‘Copy Number Variants’ (CNVs) are hot. A CNV is a sizeable chunk of DNA that’s either missing from your genome or present in extra copies. Chunks of DNA get copied or deleted on a surprisingly frequent basis. We’ve all got CNVs, most cases they are probably benign, but CNVs are becoming an increasingly appreciated as a significant source of medically important genetic variation. ‘Recently appreciated’ because we now have the technology to detect CVNVs reliably.
A recent paper in The Lancet links CNVs with attention-deficit-hyperactivity disorder, and find that genetic variants in ADHD occur in the same genes linked with autism and schizophrenia. What this suggests is that CNVs are the reason my ADHD child unfailingly neglects to turn in her completed homework.
Before we look at the paper, it’s worth clarifying the distinction between rare and common CNVs. We’ve all got CNVs. Some particular CNVs, a deletion here, a duplication there, are common in the population, while others are much more rare. Common CNVs may be medically relevant, but it’s difficult to link them with diseases because they are so common. Thus most people who have those CNVs are healthy. On the other hand, rare CNVs have the disadvantage of being infrequent (and hard to find), but they’re easier to link with a disease.
The paper at issue focuses on rare CNVs. The researchers looked for rare CNVs in the genomes of a few hundred ADHD patients and over 1000 control subjects.
They did it like this:
1. Identify CNVs by hybridizing fluorescently labeled DNA to an array, and use changes in fluorescence to identify spots with more or less than the normal 2 copies of any particular genomic region.
2. Filter out common CNVs and keep the rare ones. Why? They are specifically going after the hypothesis that rare CNVs cause ADHD; in other words, their hypothesis is that most people don’t have the particular CNVs that cause ADHD symptoms. An alternate hypothesis would be that CNVs affecting ‘ADHD’ genes are common, but require a rare environmental trigger to generate ADHD, or another genetic variant in some other place in the genome. There are basically three possible ADHD/CNV hypotheses one could test. These authors are (quite reasonably) only testing one: single rare ‘hits’ cause ADHD; common hits, under the right environment cause ADHD, or rare combinations of common hits cause ADHD. (A ‘hit’ here is a CNV that damages a gene, resulting in ADHD.)
Of course, all three hypotheses might be true to some degree, but this paper just focuses on the first one.
3. In addition to looking for rare CNVs, they focused their search on CNV’s that specifically hit genes previously linked with autism or schizophrenia. The hypothesis here is that autism and ADHD, or schizophrenia and ADHD have a common genetic basis: you damage a gene one way, and you get autism. You damage that same gene another way, and you get ADHD., etc. Keep in mind that the answer to the question ‘which gene’ to a complex genetic disorder like autism and ADHD is that, it’s not a single that is altered in all cases. Sometimes its one, sometimes its another, or any of a dozen perhaps.
OK, so that’s the idea behind their methodology. What are the results?
1. ADHD kids as a cohort have a lot of rare CNVs. In terms of individual kids, this means that a given kid is much more likely to have a rare CNV than a non-ADHD kid, which is consistent with the hypothesis that ADHD is caused by a rare CNV.
2. Of the rare CNVs found in ADHD kids, a surprising number of these lie over genes previously linked to autism and schizophrenia. So, if you are a person with ADHD, you’re more likely to have a CNV sitting on an autism or schizophrenia-linked gene than a person without such a CNV.
3. Kids with ADHD and severe intellectual disability (IQ<70) are much, much more likely to have a rare CNV, and more likely to have a rare CNV that hits and autism or schizophrenia gene.
Conclusion: The evidence here does support the authors' hypothesis that rare CNVs can undelry ADHD, particularly those that hit genes that also tend to be hit in autsim or schizophrenia. What that means then, if these results hold up in other studies, is that 1) autism and ADHD (and perhaps schizophrenia and ADHD) share a common biological basis – the same genes are hit, affecting similar neurodevelopmental pathways, although the actual effects are obviously different. The other result the resarchers walk away with is a list of candidate genes – a list of genes which ADHD researchers can now focus on, in an effort to understand 1)what functions those genes are involved in and 2)how those functions are altered when the genes are damaged.