Why Do Some People With a Parkinson’s Risk Gene Never Get the Disease? This New Study Offers Clues

If you’ve ever had genetic testing or heard people talk about “Parkinson’s risk genes,” one name you might have come across is GBA1. It’s one of the most common genes linked to Parkinson’s Disease. But here’s the mystery: not everyone who carries a risky GBA1 variant ends up developing Parkinson’s. So what gives? A recent study, published in npj Parkinson’s Disease, set out to unravel this puzzle. It looked at how different types of GBA1 gene variants—and your overall genetic background—interact to influence the chance of getting Parkinson’s. The results are not just fascinating—they’re an important step toward personalised care and earlier interventions. GBA1: A Gene with a Reputation Let’s start with the basics. GBA1 is a gene that helps your cells break down certain types of fats. If this gene doesn’t work properly, those fats can build up, and in some cases cause Gaucher’s disease, a rare inherited condition. But here’s where it gets interesting: even people with just one faulty copy of GBA1 (what’s called being “heterozygous”) can be at higher risk of Parkinson’s, even if they don’t have Gaucher’s. Scientists have known this for a while. But what they didn’t know is why some people with a GBA1 variant develop Parkinson’s and others don’t. Not All GBA1 Variants Are Created Equal The researchers behind this new study, led by a team at the Luxembourg Centre for Systems Biomedicine and collaborating with UK Biobank, looked at three kinds of GBA1 variants: Severe variants, which are known to cause Gaucher’s if both copies are affected, and which carry a high Parkinson’s risk. Mild variants, which are less dangerous but still raise PD risk. Risk variants, which aren’t associated with Gaucher’s but are linked to Parkinson’s. The team studied data from over 185,000 people in the UK Biobank, including more than 1,600 with Parkinson’s, and validated their findings in a separate group from Luxembourg. One Gene Isn't the Whole Story Now here’s where things get really clever. The researchers didn’t just look at GBA1. They also calculated something called a Polygenic Risk Score (PRS) for each person. Think of this as your overall “genetic background noise” when it comes to Parkinson’s—lots of little genetic variations that, on their own, might not do much. But together, they can raise (or lower) your risk. When they combined GBA1 status with each person’s PRS, a pattern emerged. Double Trouble: When GBA1 and PRS Join Forces People who carried any form of a GBA1 variant had an increased risk of developing Parkinson’s. No surprises there. But if those same people also had a high PRS—in other words, a high level of other Parkinson’s-linked genes—then their risk was even higher. In fact, having both a risky GBA1 variant and a high PRS could double the odds of developing Parkinson’s compared to someone with a low PRS and the same GBA1 variant. That’s a big deal. Interestingly, the type of GBA1 variant mattered too. Severe and mild variants were more dangerous than the “risk” variants, especially when combined with a high PRS. So What Does This Mean for You and Me? This research helps explain why some people with a known risk gene like GBA1 never develop Parkinson’s—because their broader genetic background isn’t “primed” for it. And vice versa: someone with a mild GBA1 variant but a high-risk background might be more vulnerable than we previously thought. It’s a bit like making soup. GBA1 might be a strong ingredient, but the rest of the recipe (your other genes) affects the final flavour. Looking Ahead: More Personal, More Precise This kind of study is paving the way for a future where we can tailor risk assessments to the individual. Imagine going to a doctor and getting not just a vague "you have a risk gene" warning—but a personalised breakdown of what that means for you, based on your entire genetic profile. It could also help researchers design better clinical trials. If you’re testing a drug meant for people with GBA1-linked Parkinson’s, it makes sense to include those with higher risk scores first. That way, you’re more likely to see if the treatment works.