Filling the gaps: connecting genes to diseases through proteins – EurekAlert

Posted: October 17, 2021 at 5:15 pm

image:By creating a genome-proteome map scientists have uncovered hundreds of novel connections between different human diseases. view more

Credit: Omicscience This figure has been generated with

Hundreds of connections between different human diseases have been uncovered through their shared origin in our genome by an international research team led by scientists from the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge, challenging the categorisation of diseases by organ, symptoms, or clinical speciality.

A new study published in Science today generated data on thousands of proteins circulating in our blood and combined this with genetic data to produce a map showing how genetic differences that affect these proteins link together seemingly diverse as well as related diseases.

Proteins are essential functional units of the human body that are composed of amino acids and coded for by our genes. Malfunctions of proteins cause diseases across most medical specialties and organ systems, and proteins are also the most common target of drugs that exist today.

The findings published today help explain why seemingly unrelated symptoms can occur at the same time in patients and suggest that we should reconsider how diverse diseases can be caused by the same underlying protein or mechanism. Where a protein is a drug target, this information can point to new strategies for treating a variety of conditions, as well as minimising adverse effects.

In the study using blood samples from over 10,000 participants from the Fenland study, the team led by senior author Dr Claudia Langenberg at the MRCEpidemiology Unit and Berlin Institute of Health at Charit Universittsmedizin, Germany, demonstrated that natural variation in 2,500 regions of the human genome is very robustly associated with differences in abundance or function of 5,000 proteins circulating in the blood.

This approach addresses an important bottleneck in the translation of basic science to clinically actionable insights. While large scale studies of the human genome have identified many thousands of variants in our DNA sequence that are associated with disease, underlying mechanisms remain often poorly understood due to uncertainties in mapping those variants to genes. By linking such disease-related DNA variations to the abundance or function of an encoded protein, the team produced strong evidence for which genes are involved, and identified novel mechanisms by which proteins mediate genetic risk into disease onset.

For example, multiple genome-wide association studies (GWAS) have linked a region of the human genome known as KAT8 with Alzheimers disease but failed to identify which gene in this region was involved. By combining data on both proteins and genes the team was able to identify a gene in the KAT8 region named PRSS8, which codes for the protein prostasin, as a novel candidate gene in Alzheimers disease. Similarly, they identified a novel risk gene for endometrial cancer (RSPO3).

The authors used these new insights to systematically test which of these protein-encoding genes affected a large range of diseases. They discovered more than 1,800 examples in which more than one disease was driven by variations in an individual gene and its protein products. What emerged was a network-like structure of human diseases, because many of the genes connected a range of seemingly diverse as well as related conditions in different tissues. This provides strong evidence that the respective protein is the origin, and points to new potential strategies for treatment.

Dr Langenberg explained:

An extreme example we discovered of how one protein can be connected to several diseases is the protein Fibulin-3, which we connected to 37 conditions, including hypermobility, hernias, varicose veins, and a lower risk of carpal tunnel syndrome. A likely explanation is atypical formation of elastic fibres covering our organs and joints, leading to differences in elasticity of soft and connective tissues. This is also in line with features that others have observed in mice where this gene was deleted.

Dr Maik Pietzner, a researcher at the MRC Epidemiology Unit and co-lead author of the study, added:

Using our genome as the basis was key to the success of this study. Because we know that most of the proteins detected in blood have their origin in cells from other tissues, we integrated different biological layers, like gene expression, to enable us to traceproteins back to disease-relevant tissues. For example, we found that higher activity of the enzyme bile salt sulfotransferase was associated with an increased risk of gall stones through a liver specific mechanism. We linked around 900 proteins to their tissue of origin in this way.

In collaboration with colleagues at the Helmholtz Centre in Munich, Germany, the authors have developed a bespoke web application ( to enable immediate dissemination of the results, and allow researchers worldwide to dive deeply into information on genes, proteins and diseases they are most interested in.

Dr Eleanor Wheeler, also at the MRC Epidemiology Unit and co-lead author of the study, concluded:

For most genomic regions associated with disease risk, the underlying causal gene and mechanism are not known. Our work demonstrates the distinctive value of proteins to zoom in on the causal gene for a disease and helps us to understand the mechanism through which genetic variation can cause disease. We envisage that the large amount of information we are sharing with the scientific community will help ongoing and emerging efforts to connect genes to diseases more directly via the encoded protein, thus facilitating accelerated identification of drug targets.


Pietzner M., Wheeler E., et al. Mapping the proteo-genomic convergence of human diseases. Science 2021;14 Oct 2021; DOI:10.1126/science.abj1541


About the MRC Epidemiology Unit

The MRC Epidemiology Unit is a department at the University of Cambridge. It is working to improve the health of people in the UK and around the world.

Obesity, type 2 diabetes and related metabolic disorders present a major and growing global public health challenge. These disorders result from a complex interplay between genetic, developmental, behavioural and environmental factors that operate throughout life. The mission of the Unit is to investigate the individual and combined effects of these factors and to develop and evaluate strategies to prevent these diseases and their consequences.

About the University of Cambridge

The University of Cambridge is one of the worlds top ten leading universities, with a rich history of radical thinking dating back to 1209. Its mission is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence.

The University comprises 31 autonomous Colleges and 150 departments, faculties and institutions. Its 24,450 student body includes more than 9,000 international students from 147 countries. In 2020, 70.6% of its new undergraduate students were from state schools and 21.6% from economically disadvantaged areas.

Cambridge research spans almost every discipline, from science, technology, engineering and medicine through to the arts, humanities and social sciences, with multi-disciplinary teams working to address major global challenges. Its researchers provide academic leadership, develop strategic partnerships and collaborate with colleagues worldwide.

The University sits at the heart of the Cambridge cluster, in which more than 5,300 knowledge-intensive firms employ more than 67,000 people and generate 18 billion in turnover. Cambridge has the highest number of patent applications per 100,000 residents in the UK.

About the Medical Research Council

The Medical Research Council is at the forefront of scientific discovery to improve human health. Founded in 1913 to tackle tuberculosis, the MRC now invests taxpayers money in some of the best medical research in the world across every area of health. Thirty-three MRC-funded researchers have won Nobel prizes in a wide range of disciplines, and MRC scientists have been behind such diverse discoveries as vitamins, the structure of DNA and the link between smoking and cancer, as well as achievements such as pioneering the use of randomised controlled trials, the invention of MRI scanning, and the development of a group of antibodies used in the making of some of the most successful drugs ever developed. Today, MRC-funded scientists tackle some of the greatest health problems facing humanity in the 21st century, from the rising tide of chronic diseases associated with ageing to the threats posed by rapidly mutating micro-organisms. The Medical Research Council is part of UK Research and Innovation.

Observational study


Mapping the proteo-genomic convergence of human diseases


Robert A. Scott and Adrian Cortes are current employees and/or stockholders of GlaxoSmithKline. ERG receives an honorarium from the journal Circulation Research of the American Heart Association as a member of the Editorial Board. Stephen O'Rahilly has received remuneration for consultancy services provided to Pfizer Inc, Astra Zeneca, ERX Pharmaceuticals, GSK, Third Rock Ventures and LG Life Sciences. All other authors declare that they have no competing interests.

Filling the gaps: connecting genes to diseases through proteins - EurekAlert

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