In a break with past practice, publication of a new full genome autism study was just announced with relatively little fanfare. Published today by the highly prestigious journal Nature, this new study by the Harvard based Autism Consortium was released with almost none of the promotional hype and editorial celebration that we’ve typically seen in studies of this type. To be sure, the investigators put on a brave face and claimed success in discovering yet another new “snip” (aka SNP, for single nucleotide polymorphism) that they claim to have located near a neuronal gene called semaphorin 5A. The fact that it’s not on any actual gene is critical, since that means they have no idea what biological function might be going awry in autism. But as the standards for judging autism gene findings have progressively degraded, even though the positive finding is not exactly on the gene, it’s close enough. Because if close is good enough for horseshoes and hand grenades, that must be good enough for genes and autism too.
But what is most striking about this report is a little nugget buried deep in the paper. Age of Autism readers may remember the last big autism gene study that I wrote about earlier this year (see HERE). That study, conducted by Paul Offit’s friends at the Children’s Hospital of Philadelphia (CHOP), reported that a common genetic variant was found more frequently in autistic genomes. More specifically, a DNA sequence in between two genes on chromosome 5p14 (again, this finding was just near the known genes, not on them) that was present in 61% of normal controls, was present in 65% of autism cases.
Now, if you're like me, you may not find that difference particularly earth shattering: the idea that the most prominent “abnormal” gene in autism is present in 61% of the neurotypical population. But that didn’t stop the celebration at the time, this finding was presented as one of the great breakthroughs of modern autism research. Not surprisingly, therefore, the Harvard group looked at the same region in their latest genome scan. Here’s what they reported.
During review of this manuscript, another genome-wide association study was published which identified significant association to SNPs on chromosome 5p14. Although there was significant overlap between study samples, each of these scans contained a large set of unique families, so we sought to evaluate independent evidence of the top SNP (rs4307059) reported at 5p14…[W]e observed no support for association at this locus..[and instead found a gene transmission frequency] in favour of the minor allele, a trend in the opposite direction as reported.
In other words, paraphrasing the words of Cool Hand Luke, what we’ve got here is a failure to replicate.
Results like this are remarkably common in full genome autism studies, whether (like the latest one), they’re reporting on inherited genes or (like an earlier study from the Harvard group) genetic mutations called “de novo copy number variants” (CNVs). The plot is so familiar by now that it’s worth betting on. In response to the failure of the last round of gene hunts, a new research group raises money for the largest sample of autism families ever collected. They apply the latest technology, check their results with other samples and set the computers in motion. When the results come back, lo and behold, they find that virtually all of the prior “autism genes” don’t show up significant in the latest analysis; in fact, some of the highest and best hopes of the autism genetics community are dashed by negative findings. But some brand new shiny region emerges out of the massive number crunchers and this new “discovery” goes straight to the headlines.
The sad part, of course, is that the human genome is so large is that when one runs numbers like this you’d almost always expect to find a result that approaches significance somewhere on the genome. But the gene hunters continue to sally forth undaunted. And since no one in the medical press ever bothers to go back to read any of the previous studies, they’re more than happy to file a story celebrating the triumphant march of medical science.
The funny part is, the last time we saw this dynamic, it was the CHOP group dashing the hopes of the Harvard group, which had claimed to find a “hot spot” of genetic instability on chromosome 16 (an excessive rate of deletions on chromosome 16p11). In their study published in April of this year, the CHOP group tried to replicate this finding in a follow on study of de novo CNVs. Here’s what they reported.
“We observed a similar frequency of deletions and duplications of the 16p11.2 locus in the ASD cases (~0.3%) as previously reported; however the CNV frequency in the control subjects at this locus was also comparable to that of the cases.”
In other words, the rate of mutation was no different between autism cases and controls and the Harvard group may simply not have had a large enough sample to detect such a low rate of mutations in the normal controls, where the CHOP group found plenty of deletions.
So much for the hot spot.
So now we have another darling gene, semaphorin 5A. The gene hunters will add it to the list of “known autism genes”, but I’d be more than happy to take money from anyone who wants to bet that we’ll find it semaphorin 5A coming up positive in future studies. After all, no one ever found it before during years of searching, so why should we give this latest finding any more credence than a random number generator. Still, the thirst for positive results is strong in autism geneticists. That said, even the gene hunters are beginning to sound weary now. “It’s a nice finding”, said Mark Daly, one of the Harvard study’s senior authors “but it’s just a small step in what’s really the first step of addressing autism.” In yet another metaphorical plea for patience he remarked, “It’s a long road ahead, [but] at least we found the road.”
Autism rates are now up to more than 1% of American children, nearly 2% of boys. Genetic research is in disarray, reeling from years of incoherent findings and an incoherent logic that ihas become increasingly exposed. We all get tired of saying it, but it bears repeating that there’s no such thing as a genetic epidemic. Yet NIH continues to pour millions more of our tax dollars down the gene hunting rat hole and, in a trend that is even more disturbing, the new administration appears to be doubling down on the failures of the past.
In the face of such obvious irrationality from so many highly educated analysts, it’s enough to make you ask, do any of these people have a brain?
Mark Blaxill is Editor-At-Large for Age of Autism.