Richard Border of the University of Colorado at Boulder and his colleagues picked the 18 candidate genes that have been most commonly linked to depression—SLC6A4 chief among them. Using data from large groups of volunteers, ranging from 62,000 to 443,000 people, the team checked whether any versions of these genes were more common among people with depression. “We didn’t find a smidge of evidence,” says Matthew Keller, who led the project.

Between them, these 18 genes have been the subject of more than 1,000 research papers, on depression alone. And for what? If the new study is right, these genes have nothing to do with depression. “This should be a real cautionary tale,” Keller adds. “How on Earth could we have spent 20 years and hundreds of millions of dollars studying pure noise?”

“What bothers me isn’t just that people said [the gene] mattered and it didn’t,” wrote the pseudonymous blogger Scott Alexander in a widely shared post. “It’s that we built whole imaginary edifices on top of this idea of [it] mattering.” Researchers studied how SLC6A4 affects emotion centers in the brain, how its influence varies in different countries and demographics, and how it interacts with other genes. It’s as if they’d been “describing the life cycle of unicorns, what unicorns eat, all the different subspecies of unicorn, which cuts of unicorn meat are tastiest, and a blow-by-blow account of a wrestling match between unicorns and Bigfoot,” Alexander wrote.

Read: Why are so many teen athletes struggling with depression?

Border and Keller’s study may be “bigger and better” than its predecessors, but “the results are not a surprise,” says Cathryn Lewis, a geneticist at Kings College London. Warnings about the SLC6A4/depression link have been sounded for years. When geneticists finally gained the power to cost-efficiently analyze entire genomes, they realized that most disorders and diseases are influenced by thousands of genes, each of which has a tiny effect. To reliably detect these minuscule effects, you need to compare hundreds of thousands of volunteers. By contrast, the candidate-gene studies of the 2000s looked at an average of 345 people! They couldn’t possibly have found effects as large as they did, using samples as small as they had. Those results must have been flukes—mirages produced by a lack of statistical power. That’s true for candidate-gene studies in many diseases, but Lewis says that other researchers “have moved on faster than we have in depression.”

Marcus Munafò of the University of Bristol remembers being impressed by the early SLC6A4 research. “It all seemed to fit together,” he says, “but when I started doing my own studies in this area, I began to realize how fragile the evidence was.” Sometimes the gene was linked to depression; sometimes it wasn’t. And crucially, the better the methods, the less likely he was to see such a link. When he and others finally did a large study in 2005—with 100,000 people rather than the 1,000 from the original 1996 paper—they got nothing.