A genetic exploration of ASD resiliency
As I mentioned in my earlier post, among the many papers that I bookmarked for “reading later”, this preprint was in the top of my list, and I managed to read it today. There are two reasons why I had a special interest in this preprint.
First, it addresses a question that I—and probably many others—were thinking about more and more recently: why some individuals carrying a large effect mutation(s) for a particular disease do not develop the disease; what factors make them resilient to the disease?
Second, I learnt about this preprint through Dr. Sébastien Jacquemont (a co-author in this paper,) a scientist whose work I’ve started admiring a lot recently. For e.g. I found two of his papers on the associations between copy number variants and intelligence highly insightful, which I have also summarized as twitter threads (thread1, thread2.)
In this paper, the authors have analyzed the exomes of around 10,000 ASD cases and 100,000 non-ASD individuals (who were mainly from the UK Biobank) with one particular aim: what makes non-ASD individuals who carry loss of function (LOF) mutations in known ASD genes resilient to ASD?
The authors have looked into a list of 156 genes what seem to be “robustly associated with ASD.” For each gene, the authors calculated the ASD penetrance (in terms of relative risk, which is “the risk of being diagnosed with ASD when carrying such variants,”) and compared the penetrance estimates with the LOF intolerance measures, and found them to be highly concordant. This reinforces the notion that genes linked to ASD are simply genes linked to brain in general. The most robust metric of a gene’s specificity to brain is its mutation constraint. And we see it for the ASD genes as well, also intellectual disability (ID) genes. Note that there is no clear distinction across ASD specific genes, ID specific genes and brain specific genes. And this has been the basis of a paper titled ‘Insufficient Evidence for “Autism-Specific” Genes,’ that came out last year, and stirred some tension among the ASD researchers.
Despite the high concordance between ASD penetrance and mutation constraints, there seem to be some interesting exceptions, e.g. PTEN, SHANK2, which are highly penetrant for ASD, yet less intolerant to LOF mutations. That is, despite mutations in these genes often leading to ASD or ID, they seem to evade natural selection. How? Such outlier genes, perhaps, hold the key to opening the ASD mystery? The authors also report a list of 25 genes that are fully penetrant for ASD. That is, among the 100k non-ASD individuals, the authors found not even one person who carried a LOF mutation in any of these 25 genes and did not develop ASD. I find this list extremely intriguing, and I plan to dive deep into this list later.
The authors found that the cognitive functions of non-ASD LOF carriers in the UK biobank are significantly lower compared to non-ASD non-carriers. More penetrant the genes are for ASD, higher the differences in cognitive functions between carriers and non-carriers. My immediate thought on reading this finding is if the authors repeated the same analysis in some brain-specific highly constrained genes (irrespective of their association with ASD), they would have seen the same. In fact, that’s what exactly was shown in Dr. Jacquemont’s previous paper. My point is all these analyses are reflecting brain specificity, rather than ASD specificity.
Importantly, the authors found that the liability threshold model holds true for ASD; non-ASD LOF carriers had lower burden of common ASD risk variants than ASD LOF carriers, which seems to indicate that the decreased common variant burden might have contributed to the resiliency of the non-ASD LOF carriers.
Finally, the authors searched for clues that might support the “female protective effect” hypothesis. The authors expected (or may be they didn’t) that female sex might be one of the contributing factors for ASD resiliency in non-ASD LOF carriers. Unfortunately, that wasn’t the case. The non-ASD LOF carriers were equally distributed among males and females.
Overall, this is a fascinating and thought-provoking paper, and I enjoyed reading it, tweeting about it, and also, summarizing it here.