New research on depression has debunked decades of work that singled out individual genes responsible for the major mood disorder.

That's not to say depression isn't passed on through families - but it means that any genes that might play a role aren't acting alone.

The analysis of more than 620,000 individuals by researchers from across the US represents the largest and most comprehensive study of its kind. After an intensive search, the team came up empty handed.

"This study confirms that efforts to find a single gene or handful of genes which determine depression are doomed to fail," says geneticist Richard Border from the University of Colorado Boulder.

Its conclusion is a massive blow for any clinical agencies hoping to create diagnostic tools and treatments based on the belief that depression is the result of something as simple as a few broken genes.

For more than 20 years, researchers have suspected chronic mood disorders such as anxiety and depression have their roots in malfunctioning cell transport systems in the brain.

Digging deeper, genes responsible for regulating the uptake of neurotransmitters such as serotonin have attracted much of the blame, leading to suspicions that a mutation or two, and perhaps timely exposure to trauma, is all it takes to be at risk of a serious mental illness.

A number of studies in recent years have sifted through gene banks in search of possible relationships between mood disorders and genetic 'tweaks' called single nucleotide polymorphisms, finding no shortage of candidates.

It's an alluring idea, promising that genetic screening could tell us who might benefit from tailored pharmaceuticals targeting the deficiency.

Maybe it's too good to be true after all.

"Any time someone claims to have identified the gene that 'causes' a complex trait is a time to be sceptical," says Border.  

The researchers didn't test every DNA change ever claimed to be responsible for depression – just the 18 most likely candidates, which have appeared at least 10 times in the literature.

Scanning through databases belonging to 23andMe, the Psychiatric Genomics Consortium, and the UK Biobank, the researchers amassed a genetic sample covering more than half a million individuals.

They included various measures of mood disturbance and applied an array of statistical measures to zero in on potential links between those 18 genetic differences and depression.

The researchers even took into account the potential for variations that required some sort of environmental trigger, such as socioeconomic adversity or sexual abuse. Nothing stood out.

"We found that, as a set, these candidate genes are no more related to depression than any random gene out there," says Matthew Keller, a neuroscientist from the University of Colorado Boulder.

"We are not saying that depression is not heritable at all. It is. What we are saying is that depression is influenced by many, many variants, and individually each of those has a minuscule effect."

That means we still have good reason to keep studying our DNA for causes of depression, but we can't just focus on single genes - instead, researchers need to look for networks acting in collaboration.

Failure to find such simple links isn't the fault of geneticists, the researchers are quick to point out. Hypotheses based on basic relationships between behaviour and candidate genes are widely known to be flawed.

But other fields have been less critical, they claim, keeping hope alive that we'll find examples of a 'depression gene'. It's time to move on.

"It's like in 'The Emperor Wears No Clothes.' There's just nothing there," says Keller.

"I hope this is the final nail in the coffin for those kind of studies."

This research was published in the American Journal of Psychiatry.