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OK, stop.. hammertime.. a few descriptions and details are needed first as well as a caveat about my amateur status when it comes to all things genetics.
SNPs and mutations. A short description is included here but basically think small changes to the letters of the genetic code. Suffice to say that I've covered SNPs and those copy number variations (CNVs) and autism on more than one occasion on this blog as per posts like this one on no single SNP being associated with the universality that is the autism label and this one on just how complex autism seems to be from a genetics perspective.
I hope I've not been too unkind to genetic mutation research (sorry for the cold science term) specifically with autism in mind, but like other developmental conditions such as attention-deficit hyperactivity disorder (ADHD), the whole 'genetics is absolute ruler' argument has not been borne out by the data produced so far. Each and every one of us, whether diagnosed with autism or anything else, are the product of mutation and autism is a mighty diverse condition.
With all this in mind, the Klei paper whilst open-access has a few interesting points worth noting:
- This was a study aiming to look at a few important issues. Not only the question of simplex (one child) vs. multiplex (more than one child) genetic risk of autism and whether they might be different, but whether despite not one SNP being universally applied across all autism, there may be some argument for more [important] SNPs cumulatively = a greater risk of autism.
- Based on genotype data derived from two autism-related datasets representing simplex and multiplex families respectively, the Simons Simplex Collection (SSC) and the Autism Genome Project (AGP), comparisons were made with control data (HealthABC) across several hundred thousands of SNPs for something called narrow-sense heritability - in effect additive genetic variance. There was also a further test group used to assess the robustness of findings (Neurogenetics Research Consortium, N=1986).
- Results: "For simplex families, who have only a single affected individual in multiple generations, approximately 40% of liability traces to additive effects whereas this narrow-sense heritability exceeds 60% for ASD individuals from multiplex families". The actual results were: simplex (39.6%) and multiplex (65.5%); this last figure reflective of the AGP cohort splitting, with some simplex and some multiplex families included; simplex heritability in the AGP group being estimated at 49.8%. These estimates also bearing in mind the "unrealized multiplex potential" of taking snapshots of families.
- Another result: "These results suggest that AGP parents carry a greater load of additive risk variants than SSC parents and thus are, on average, closer to the threshold of being affected". Translation: parents of participants in the AGP cohort, bearing in mind this included both simplex and multiplex families, showed more additive risk SNPs and hence were closer to the diagnosis of autism or the broader phenotype than in the SSC cohort taking into account differences in screening for autism in parents between the two cohorts.
- And another result: "A curious observation from AGP multiplex families was that fathers generate larger heritability than mothers". Translation: lots of potential reasons for it (including the issue of mums, dads and differing proportions of sex hormones) but dads seemed to generate more 'risk' than mums in multiplex autism.
- And a final result: "Our results suggest that common variants affecting liability do not cluster on chromosome X". An interesting observation given the focus on the X chromosome as a result of the reported male domination of autism.
- Mention is also made of assortative mating as being involved in the results but as yet no new data is presented on this possibility.
I like the quote from one of the chief authors on the paper, Prof. Bernie Devlin reported here: "The genetic components alone are far more complex than many imagined a decade ago, including the additive effects we have found, rare inherited mutations, and new mutations arising spontaneously before conception." To me this embodies everything about the current state of knowledge on the genetics of autism in that (a) there is probably no universal 'autism' gene, (b) mutations are likely to be an important part of autism risk and (c) new mutations opens the door up to environment as playing a hand (spontaneous eh?). Indeed the only thing missing from this sentence is discussion about the relative newcomer, epigenetics, and how looking at the function of genes might be able to plug some of that gap in the risk for developing autism.
As per my recent post on systems biology and autism, one also has to ask whether there might be some common biochemical pathways to be derived from these additive genetic effects. Not so long ago, Skafidas and colleagues** were discussing SNPs in relation to gene and biochemical functions, with some interesting observations detailed (see this post). I'd be very interested to see what might come from similar analyses on the Klei data and whether there is overlap or differences based on simplex or multiplex cases.
Whilst an interesting paper, there still remains some significant holes in our knowledge about autism and the risk factors for receiving a diagnosis of autism. Those 40% and 60% risk figures are probably what many people are going to focus on, but my question is what about the remaining 60% or 40% of risk and indeed the question of 'where did the heritability go?' based on previous twin studies lining the autism research trail (see here). Where does that risk come from? and should we perhaps be looking at environmental factors with as much assiduity as we do genetic ones?
* Klei L. et al. Common genetic variants, acting additively, are a major source of risk for autism. Molecular Autism. 2012; 3: 9. doi:10.1186/2040-2392-3-9
** Skafidas E. et al. Predicting the diagnosis of autism spectrum disorder using gene pathway analysis Molecular Psychiatry. September 2012; DOI: 10.1038/mp.2012.126
Klei, L., Sanders, S., Murtha, M., Hus, V., Lowe, J., Willsey, A., Moreno-De-Luca, D., Yu, T., Fombonne, E., Geschwind, D., Grice, D., Ledbetter, D., Lord, C., Mane, S., Lese Martin, C., Martin, D., Morrow, E., Walsh, C., Melhem, N., Chaste, P., Sutcliffe, J., State, M., Cook, E., Roeder, K., & Devlin, B. (2012). Common genetic variants, acting additively, are a major source of risk for autism Molecular Autism, 3 (1) DOI: 10.1186/2040-2392-3-9