Tuesday, March 22, 2016

A polygenic risk for autism spectrum disorders

The full title of the paper in the news today is "Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population" authored by a cast of thousands. It's published in Nature Genetics - here's the abstract.
"Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of this risk are unclear in people not ascertained for neuropsychiatric symptoms. Using several large ASD consortium and population-based resources (total n > 38,000), we find genome-wide genetic links between ASDs and typical variation in social behavior and adaptive functioning.

"This finding is evidenced through both LD score correlation and de novo variant analysis, indicating that multiple types of genetic risk for ASDs influence a continuum of behavioral and developmental traits, the severe tail of which can result in diagnosis with an ASD or other neuropsychiatric disorder. A continuum model should inform the design and interpretation of studies of neuropsychiatric disease biology."
At some level this is not too surprising, there's not a 'gene for autism or Asperger Syndrome' any more than there's a gene for height or intelligence. Instead a number of alleles of small effect push the genome towards or away from autism spectrum traits, with de novo negative mutations adding a sprinkling of gratuitous damage.

There is a dataset of families where one family member has an ASD (autism spectrum disorder) while the the rest are not so classified. This is the Simons Simplex Collection (SSC):
"The Simons Simplex Collection (SSC) is a core project and resource of the Simons Foundation Autism Research Initiative (SFARI). The SSC achieved its primary goal to establish a permanent repository of genetic samples from 2,600 simplex families, each of which has one child affected with an autism spectrum disorder, and unaffected parents and siblings."
There is a test, similar to an IQ test, which measures the level of difficulty experienced by people with an ASD. It's called the Vineland Adaptive Behavior Rating Scale (VABS):
"Raw scores are converted to IQ-type standard scores (mean: 100 sd: 15) for each domain and for the composite adaptive behavior score. Score ranges are as follows:
  • 70-80 borderline adaptive functioning; 
  • 51-55 -70: mildly deficient adaptive functioning ; 
  • 35-50: moderately deficient adaptive behavior; 
  • 20-35: severely deficient adaptive behavior; 
  • less than 20: markedly or profoundly deficient adaptive behavior. 
Scores above 80 are classified in approximately the same ranges (low average, average, above average, superior) as IQ scores."
When you test the SSC non-ASD people (controls) vs. SSC people with ASD (cases) using the VABS, this is what you see:

Figure 2 from the Nature Genetics paper 
You plainly observe the overlap between non-ASD and ASD people on a scale designed to measure degrees of autistic behaviour.

While this histogram does not directly exhibit the underlying genetic analysis, it's exactly what you expect to see from a polygenic syndrome.

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