NEW YORK − Rare genetic variants can be a powerful tool for understanding common, complex traits or diseases such as height, weight, or diabetes, even though they only account for a small fraction of heritability of these traits, suggests a new study led by researchers at the Broad Institute.
While previous genome-wide association studies have estimated the contribution of common variants to how traits and diseases are inherited, the same has not been done for rare genetic variants.
"Something that has been historically more difficult for the field is to estimate how much heritability comes from really rare variants," said Ajay Nadig, a Broad Institute researcher and co-lead author of the study, which was published in Nature on Wednesday. "Our method is a novel approach at estimating how much of the heritability comes from one part of rare genetic variation," he added.
For their study, Nadig and his colleagues analyzed nearly 400,000 exomes from UK Biobank participants in order to understand the contribution of rare coding variants to 22 common complex traits, including height, alcohol consumption, and blood cholesterol levels.
Specifically, they looked at what proportion of a trait's variance could be explained by such variants, the so-called "burden heritability."
Results showed that burden heritability was low, about 1.3 percent on average, across traits compared to around 13 percent heritability due to common genetic variants.
That finding wasn’t particularly surprising. "This is somewhat intuitive as, if a variant is very rare, present in only a couple of people, then the amount of population variation in the trait that can be explained by variation that is so rare has some upper bound," said co-lead author Daniel Weiner from the Broad Institute.
Next, the researchers wanted to unravel what rare and common variants involved in the same trait had in common, "whether they are equally polygenic; whether they implicate the same genes, cell types and genetically correlated risk factors; whether rare variants will contribute meaningfully to population risk stratification," they wrote.
The results revealed that while rare coding variants contributed only modestly to heritability and population risk stratification, they acted through the same genes and biological pathways as common variants.
"One of the main findings of our study is that common and rare variants seem to cluster, you could say mechanistically, around the same cell types and tissues, suggesting convergence," said Weiner.
A major implication of this finding is that rare variants could be a shortcut to identify key tissues and cell types involved in a disease, as well as disease-relevant biological processes. "If common and rare variants converge on the same disease-causing processes, therapeutics targeting rare-variant associated genes have the potential to benefit a large number of patients, not only the few who carry specific mutations," the authors wrote.
In a commentary in Nature accompanying the study, Luke Evans and Pamela Romero Villela, researchers at the University of Colorado Boulder, noted that "the evolutionarily conserved genes in which rare-variant effects tend to cluster often encode proteins that can be targeted by drugs," though they cautioned that the potential to translate the study's findings to the clinic "remains speculative for now."
As a next step, the Broad Institute researchers have developed open-source software implementing their burden heritability regression analysis, so others can apply the method easily to their own studies. They noted that several researchers have already started to use this tool.