Connecting the Dots: How Your DNA Shapes inflammatory bowel diseases at the cellular level

Read the full scientific paper here: Cell-type-resolved genetic regulatory variation shapes inflammatory bowel disease risk

The Big Picture

We know that genetics play a huge role in who develops many diseases including IBD. Over the years, scientists have found hundreds of "risk zones" in human DNA associated with Crohn's disease or ulcerative colitis. But most of these risk zones don't sit directly inside the genes themselves. Instead, they hide in the "dark matter" of our DNA otherwise known as the bits between the genes that act like control panels, turning genes off and on.

Because these switches lie in DNA dark matter, away from the genes they control, it has been incredibly difficult to know which genes are actually controlling disease and which specific cells they are malfunctioning in. To solve this puzzle, our IBDverse team set out generate a map linking genetic risk of disease to gene expression controls at an unprecedented resolution.

How We Did It

We analysed a massive dataset of 2.2 million individual cells from blood, rectal, and terminal ileal biopsies donated by 421 individuals (including 125 with IBD). Using this high resolution cellular approach together with a read of each person’s DNA profile, we were able to statistically link the changes in gene expression that occur when a genetic variant is nearby.

What We Found

Our cell-by-cell mapping revealed the hidden mechanisms of IBD genetics:

  1. Finding the "effector" genes We successfully identified the actual genes causing the problem (the "effector genes") for over half of all known IBD genetic risk zones. Amazingly, for 74 of these risk zones, this was the very first time a potential culprit gene has been identified.
  2. The problem with gut healing We found that some genetic risks specifically affect the gut's stem cells. Stem cells are responsible for constantly regenerating the lining of your intestines to keep the barrier strong. In people with certain genetic variants, genes that control cell renewal (like MYC) are disrupted, making it harder for the gut barrier to heal itself.
  3. Immune Cells Misreading Signals We also linked specific genetic risks directly to specific immune cells. We found that a vital communication process called "Notch signaling" is reduced in these cells due to genetic variants in genes like MAML2 and PSEN2. This miscommunication causes the immune system to malfunction in the gut environment.

What This Means for Patients

This study bridges the massive gap between knowing someone has a genetic risk for IBD and knowing what to do about it:

  • From "risk zone" to "drug target": By identifying the specific effector genes and the exact cells they operate in, we have handed drug developers a detailed map. Instead of just treating the general inflammation, future medications can be designed to fix the specific molecular switches that are broken, in the cell types that they are broken in. But a word of caution, drug development takes a long time so any treatments that may come about as result of our findings may not reach you for several years.
  • Personalized Medicine: Understanding exactly how different DNA variations drive the disease brings us one step closer to personalized treatments. In the future, a patient's genetic profile could tell doctors exactly which cellular pathway needs to be targeted for their specific version of IBD.
  • A Blueprint for Other Diseases: The framework we built to find these hidden genetic connections in IBD is now an open resource that scientists can use to decode other complex genetic diseases.