But a new study—the biggest and most comprehensive of its kind yet—shows that this seemingly sturdy mountain of research is actually a house of cards, built on nonexistent foundations.
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 miniscule 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 Munafo from 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nothing.e University, who did early influential work on SLC6A4, notes that the candidate-gene approach has already been superseded by other methods. “The relative volume of candidate-gene studies is going way down, and is highly likely to be trivial indeed,” she says. Border and Keller disagree. Yes, they say, their geneticist colleagues have largely abandoned the approach, which is often seen as something of a historical embarrassment. “But we have colleagues in other sciences who had no idea that there was even any question about these genes, and are doing this research to this day,” Border says. “There’s not good communication between sub-fields.” (A few studies on SLC6A4 and depression have even emerged since their study was published in March.)