What if you could visibly lay out your entire genome sequence in front of you and see almost everything that explains who you are, from your eye colour to whether you’re an introvert or an extrovert? If this were true, we look at someone’s genes and calculate whether they will develop attention deficit hyperactive disorder (ADHD) and offer them treatments right away. Unfortunately, accurately reading biomarkers isn’t as easy as laying the genome out like a map. Luckily, there are researchers working on ways to solve this problem.
Dr. Patricia Pelufo Silveira, an associate professor in McGill’s Department of Psychiatry, is one such researcher. Pelufo Silveira, along with the help of Dr. Cecilia Flores, a professor in the Department of Psychiatry, developed a novel genetic scoring technique called expression-based polygenic risk score (ePRS), which they are using to score impulsive behaviour.
“High impulsivity has been associated with several psychiatric disorders,” Flores said in an interview with The McGill Tribune. “Many times, it’s used as a trait of vulnerability.”
Their technique involves studying an entire gene network associated with DCC, a gene shown to influence impulsivity. Flores has researched the DCC gene extensively and found that it has a profound impact on guiding growing axons towards assembling the nervous system. The researchers used gene expression datasets from mice and identified the genes that had correlated co-expression with DCC. Then, a program filtered the genes according to the ones most expressed during the first 18 months of life, creating a DCC co-expression gene network. The genes were then mapped and weighed based on their effect on the brain, resulting in the genetic risk score.
“We know that [DCC] is very important in the maturation of impulse control,” Flores said. “We also identified where in the brain that the function of this gene is important for the development of impulse control.”
EPRS goes much deeper than previous genetic scoring methods, such as the original polygenic risk score (PRS), which determines whether one is at high risk for a given disorder by looking at known, correlated genes. So, instead of connecting a gene to a disease like PRS does, ePRS connects a gene to other genes.
“The main difference is, instead of marking risk for disease, we’re marking variation in a biological process,” Pelufo Silveira said in an interview with Tribune.
“It’s not only the genetic variance in a person and associating [that] with a disorder, but it’s how that variance influences the gene function of a process in particular brain regions,” said Flores.
Not only is ePRS much more accurate, but it is also excellent at controlling for genetic factors such as ethnicity.
“We want what we call external validity, to be valid to many different groups independent of their genetic background, but when you’re using genetics, this is difficult because people’s [genetic markers] vary depending on their ancestry,” Pelufo Silveira explained. “[ePRS] is strong enough to predict this difference across different ancestries.”
Flores and Pelufo Silveira also considered external factors such as social environment or drug exposure, which Flores stressed as being extremely important when researching ePRS in a clinical setting.
“You [want to] have more than one metric for each individual [which] really personalizes the intervention, that’s the goal,” Flores said.
Given that everyone is impulsive to some extent, Flores says that a holistic approach is key when distinguishing between normal impulsivity and harmful impulsive behaviour.
“A single trait is not enough, you need information about other aspects to form a diagnosis; [some behaviours and circumstances] are red flags.”
In the future, Pelufo Silveira hopes that ePRS can be used to identify other biomarkers, not just those for impulsivity.
