Giant-Scale Biobank Research Hyperlinks Main Cilium to Diabetes, Kidney Illness, and Liver Fibrosis


A new study overturns the popular belief that the primary cilium is an organelle that is only important during development and in rare diseases, revealing different roles for subcompartments of this strange and ubiquitous organelle in common diseases such as diabetes, kidney failure, and liver fibrosis – an indication of a possible way to treat or even cure it.

In contrast to the numerous hair-like cilia associated with movement in specialized cells such as those that line our windpipe, the primary cilium is a small, immobile projection of the cell surface that acts like an antenna. It occurs in almost every type of human cell.

Scientists from the University of Pennsylvania and Philadelphia Children’s Hospital conducted association studies of 16,874 common genetic variants across 122 ciliary genes with 12 quantifiable laboratory characteristics characteristic of primary ciliary disease (ciliopathy syndrome) in 452,593 individuals in the UK Biobank and identified 101 significant associations with 42 ciliary genes.

These results were published in the American Journal of Human Genetics article, “Mendelian Pathway Analysis of Laboratory Characteristics Reveals Different Roles for Ciliary Subcompartments in the Pathogenesis of Common Diseases.”

“One of the most exciting implications of our study is that the cilium is a common therapeutic target because it appears to be involved in a number of complex diseases,” says Dr. Theodore Drivas, postdoctoral fellow in the laboratory of Marylyn Ritchie, PhD, Professor of Genetics and Director of the Center for Translational Bioinformatics, Clinical Associate in Internal Medicine and lead author of the study. “The cilium has not previously been seen as a therapeutic target for drug development for common diseases. That’s an interesting prospect. “

The UK Biobank is a research database that contains electronic health records and genetic information. “Resources like the UK biobank have tremendous potential to link rare disease-related genes to common diseases and traits,” said Ritchie.

The authors find that 42 of the 122 ciliary genes studied are strongly associated with diabetes, kidney failure, liver disease, and high cholesterol levels in the blood samples examined by the team. Bioinformatic and genomic analyzes have shown that these associations are not limited to rare genetic variants, but are also linked to some of the most common ones.

“These genes were found to be widespread in all human tissues. Our data suggest that genetically encoded changes in the level of activation of these genes may be responsible for their involvement in the development of common diseases,” says Drivas. “Our results challenge the widespread belief that the cilium is an organelle primarily important in rare genetic syndromes and suggest that it may also be behind many common diseases that have yet to be cured.”

The novel connection between primary cilia and common genetic diseases opens up the possibility of new drug targets in the primary cilia and potential gene therapies for many common diseases.

Diabetes affects more than 34 million people in the United States, who make up more than 10% of the population, and many can only control it through injections of insulin. New therapies that depend on a patient’s genetics could provide more targeted and effective treatment for patients with diabetes.

Before novel therapeutics can be developed based on these new findings, the team plans to validate these discoveries in cell models.

“Ultimately, we hope to use these results to screen libraries of small molecules to identify drugs that help modulate ciliary function and potentially treat some of the diseases examined in our study,” says Drivas.

“The potential to use this study as a model for exploring other rare disease genes is exciting,” says Ritchie. “There could be many more genes that we consider to be the cause of rare diseases, which are also important for the risk of common diseases.”