Article

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What is the role of protein trunacating variants in neurodevelopmental disorders - both de-novo and inherited variation.

Summary

Previous observations:

  • ASD cases with higher IQ, family history of neuropsych disease.
  • More de-novo variation in ASD cases with co-morbid ID.
  • Most studies assume Kimura’s infinite sites model but mutational recurrence has now been observed with the amount of data we have. This means de-novo mutation is analyzed without worry about the allele frequency of these in the population.
  • The highly deleterious de-novo mutants will be weeded out by selection.
  • 7 Billion people, 1 denovo variant per 30 million bases. Every non lethal coding variant likely to be denovo in atleast one individual.
  • Class 2 denovos - denovo but also observed in the population as standing variation.
  • Class 1 denovos - denovo but not observed as standing variation.
  • Start with 10,093 variants observed denovo in ASD, ID/DD and ASD siblings.
  • Around 25-30% of these denovos are observed as standing variation in the population.
  • Same rates in the studies of schizophrenia and congenital heart disease.
  • Expected recurrence rate increases with size of referrence dataset. Makes sense since our n increases, np will be higher, assuming a constant p i.e mu.
  • Check if class1 and class2 contribute equally to risk of ASD and ID/DD.
  • Synonymous rates of class1 and class2 equal across ASD, ID/DD and unaffected ASD siblings.
  • Class2 denovo PTVs show no association with ASD or ID/DD compared to unaffected ASD siblings.
  • Class1 denovo PTVs enriched in ASD and ID/DD compared to unaffected ASD siblings.
  • Non-significance of class2 denovo PTV rate difference is not sensitive to allele frequency threshold used.
  • Removing class2 denovo PTVs should boost power to detect class1 denovo PTV effects.
  • Use rate of PTVs in Exac to determine which class1 denovo PTVs might be relevant.
  • Excess of denovo PTVs in LOF-intolerant genes in ASD and ID/DD compared to unaffected ASD sibs. Effect more extreme in individuals with ID/DD.
  • Argue that mere multiple observation of denovo PTVs in a gene not sufficient.
  • Females with comorbid ASD and ID had highest rates of denovo PTVs in loss of function intolerant genes.
  • Inherited PTV variants show modest excess when those observed in EXac are removed. Effect sizes are small.
  • Eleven genes with three or more class1 denovo PTVs in ASD cases and none in controls.
  • Looked at 400 ASD cases and 3654 controls, no difference in synonymous rates in or not in Exac between cases and controls.
  • Slight excess in singleton PTVs in ASD cases over controls. Signal stronger when Exac variation and LI tolerant genes removed.

Discussion

Some of the discussion revolved around choosing a pLI cutoff of 0.9, this seemed somewhat arbitrary and sometimes spans a range of selection coefficients. How sensitive are the results to variations in the cutoff?