Tuesday, 27 January 2015

Siblings, genetics and the autisms (plural)

The paper by Ryan Yuen and colleagues [1] suggesting that most siblings with autism do not share the same genetic variations thought to contribute to the condition has garnered quite a few media headlines of late (see here and see here).

Applying the concept of whole-genome sequencing whereby the complete genetic blueprint of a person is mapped to provide "the most comprehensive collection of an individual's genetic variation" [2], 340 genomes from 85 families with two children with a diagnosis of autism or autism spectrum disorder (ASD) were analysed. Yuen et al reported that examination of de novo and rare inherited SNPs previously linked to cases of autism were not present in some 70% of their "affected siblings" group. Further, that less than a third of siblings shared the same autism-related gene changes, potentially over-turning the idea that most affected siblings (with the same parentage) share the same genetic issues as being related to their autistic symptoms and label. That all being said, the authors did report that: "Brothers and sisters who shared autism-related mutations displayed more similar symptoms than those who did not".

This is a significant paper in quite a few ways although there are caveats. The results only covered 85 sibling-pairs and the number of autism-related genetic variations inspected was relatively limited. One therefore needs to be a little cautious about sweeping generalisations to the very wide autism spectrum, heterogeneity, comorbidity and all. “The findings suggest that there is significant genetic diversity among people which autism” was one of the commentaries on the Yuen study which I would definitely second (see here). The 'people with autism are like snowflakes' analogy has also been banded around to illustrate that idea of diversity; something that I would also agree with, although perhaps preferring the slightly more scientific idea that 'autism' should perhaps be replaced by the more plural idea: the autisms. Exactly how many 'autisms' there are, remains to be seen as it does in other areas of psychiatry.

Ways forward following the Yuen study? Well, I might suggest that alongside replicating the work in a larger cohort, one might also entertain the idea that structural issues associated with the genome might also be complemented by a little more focus on gene functions and that rising star discipline called epigenetics (see here). The idea for example, that even identical twins might vary in their 'methylomic' profile (see here) is gaining traction in autism research circles to potentially account for some of the missing heritability which has been reported in recent years (see here). I'm not saying that the significant resources ploughed into the genetic roots of autism is all bunk; merely that the idea that genes and environment might synergistically [and variably] act on autism risk should be given a lot more credence, alongside the role that common variants might play in [some] autism (see here). Air pollution is one environmental example perhaps requiring a little more study (see here), although I hasten to stress not the only variable which might need further investigation.

Finally, as part of the Google - Autism Speaks MSSNG initiative (see here), the 'de-identified' data from the Yuen study has been uploaded to the 'cloud' for other researchers to utilise in further investigations. Again, a very good idea for those interested in this branch of autism research but again with the proviso that autism is a very, very heterogeneous condition often including quite a bit of enhanced risk for various comorbidity...

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[1] Yuen RKC. et al. Whole-genome sequencing of quartet families with autism spectrum disorder. Nature Medicine. 2015. Jan 26.

[2] Ng PC. & Kirkness EF. Whole genome sequencing. Methods Mol Biol. 2010;628:215-26.

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ResearchBlogging.org Yuen, R., Thiruvahindrapuram, B., Merico, D., Walker, S., Tammimies, K., Hoang, N., Chrysler, C., Nalpathamkalam, T., Pellecchia, G., Liu, Y., Gazzellone, M., D'Abate, L., Deneault, E., Howe, J., Liu, R., Thompson, A., Zarrei, M., Uddin, M., Marshall, C., Ring, R., Zwaigenbaum, L., Ray, P., Weksberg, R., Carter, M., Fernandez, B., Roberts, W., Szatmari, P., & Scherer, S. (2015). Whole-genome sequencing of quartet families with autism spectrum disorder Nature Medicine DOI: 10.1038/nm.3792