Uncovering Rare Disease Genetic Pathways with Global Biobanks

Idiopathic pulmonary fibrosis (IPF) is a rare lung disease characterized by cellular proliferation, interstitial inflammation, and fibrosis that are not due to infection or cancer. The cause of IPF, by definition, is unknown. While scientists have delineated some genes involved in its pathogenesis, previous studies suggest that IPF is highly polygenic, with variants that remain unidentified. As a result, IPF has a poor prognosis and limited treatment options.^1,2

Genome-wide studies may provide insight into IPF’s underlying etiology and pathogenesis, but to date, these studies have been largely limited to individuals of European ancestry.² “We really want to increase the diversity of the studies…there might be a huge number of variants to be found in these understudied populations,” explained Jukka Koskela, clinician and senior researcher at the University of Helsinki Institute for Molecular Medicine, who led a large-scale meta-analysis of IPF that assessed patient data from 13 biobanks around the world.³

In the study published in Cell Genomics, Koskela’s team identified seven new significant genetic variants associated with IPF risk, six of which would not have been significant if their analysis was restricted to European ancestry.³ The researchers then used an information aggregation tool to assess the shared effects of relevant traits and the novel loci found in their catalog of genome-wide association studies (GWAS). Koskela’s team noted that three of the seven new loci have been previously associated with lung function measurements. They also found genes involved in the mTOR signaling pathway, which is central in lung fibrosis, and in mucin fucosylation, which may influence airway self-clearing mechanisms. Additionally, previous research demonstrated that genes at two of the novel loci are differentially expressed in the lungs of patients with IPF.

We really want to increase the diversity of the studies…there might be a huge number of variants to be found in these understudied populations.
- Jukka Koskela, University of Helsinki

At the loci they identified in this study, Koskela’s team also observed pleiotropy effects that confirm and further describe the genetic overlap of IPF and COVID-19. There is a shared genetic background between IPF susceptibility and COVID-19 severity.⁴ Most loci associated with increased IPF susceptibility that Koskela’s team examined were also associated with increased COVID-19 severity. However, two IPF variants showed opposite effects, with the strongest IPF risk locus, MUC5B, seemingly conferring protection from severe COVID-19. “We weren't surprised that the genetic correlation [between IPF and COVID-19] is actually very high,” said Koskela, “but the thing that I'm a bit surprised about is that the MUC5B has opposite effects across the two diseases…[It] makes me wonder how these effects come together in these diseases.” He is hopeful that new therapeutic options for IPF may arise from what researchers and clinicians are learning about COVID-19 treatment.

This study further elucidates the genetic background of IPF and provides greater insight into previously identified genetic variants. Additionally, it highlights the importance of multi-ancestry analysis. “Genetic studies of lung fibrosis are quite difficult to do because it's a relatively rare disease. And so, I think that this is quite a robust approach,” said Mark Jones, associate professor of respiratory medicine at the University of Southampton, who was not involved in the study. “Being able to do studies which are more representative of the world clearly has that potential of increasing understanding.” Indeed, this study demonstrates how a multi-ancestry meta-analysis approach boosts the power of rare disease research by incorporating a broader set of genetic variation, enabling cross-validation of new findings across biobanks, and increasing representation of understudied populations.