A new study published in Nature Genetics and involving researchers from the Universities of Oxford, Bristol, UCL and Regeneron has revealed that genetic mutations have remarkably consistent effects across populations. The work shows that most biological factors operate similarly in all of us.
Efforts over the last ten years have shown that alongside lifestyle factors, genetic information can help predict many traits - from height, to metabolic rate and cholesterol levels. Studies have linked tens of thousands of mutations to differences between people in a huge variety of traits. It is now clear that for most traits, small influences of many mutations – often thousands – spread across our chromosomes act together. By adding up these tiny individual effects, researchers can make genetic predictions, such as an individual’s risk of developing a particular disease. However, a major current challenge is that predictions based on many large studies, so far mainly including people of European ancestry, often provide limited information in people of other ancestries that have been less studied.
In this study, the researchers set out to understand ther causes of this issue, which have been controversial. They focused on two possibilities. The first is that a mutation’s effect differs between groups, perhaps because its effect depends on environmental (e.g. lifestyle) differences (referred to as a “gene-environment interaction”). The second is more subtle, in that the mutations identified as important in genetic studies sometimes are not the actual ones that actually impact the trait. Instead they often are a proxy for the true causal mutation, for example they live on the genome nearby the true mutation. And being a good proxy in one group, i.e. the one they were identified in, does not guarantee they will be a good proxy in a second group of different ancestry.
To determine which of the two issues above is driving this discrepancy, the scientists leveraged data from the UK Biobank, a study which has mapped variation and measured traits in almost half a million people. They first developed methods with the resolution to tell apart people from adjacent UK counties, and then applied these to compare traits, and genetic predictions of those traits, in people of different ancestries within the study. By leveraging the fact that many people in the study possess mixtures of different ancestries, they were able to show that a person’s ancestry background typically does not influence the effect of a mutation, largely ruling out the first possibility above. In particular, across 53 different traits, the estimated correlation of effect sizes in African and European ancestry individuals was 98%For a few traits though, including white blood cell count, there was some evidence of mutations having different effects in different groups. In the future, it will be important to further examine these, and other, traits, by conducting diverse studies that sample individuals from many countries and ancestry backgrounds.
One implication of the study is that findings from a genetic study in one human population are typically applicable in all. However, the study also reinforces that studying multiple populations is essential to identify the correct causal mutations. Ultimately, studies incorporating people of diverse ancestries will allow predictions that are powerful across people, regardless of their ancestry.