptor, but not with COMT (which metabolizes dopamine). The most significant association is within the major histocompatibility complex (MHC).

The paper in Neuron cited above notes that schizophrenia genetics is a “field plagued by inconsistency, and perhaps even a degree of charlatanism” and that that there have been 800 associations ‘of dubious value’. The statistical sins of earlier work are described resulting in many HUNDREDS of variant associations with schizophrenia, and scores of falsely implicated genes. Standards have been developed to eliminate them [ Nat. Rev. Genet. vol. 9 pp. 356 – 369 ’08 ].

Here is their description of the statistical sins prior to GWAS “Before GWAS, the standard practice for investigating schizophrenia genetics (as well as many other areas) was to pick a candidate gene (usually based on dopamine or glutamate pathways or linkage studies) and compare the frequency of genetic variants in cases and controls. Any difference with a p value 0.05) p values, and associations seen in partitions of a data set. Beyond all of these obvious statistical transgressions, these studies often entirely ignored well-established causes of spurious associations such as population stratification. Labs would churn out separate papers for gene after gene with no correction for multiple testing, and, on top of all of that, there was a publication bias against negative findings. “

There is a hockey stick model in which few real associations aren’t found until a particular sample size is breached. This works for hypertension.

GWAS identifies genomic regions, not precise risk factors. It is estimated the the 108 loci implicate 350 genes. However the Major Histocompatibility Complex (MHC) counts as one locus and it has tones of genes.

The NHGRI website tracks independent GWAS signals for common diseases and traits, and currently records 7,300 associations with a p value under 5 * 10^-8. Only 20 have been tracked to causal variants (depending on criteria.

The number of genes implicated will only grow as the PGC continues to increase the sample size to capture smaller and smaller effect sizes — how long will it be until the whole genome is involved? There are some significant philosophical issues involved, but this post is long enough already.

*****
What Schizophrenia is really Like

I feel that writing to you there I am writing to the source of a ray of light from within a pit of semi-darkness. It is a strange place where you live, where administration is heaped upon administration, and all tremble with fear or abhorrence (in spite of pious phrases) at symptoms of actual non-local thinking. Up the river, slightly better, but still very strange in a certain area with which we are both familiar. And yet, to see this strangeness, the viewer must be strange.”

“I observed the local Romans show a considerable interest in getting into telephone booths and talking on the telephone and one of their favorite words was pronto. So it’s like ping-pong, pinging back again the bell pinged to me.”

Could you paraphrase this? Neither can I, and when, as a neurologist I had occasion to see schizophrenics, the only way to capture their speech was to transcribe it verbatim. It can’t be paraphrased, because it makes no sense, even though it’s reasonably gramatical.

What is a neurologist doing seeing schizophrenics? That’s for shrinks isn’t it? Sometimes in the early stages, the symptoms suggest something neurological. Epilepsy for example. One lady with funny spells was sent to me with her husband. Family history is important in just about all neurological disorders, particularly epilepsy. I asked if anyone in her family had epilepsy. She thought her nephew might have it. Her husband looked puzzled and asked her why. She said she thought so because they had the same birthday.

It’s time for a little history. The board which certifies neurologists, is called the American Board of Psychiatry and Neurology. This is not an accident as the two fields are joined at the hip. Freud himself started out as a neurologist, wrote papers on cerebral palsy, and studied with a great neurologist of the time, Charcot at la Salpetriere in Paris. 6 months of my 3 year residency were spent in Psychiatry, just as psychiatrists spend time learning neurology (and are tested on it when they take their Boards).

Once a month, a psychiatrist friend and I would go to lunch, discussing cases that were neither psychiatric nor neurologic but a mixture of both. We never lacked for new material.

Mental illness is scary as hell. Society deals with it the same way that kids deal with their fears, by romanticizing it, making it somehow more human and less horrible in the process. My kids were always talking about good monsters and bad monsters when they were little. Look at Sesame street. There are some fairly horrible looking characters on it which turn out actually to be pretty nice. Adults have books like “One flew over the Cuckoo’s nest” etc. etc.

The first quote above is from a letter John Nash wrote to Norbert Weiner in 1959. All this, and much much more, can be found in “A Beatiful Mind” by Sylvia Nasar. It is absolutely the best description of schizophrenia I’ve ever come across. No, I haven’t seen the movie, but there’s no way it can be more accurate than the book.

Unfortunately, the book is about a mathematician, which immediately turns off 95% of the populace. But that is exactly its strength. Nash became ill much later than most schizophrenics — around 30 when he had already done great work. So people saved what he wrote, and could describe what went on decades later. Even better, the mathematicians had no theoretical axe to grind (Freudian or otherwise). So there’s no ego, id, superego or penis envy in the book, just page after page of description from well over 100 people interviewed for the book, who just talked about what they saw. The description of Nash at his sickest covers 120 pages or so in the middle of the book. It’s extremely depressing reading, but you’ll never find a better description of what schizophrenia is actually like — e.g. (p. 242) She recalled that “he kept shifting from station to station. We thought he was just being pesky. But he thought that they were broadcasting messages to him. The things he did were mad, but we didn’t really know it.”

Because of his previous mathematical achievments, people saved what he wrote — the second quote above being from a letter written in 1971 and kept by the recipient for decades, the first quote from a letter written in 12 years before that.

There are a few heartening aspects of the book. His wife Alicia is a true saint, and stood by him and tried to help as best she could. The mathematicians also come off very well, in their attempts to shelter him and to get him treatment (they even took up a collection for this at one point).

I was also very pleased to see rather sympathetic portraits of the docs who took care of him. No 20/20 hindsight is to be found. They are described as doing the best for him that they could given the limited knowledge (and therapies) of the time. This is the way medicine has been and always will be practiced — we never really know enough about the diseases we’re treating, and the therapies are almost never optimal. We just try to do our best with what we know and what we have.

I actually ran into Nash shortly after the book came out. The Princeton University Store had a fabulous collection of math books back then — several hundred at least, most of them over $50, so it was a great place to browse, which I did whenever I was in the area. Afterwards, I stopped in a coffee shop in Nassau Square and there he was, carrying a large disheveled bunch of papers with what appeared to be scribbling on them. I couldn’t bring myself to speak to him. He had the eyes of a hunted animal.

Here’s a drug target for schizophrenia and other psychiatric diseases

All agree that any drug getting schizophrenics back to normal would be a blockbuster. The more we study its genetics and biochemistry the harder the task becomes. Here’s one target — neuregulin1, one variant of which is strongly associated with schizophrenia (in Iceland).

Now that we know that neuregulin1 is a potential target, why should discovering a drug to treat schizophrenia be so hard? The gene stretches over 1.2 megaBases and the protein contains some 640 amino acids. Cells make some 30 different isoforms by alternative splicing of the gene. Since the gene is so large one would expect to find a lot of single nucleotide polymorphisms (SNPs) in the gene. Here’s some SNP background.

Our genome has 3.2 gigaBases of DNA. With sequencing being what it is, each position has a standard nucleotide at each position (one of A, T, G, or C). If 5% of the population have any one of the other 3 at this position you have a SNP. By 2004 some 7 MILLION SNPs had been found and mapped to the human genome.

Well it’s 10 years later, and a mere 23,094 SNPs have been found in the neuregulin gene, of which 40 have been associated with schizophrenia. Unfortunately most of them aren’t in regions of the gene which code for amino acids (which is to be expected as 640 * 3 = 1920 nucleotides are all you need for coding out of the 1,200,000 nucleotides making up the gene). These SNPs probably alter the amount of the protein expressed but as of now very little is known (even whether they increase or decrease neuregulin1 protein levels).

An excellent review of Neuregulin1 and schizophrenia is available [ Neuron vol. 83 pp. 27 – 49 ’14 ] You’ll need a fairly substantial background in neuroanatomy, neuroembryology, molecular biology, neurophysiology to understand all of it. Included are some fascinating (but probably incomprehensible to the medicinal chemist) material on the different neurophyiologic abnormalities associated with different SNPs in the gene.

Here are a few of the high points (or depressing points for drug discovery) of the review. Neuregulin1 is a member of a 6 gene family, all fairly similar and most expressed in the brain. All of them have multiple splicing isoforms, so drug selectivity between them will be tricky. Also SNPs associated with increased risk of schizophrenia have been found in family members numbers 2, 3 and 6 as well, so neuregulin1 not be the actual target you want to hit.

It gets worse. The neuregulins bind to a family of receptors (the ERBBs) having 4 members. Tending to confirm the utility of the neuregulins as a drug target is the fact that SNPs in the ERBBs are also associated with schizophrenia. So which isoform of which neuregulin binding to which iso form of which ERBB is the real target? Knowledge isn’t always power.

A large part of the paper is concerned with the function of the neuregulins in embryonic development of the brain, leading the the rather depressing thought that the schizophrenic never had a change, having an abnormal brain to begin with. A drug to reverse such problems seems only a hope.

The neuregulin/EBBB system is only one of many genes which have been linked to schizophrenia. So it looks like a post of a 4 years ago on Schizophrenia is largely correct — https://luysii.wordpress.com/2010/04/25/tolstoy-was-right-about-hereditary-diseases-imagine-that/

Happy hunting. It’s a horrible disease and well worth the effort. We’re just beginning to find out how complex it really is. Hopefully we’ll luck out, as we did with the phenothiazines, the first useful antipsychotics.

How fast is your biological clock ticking – II ?? Latest results.

The acceleration in genome sequencing capacity is just incredible.  In May 2010, I posted on the sequencing of the complete genomes of two parents and two of their kids.  Now in August of 2012 we have the results on the complete genomes of 78 parent children trios, along with 1,859 complete sequences from the same population, for comparison.

To get you started here’s the first post:

***

My family breeds about as fast as sequoias.  A cousin had a child at 46 who is presently burning up Columbia.  My brother had a child at 48, also doing OK.  But we do know that the older the parents, the more likely a kid is to have genetic problems (Sarah Palin & Trig).  So what are the odds and how do they change with age?

We don’t really know, but in the next five to ten years, we’ll have a good idea.  The first human genome project sequenced most of the 3,200,000,000 positions in our DNA. It cost billions and took years.  DNA sequencing technology marches on at an incredible pace.   A recent paper rated only 4 pages [ Science vol. 328 pp. 636 – 639 ’10 ].  The complete genome sequence of 2 parents and 2 of their children was performed (to 1/100,000 accuracy yet).  There was known genetic disease in the family and the authors were looking for its cause.  The genome sequences of the parents and their children were compared position by position (using computers of course). If the base (adenine, thymine, guanosine, cytosine) at a given position differed from that of the parent supplying the surrounding DNA, a mutation had taken place between the generations.  Since they had looked at the entire genome, they could count the number of mutations they found.  The rate of mutation was 1.1 per 100 million positions, making about 30 new mutations between generations.

So this isn’t by guess and by gosh, but an actual mutation rate and a count.  While medical science marches on,  our biology has not.  We’ll soon be able to give the numbers of the mutations occurring between parents and progeny at a variety of parental ages, when enough of this sort of thing is done. And it definitely will be done as only 10 years separates the incredibly laborious first human genome project from this paper.

Interestingly, the authors didn’t mention anything about this application in their paper, so this may be (gasp) an original idea.

***

This brings us to [ Nature vol. 488 pp. 439, 467 – 468 (editorial) and 471 – 475 (the actual paper) ].  Some 78 trios (momma poppa and baby) had their entire genomes sequenced, looking for changes found in the baby, not present in either parent.  The paper is from Iceland, which has a small population (317,000), and complete genealogical records going back 10 generations (thanks to National Censuses and Parish records).  In addition, to find out what a normal Icelandic genome was, they completely sequenced the genomes of 1,859 more.   The more times a single genome is sequenced, the more accurate it is, and 78 trios were sequenced to 30x coverage — making it quite accurate.  Knowing both the father’s genome and the mothers (which are of course different), any change in the baby from a carbon copy could be definitively linked to the parent providing the mutated sperm or egg.

The bottom line is that mothers contribute 15 mutations to the baby regardless of age, while fathers transmit more (25 to 65).  The most important point, is that the older the father, the greater the number of mutations transmitted.  Why do men transmit more than women — because they are continually producing new sperm, while the eggs each woman possesses were present at birth.  Anyone who has ever played the telephone game knows that messages get distorted when copied.  Nonetheless, the accuracy of the copying is incredible (around 1 error per 100 million bases copied).

Should you be worried about this?  Possibly, but look who they studied — of the 78 children studied 44 had autism spectrum disorder and 21 were schizophrenic.  They don’t say anything about the other 13.

I can’t fault the authors for looking for genetic information to help us all understand autism and schizophrenia, but remember these weren’t normal kids. This work may not generally apply.  The study definitely needs to be repeated with normal progeny before getting too excited.

As usual, even though there 4,933 mutations were discovered in this population, none were found more than once.  This has been discussed before.  For details see https://luysii.wordpress.com/2010/04/25/tolstoy-was-right-about-hereditary-diseases-imagine-that/ and

https://luysii.wordpress.com/2010/07/29/tolstoy-rides-again-autism-spectrum-disorder/