Wednesday, November 21, 2012

A Genetic Epidemic of Down Syndrome?

Over at Left Brian Right Brian, Sullivan (aka Matt Carey) is attempting to make an argument that there can be a genetic epidemic.  He says -
It’s a phrase that is heard a great deal in online discussions about autism: there are no genetic epidemics. Genes don’t change quickly enough for a genetic condition to see an increased prevalence over a single generation, right? Well, yes and no.
Before going on to suggest Down Syndrome might be a model for how a genetic epidemic might work.  But while it is true that Down Syndrome is caused by an underlying genetic mutation and that the number of people with Downs is increasing, it does not classify as a "genetic epidemic".

The main reason is that for the most part1 Down Syndrome is not an inherited condition.  A child does not have Downs because their parents passed along any sort of mutation.  Downs is caused by a mistake in cell division during the development of the egg, sperm, or embryo.  So while there is a genetic mutation responsible for the condition, the mutation is caused by some non-genetic factor.

Down syndrome (again, for the most part) doesn't run in families.  Having one child with Downs only slightly increases your chance of having a second child with Downs.

And a person with Downs in unlikely to pass the condition along to another generation because most people with Downs have problems with fertility.  Men with Downs are thought to be sterile and women are only fertile about a third of the time.  Although, if a person with Downs has a child, there is a significant chance that their child will inherit their condition.

So while Downs might be caused by genetic mutations (aka is "genetic"), it is not a "genetic epidemic" because the increasing number of people with Downs is not due to the mutations becoming more common in the gene pool.  What is causing the increasing number of people with Downs is due to a few social changes.

First, there is an ongoing trend for women to have children later in life and maternal age is a demonstrated risk factor for Downs (although, as a side note, I have never read a good explanation as to why exactly that is the case).  The risk of having a child with Downs increases with age, going from 1 in 1,600 when a mother is twenty to 1 in 1,000 at thirty and 1 in 90 by forty.

Second, people with Downs are surviving longer.  Down syndrome comes with a variety of related health problems and these problems can shorten a persons life.  About eighty years ago, people with Downs often didn't survive past their tenth birthday.  Over time that age has gradually increased so that today people with Downs can expect to live to 50 and beyond.

Finally, people today seem to be more willing to have a child with Downs.  Abortions of children with Downs is a contentious subject, but as life expectancy and quality of life for a person with Downs has been improving, there seem to be fewer abortions.

These three factors can explain the modest increase in the number of people with Downs that has been seen over the past several decades.

So, back to Sullivan's original argument, there is no "genetic epidemic" of Down Syndrome.  There isn't really even an "epidemic" of Down Syndrome - the growth has been modest and is what would be expected given the social trends listed above.

More importantly, there aren't that many similarities between Downs and autism -

In autism, there is no single mutation that can account for more than a small fraction of cases and yet having one child with autism does significantly increase the risks of having another child with autism.  Down Syndrome centers on a mutation on one chromosome while autism has been tentatively linked to many places across our genes.  So, from the little we know about the genetics of autism, the underlying genetics of autism and Down Syndrome are quite different.

Autism does not automatically come with medical conditions that shorten life expectancy.  And there is no prenatal test for autism2 and so there are no widespread abortion trend that is reversing.

Autism is growing much, much faster than Down Syndrome.  Over a twenty four year period (1979 to 2003), the number of people born with Down Syndrome grew by 31.1%.  Over the same time period, the number of case of autism grew from about 2-4 per 10,000 to 66 per 10,000 or about 1500%3.  If you take a more conservative time period (2000 to 2008), autism has grown about 160%.  Anyway you slice it, autism is growing significantly faster than Downs.

The only real link between Downs and autism is parental age, and that is a nebulous one at best.  Some studies of autism involving parental age show a small relationship with maternal age but not paternal age, some show a relationship with paternal age and not maternal, some show a relationship with both, and some show no relationship to either.

At the present time, the best that we can say is that there might be some relationship between maternal or paternal age and risk of autism.  Compare that to Down Syndrome where there is a clear link between maternal age and the risk of having a child with Downs.

So, not only is Sullivan wrong to suggest that there is a "genetic epidemic" of Downs Syndrome, he is wrong to suggest that there is any epidemic of Downs at all or that this tells us anything about what is going on with autism.

1. There are actually three different known types or styles of genetic mutations that can cause Down Syndrome. The most common one, trisomy 21, accounts for more than 90 percent of cases and is almost never inherited.  Another form, which is almost not normally inherited, involves a mutation of chromosome 21 where only some of the cells have the mutation and others don't.  The final form, called translocation Down Syndrome, can be passed from carrier parents to children.  However, only about 4% of Downs cases are these type and only about half of these cases involve inheritance.  Source

2. Well, technically, there are prenatal tests for some known genetic forms of autism, such as Rett Syndrome and Fragile X.

3. A large part of the growth in autism from the 1980 to 2000 is probably due to the condition being added t the DSM III and then its changes in the DSM IV.

Saturday, November 17, 2012

Diabetes More Common in US

In health news that is not related to autism, the CDC has published a report that the prevalence of diabetes in the United States has risen sharply over the past fifteen years.  This report estimates that 8.2% of the adult population suffers from diabetes in 2010, up from 4.5% percent in 1995.

Yes, you read that figure correctly - roughly 1 out of every 12 adults in the US now has diabetes.

The CDC gives a few possible reasons for the increase -
  1. Improved survival of people with diabetes.  Deaths among US adults with diabetes declined substantially over the same time period.
  2. An actual increase in the number of cases.  
  3. Changes in diagnostic criteria, demographics, and lifestyle.
  4. Enhanced detection.
The report also notes that  the increase of diabetes coincides with the increase in obesity across the United States, although it does not draw any firm conclusions from the association.

And just to drive the point home, here is a chart of how the prevalence of diabetes has changes over the past 15 years.  I think the trend is rather clear, don't you?

Thursday, November 15, 2012

Study : Fecundity of People With Mental Disorders

According to a recent study, people who have schizophrenia, autism, and anorexia nervosa have fewer children than the general population.  This isn't a particularly happy topic or one that I enjoy dwelling on, but it is a rather important topic to think about when trying to understand whether autism is becoming more common.

One the one hand you have the idea that autism is strongly genetic and runs in families but on the other you have the inconvenient fact that having autism greatly reduces your chances of having children.  You would think that those ideas aren't compatible, that the families who have a higher than normal number of members with autism would not keep going generation after generation as they would be "strongly selected against".

Of course the issue isn't really that simple as that.  There are many other factors involved that might be contributing to these families staying around such as extremely mild symptoms of autism, recessive traits, the relative rarity of autism, and the like that could explain both facts.

But still, even if both ideas are true and autism is strongly genetic and "strongly selected against", you would, at best, expect it to stay about the same prevalence.  It would look more like schizophrenia which is "genetic" (and environmental), runs in families, and is "strongly selected against" and still manages to stay at a relatively constant 1% of the population.

Yet with autism we have three ideas that really can't go together - that autism is strongly genetic, that autism makes you a lot less likely to have children, and that the number of cases of autism is growing fairly rapidly.  Although to be fair, all three of these statements are gross oversimplifications of the complex realities of autism.

Just food for thought.  The abstract of the study is below.

Fecundity of Patients With Schizophrenia, Autism, Bipolar Disorder, Depression, Anorexia Nervosa, or Substance Abuse vs Their Unaffected Siblings

Context  It is unknown how genetic variants conferring liability to psychiatric disorders survive in the population despite strong negative selection. However, this is key to understanding their etiology and designing studies to identify risk variants.

Objectives  To examine the reproductive fitness of patients with schizophrenia and other psychiatric disorders vs their unaffected siblings and to evaluate the level of selection on causal genetic variants.

Design  We measured the fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse and their unaffected siblings compared with the general population.

Setting  Population databases in Sweden, including the Multi-Generation Register and the Swedish Hospital Discharge Register.

Participants  In total, 2.3 million individuals among the 1950 to 1970 birth cohort in Sweden.

Main Outcome Measures  Fertility ratio (FR), reflecting the mean number of children compared with that of the general population, accounting for age, sex, family size, and affected status.

Results  Except for women with depression, affected patients had significantly fewer children (FR range for those with psychiatric disorder, 0.23-0.93; P < 10-10). This reduction was consistently greater among men than women, suggesting that male fitness was particularly sensitive. Although sisters of patients with schizophrenia and bipolar disorder had increased fecundity (FR range, 1.02-1.03; P < .01), this was too small on its own to counterbalance the reduced fitness of affected patients. Brothers of patients with schizophrenia and autism showed reduced fecundity (FR range, 0.94-0.97; P < .001). Siblings of patients with depression and substance abuse had significantly increased fecundity (FR range, 1.01-1.05; P < 10-10). In the case of depression, this more than compensated for the lower fecundity of affected individuals.

Conclusions  Our results suggest that strong selection exists against schizophrenia, autism, and anorexia nervosa and that these variants may be maintained by new mutations or an as-yet unknown mechanism. Bipolar disorder did not seem to be under strong negative selection. Vulnerability to depression, and perhaps substance abuse, may be preserved by balancing selection, suggesting the involvement of common genetic variants in ways that depend on other genes and on environment.

Power RA, Kyaga S, Uher R, Maccabe JH, Långström N, Landen M, McGuffin P, Lewis CM, Lichtenstein P, Svensson AC. Fecundity of Patients With Schizophrenia,  Autism, Bipolar Disorder, Depression, Anorexia Nervosa, or Substance Abuse vs Their Unaffected Siblings. Arch Gen Psychiatry. 2012 Nov 12:1-8. doi: 10.1001/jamapsychiatry.2013.268. [Epub ahead of print] PubMed PMID: 23147713