Scientists Unearth Brand New Links Between Genes and Disease in Our Blood

A blood draw is one the most mundane clinical tests. It’s can also be a Rosetta stone for decoding genetic information and linking DNA typos to health and disease.

This week, three studies in Nature focused on the watery component of blood—called plasma—as a translator between genes and bodily functions. Devoid of blood cells, plasma is yellowish in color and packs thousands of proteins that swirl through the bloodstream. Plasma proteins trigger a myriad of biological processes: they tweak immune responses, alter metabolism, and even spur—or hinder—new connections in the brain.

They’re also a bridge between our genetics and health.

Ever since first mapping the human genome, scientists have tried to link genetic typos to health and disease. It’s a tough problem. Some of our most troubling health concerns—cancer, heart and vascular disease, and dementia and other brain disorders—are influenced by multiple genes working in concert. Diet, exercise, and other lifestyle factors muddle gene-to-body connections.

The new studies tapped into the UK Biobank, a comprehensive database containing plasma samples from over 500,000 people alongside their health and genetic data.

The research found multiple protein “signatures” in plasma that mapped onto specific parts of the genetic code—for example, rare DNA letter edits that were previously hard to capture. Digging deeper, several plasma protein signatures reflected genetic changes that linked to fatty liver disease. Other associations between gene and plasma predicted blood type, gut health, and other physical traits.

These proof-of-concept examples may bring new medical discoveries. Plasma is easily obtainable through a blood draw. As a translator between genetic and physical profiles, their protein signatures can potentially inform new medications, diagnosis, or treatments.

To be very clear: the trio of studies came from an unexpected coalition—13 biopharmaceutical companies working together in a precompetitive pact. The arrangement is exactly what it sounds like. Instead of competing against each other, the companies are sharing results to solve one of the toughest biological mysteries—how do genes, with a hefty dose of environmental influences, make us who we are.

Pharma Frenemies

Back in 2020, a handful of the world’s most influential pharmaceutical companies made a pact to collaborate on a single endeavor—the Pharma Proteomics Project.

The UK Biobank, one of the world’s largest and most comprehensive biomedical resources, was the core organizer. First launched in 2006, the biobank has grown into an enormous database: So far, over half a million participants in the UK have signed up, including people of diverse ethnicities. The database contains biographical information—age, gender, and health status—and more in-depth measures such as brain scans, gene sequences, and blood tests.

These aren’t just clinical blood tests to check your mineral or hormone levels. Using blood samples, the Biobank has a full profile of each participant’s plasma protein.

Over the last few years, with consent from the volunteers, the Biobank has released their dataset to scientists. All genetic data were scraped of information that could trace back to any volunteer.

The massive dataset caught big pharma’s eye. Plasma proteins are easy to collect and analyze, making them perfect for diagnosing diseases. Deciphering how they work in the body could also help researchers discover potential disease targets.

Dr. Naomi Allen, chief scientist of the UK Biobank, agreed. “Measuring protein levels in the blood is crucial to understanding the link between genetic factors and the development of common life-threatening diseases,” she said when the project launched in 2020.

“With data on genetic, imaging, lifestyle factors and health outcomes over many years, this will be the largest proteomic [a collection of all proteins] study in the world to be shared as a global scientific resource.”

A Bloody Good Link

The consortium paid off.

In one study, from Biogen and collaborators, the team took a first step toward linking genetic diversity to health status.

Every human shares similar genes, but these genes vary in their precise lettering. A single-letter DNA swap can lead to inherited diseases, such as sickle cell. Other times, a gene copies itself when it’s not supposed to causing deadly neurological problems such as Huntington’s disease.

Yet how most genetic typos contribute to health largely remains a mystery.

Here, the team analyzed nearly 3,000 plasma proteins from 54,219 UK Biobank participants along with their genetic profiles. The proteins were selected to best capture a person’s general health status, including their heart health, metabolism, inflammation, brain function, and any cancer indicators.

Overall, they unearthed roughly 16 million single-letter DNA letter swaps that mapped to more than 3,700 different locations in the genome. Called “genomic loci,” these sites are extremely valuable for bridging genetic data to proteins associated with diseases. Compared to previous studies, 81 percent of these gene-to-protein associations are new.

Meanwhile, the plasma proteins formed a “fingerprint” of sorts, allowing scientists to predict a person’s age, sex, body mass index, blood groups, and even kidney and liver functions.

In one test using the plasma “fingerprint,” the team discovered a genetic network that boosts immune cell function. Other tests found an intriguing link between blood type and gut health and decoded how genetic variations affect immune responses in different people.

In other words, the team built a genetic atlas that maps onto the plasma protein universe.

Rare Genetics Swaps and Broader Ancestry

Another study called the plasma-genetics screen by its name: proteogenomic.

Led by AstraZeneca, the team mined the same biobank dataset for rare genetic variants that link to changes in plasma proteins and diseases. Integrating the two could help solve “disease mechanisms, identify clinical biomarkers, and discover drug targets,” the team said.

Scanning through the biobank, they found over 5,400 rare associations between genes and plasma protein signatures. In an early Halloween twist, two genes especially stood out: STAB1 and STAB2. Normally thought to be involved in clearing off old plasma proteins, the genes also surprisingly associated with dozens of protein partners, suggesting they have other roles.

“What’s exciting about this research is that we are now able to link these high-impact rare genetic variants to effects on the human plasma proteome,” said study author Dr. Slavé Petrovski with AstraZeneca and the University of Melbourne.

The coalition also bolstered genetic diversity in research. Most studies that associate genes to diseases are based on people from European ancestry.

Here, the third study focused on Biobank participants of either British or Irish, African and South Asian ancestries to reveal genetic “hotspots.” They then matched those data with a dataset previously collected from an Icelandic population. There’s a “modest correlation,” said the team, adding that differences in technology could have altered results—something to consider going forward.

Linking genes to proteins to health has always been a difficult game of biomedical telephone. With plasma proteins as a guide, we may have a proxy to bridge genetics to health and disease. The consortium has made all data publicly available for other research teams to explore.

Image Credit: National Institutes of Health