BY CATHLEEN O’GRADY
If you have ADHD, chances are higher that your siblings do, too. Estimates differ as to how strong the connection is, but the arrows point in the same direction: genetics helps determine someone’s risk for ADHD. Beyond that, we still have myriad questions and not many answers—which genes play a role? And how do those genes affect someone’s ability to focus or sit still?
Some conditions, like sickle-cell anemia, rest entirely on a single small genetic change; but others, like schizophrenia, rest on a dizzying array of genetic differences, all seemingly linked to an infinitesimally tiny increase in risk.
ADHD is much closer to schizophrenia. A paper published in Nature Genetics this week looked at genetic data from more than 50,000 people, finding 12 different regions of DNA that seemed to play a role in increasing ADHD risk.
A genome-wide view
This evidence comes from a genome-wide association study, or GWAS: a close look at how the DNA of people with ADHD differs from those without. People can have slightly different versions of the same gene—like having just a single letter swapped out for a different one in a paragraph. If any of these variants make a difference to a particular disease, you should find that people with the condition tend to be more likely to have one variant and people without the condition to have a different one. So, scanning across the genome, those variants that pop up as being different between the two groups are worth paying attention to.
As it has become easier to create and analyze data from ever-larger sample sizes, GWAS studies have been examining the genomes of tens of thousands of people—in some cases hundreds of thousands. Those huge numbers are necessary for researchers to detect the tiny differences that can be at play. Smaller studies tend to come up empty or identify a handful of genetic regions that seem to play a role, while larger studies can kick up huge numbers of variants.
Previous efforts to find ADHD-related variants hadn’t turned up anything, but that could have been because they didn’t have big enough sample sizes.
Geneticist Ditte Demontis and her colleagues used data from more than 20,000 people with ADHD, comparing them to a control group of 35,000 people without an ADHD diagnosis. They found 304 points where tiny differences in DNA—like single letter swaps—were distributed across their two groups in a statistically telling way. If any of those variants were very close together, the researchers counted them as representing the same stretch of DNA, grouping them together into 12 important regions.
There’s no “gene for ADHD”
It’s not clear yet what information GWAS research can give us. Large studies can identify many genes implicated in a condition, each having a tiny influence, causing a lot of debate about how best to interpret them. Some researchers even argue that, in some cases, what we’re seeing is essentially the whole genome playing a role in a particular condition.
Combining all the tiny risks conferred by different genetic variants can yield what’s called a “polygenic risk score”—a way of capturing how high a person’s risk for a condition is, based on the number of individual risky variants they have. Even these have limited applicability, though: “for schizophrenia, these scores can explain about five percent of the variance in disease status,” writes neuroscientist Kevin Mitchell.
In fact, the multitude of tiny increases in risk might tell us that the genes involved aren’t directly related to the condition. Instead, they might be creating an underlying state in which plenty of different genes end up functioning in a slightly less than ideal way, making it harder to “buffer the effects of rare mutations,” Mitchell writes. There’s also significant overlap between the polygenic risk scores for different conditions, suggesting that the genetic variation identified in GWAS studies seems to leave people vulnerable to a range of different conditions.
That overlap is precisely what Demontis and her colleagues found with ADHD. There were correlations between the genetic risk for ADHD and a range of other conditions, including depression and anorexia. That ties in with the idea that genetic variation might be important in a way that plays out system-wide. Some of the genes they identified are also known to be involved in other neurological conditions, including speech and learning disabilities, depression, and schizophrenia.
This research is light-years away from anything that will immediately affect people with ADHD—like a genetic test or a medication. But that doesn’t make it useless. It’s just creating routes for additional research, rather than practical application. Scientists will obviously want to look carefully at these genes to study how they work in humans. But the most obvious next step is a much bigger study: although this sample size seems large, a bigger GWAS could identify even more genetic variants involved in ADHD, helping to clarify its overlaps with other conditions.