Genomic studies of isolated populations can help identify very rare genetic variants that significantly impact human traits, including obesity, a new Finnish study demonstrates.
Titled “Exome sequencing of Finnish isolates enhances rare-variant association power,” the study was published in the journal Nature.
One of the overarching goals of genetics research is to understand how particular mutations affect human traits. Nowadays, these associations are often found by investigating the genetic variations of individuals in a population — via sequencing or other methods — then looking for statistically significant links between individual gene variants and traits.
There’s a problem with this strategy, though: many gene variations — and particularly those that have a negative impact on health — are very rare. This means that, to find an association that reaches statistical significance, a large population — hundreds of thousands, or even millions — is required. That just isn’t feasible a lot of the time.
In this new study, the researchers demonstrated that this problem could be overcome, at least in part, by picking out populations more likely to have rare genetic variations at a higher frequency. The case in point: the population of northern Finland.
The researchers noted that, when people become geographically isolated and only reproduce with those around them for generations, rare mutations tend to increase in frequency. A smaller pool of genes to choose from at the beginning leads to the accumulation of otherwise rare — and often problematic — mutations. An extreme example of this phenomenon would be inbreeding among royalty.
For this reason, the investigators chose to study the population of northern Finland, where the inhabitants have remained relatively more isolated than, say, in the U.S., U.K., or France. Indeed, there are 36 rare genetic diseases already known to be disproportionately common in this region — conditions collectively known as Finnish heritage disease.
Now, researchers sequenced genes from 19,292 people from northern Finland. Specifically, they sequenced participants’ exomes — the part of the genome that codes for proteins, which accounts for around 1% of the total genome — because this was more affordable.
More than one million individual genetic variations were identified, and the researchers found hundreds of associations between genes and traits. Of these, 43 associations with 26 variants had not been previously reported. Some genetic variants were associated with multiple traits, the researchers noted.
Among the associations, 34 — with 19 variants — were either unique to Finland or were enriched more than 20-fold compared with other populations.
As an example of the associations identified, a variant (Arg94Cys) of the gene THBS4 was associated with a lower body weight, of 5.9 kg (13 lb) on average. Similarly, a variant (Val104Met) in the gene DLK1 was associated with an average of 1.3 cm (0.5 in) shorter height.
These findings support the idea that more isolated populations can be used to help identify rare, but important, genetic variants. More broadly, they demonstrate that such rare variations exist and can be detected with a sufficiently large and smartly designed study.
“We learned that sequencing — not the entire genome but the genes within the genome — is more affordable than whole genome sequencing and just as reliable for finding variations that have a pretty strong effect on common traits such as height, weight and cholesterol level,” Nelson Freimer, professor at UCLA and a study co-author, said in a press release.
“We found that the strategy of sequencing large samples of people to find genetic variants that influence disease will work,” Freimer said. “But in populations like that of the U.S., or large European countries like the U.K., it will take sequencing, not of 20,000 people, but of several hundred thousand to millions of people before you get the same type of finding.”
Freimer said precision medicine will have to take regional differences into account.
“There are some people who ask, ‘Should we really be devoting the resources to sequencing large human populations?’ And I think the study shows us it is worth the investment,” he said.