Genetics & Genomics

October 21, 2021

Study links genetic variants, protein expression and human diseases

An international research team has developed a new resource that connects genetic variants and protein expression, which is expected to speed the identification of genes that cause disease — and point to novel treatment strategies.

An international research team has connected genetic information and data on thousands of proteins circulating in the blood to develop a gene-protein-disease atlas. The new resource, reported Oct. 14 in the journal Science, shows how genetic variants that regulate protein expression may underlie both related and diverse human diseases.

Eric Gamazon, PhD

“This study linking disease-related DNA variation to levels or function of proteins is the largest of its kind,” said Eric Gamazon, PhD, MS, assistant professor of Medicine in the Division of Genetic Medicine and an author of the Science report. “The resulting dataset will serve as an important resource for the scientific community to stimulate studies on how proteins mediate genetic risk into disease onset.”

Over the years, investigators around the world have used large-scale genome-wide association studies (GWAS) to identify thousands of genetic variants associated with a range of complex diseases, such as cardiovascular disease, type 2 diabetes and Alzheimer’s disease.

“Identifying the underlying biological mechanisms for all of these disease-associated variants remains a critical challenge,” said Gamazon, who is also an investigator in the Vanderbilt Genetics Institute.

The new effort seeks to identify potential causal disease genes by linking the impact of genetic variants to protein expression levels. It builds on the Genotype-Tissue Expression (GTEx) resource of RNA expression in a broad collection of human tissues. Gamazon served as co-chair of the GWAS Working Group of the GTEx Consortium and led a study that integrated disease association data and gene expression in 44 human tissues.

The current study, led by Claudia Langenberg, MD, PhD, used blood samples from over 10,000 participants in the United Kingdom. The researchers identified 2,500 regions of the human genome that are significantly associated with interindividual differences in the amount of 5,000 protein targets circulating in the blood.

The network of protein-gene-disease connections anchors diseases in their shared genetic causes, providing new opportunities for mechanistic understanding and for the identification of treatment strategies that target the underlying genetic causes.

Because participants of the current study were mostly of European ancestry, additional studies are needed to explore the gene-protein-disease network in ethnically diverse populations, Gamazon said.

Langenberg, a former visiting scholar at Vanderbilt University Medical Center, is professor of Computational Medicine at the Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Germany and Programme Leader at the MRC Epidemiology Unit, University of Cambridge, UK.

To facilitate exploration of protein targets, the research team created an interactive online resource ( The study was supported in part by grants from the National Institutes of Health (HG010718, HG011138, GM140287, AG068026). Gamazon is a Life Member of Clare Hall, University of Cambridge, which has facilitated his work on the study.