Previous research has linked RNF123 with changes in the hippocampus, which is known to be altered in people with the condition, although it has not been linked with major depression before.
Led by Dr David Glahn, Yale University and Hartford Hospital's Institute of Living, the team looked to combine previous research on alterations in brain structure and function as measured by MRI, and gene expression patterns in post-mortem brain tissue that sought to identify the genes responsible.
By doing this, they hoped to find the gene capable of building the "whole picture" of the condition.
Dr John Krystal, Editor of Biological Psychiatry, which published the research, said: "We assume that the biological measures are closer mechanistically to the underlying disease processes in the brain.
"Yet, ultimately we are interested in the subjective experiences and functional impairment associated with mental illness."
In the past, techniques such as volumetric brain measurements using magnetic resonance imaging (MRI) and the patterns of gene expression in white blood cells were used to identify the biology underpinning the condition.
The research had two key goals, to describe a new method for ranking measures of brain structure and function on their genetic importance for an illness, and to indentify a candidate gene for major depression.
Major depression is characterised by a combination of physical, behavioural and emotion symptoms which impact a person's ability to eat, work, sleep and enjoy life. The symptoms can occur once, twice or several times during a person's life time.
It's hoped that the new research into RNF123 could offer a future potential target for treatment.
"We still have more work before we truly believe this is a home-run gene, but we've got a really good candidate. Even that has been tough to do in depression," Dr Glahn said.