Scientists have raised hopes for more effective treatments for depression, a condition that affects over 300 million people globally, after mapping out the genetic foundations of the mental disorder in unprecedented detail. In the world’s largest investigation into the impact of DNA on the mental disorder, more than 200 researchers identified 44 gene variants that raise the risk of depression. Of those, 30 have never been connected to the condition before. By tripling the number of gene regions linked to depression, scientists now hope to understand more about why the disorder strikes some but not others, even when they have similar life experiences. The work could also help in the search for drugs to treat the condition which affects as many as one in four people over a lifetime. “If you have a lower genetic burden of depression, perhaps you are more resistant to the stresses we all experience in life,” said Cathryn Lewis, professor of statistical genetics and a senior author on the study at King’s College London.
Previous work with twins suggests that genetics explains about 40% of depression, with the rest being driven by other biological factors and life experiences. If people are ranked according to the number of genetic risk factors for depression they carry, those in the top 10% are two-and-a-half times more likely to experience depression than those in the bottom 10%, Lewis said. While the scientists found 44 gene variants linked to depression, these are only a small fraction of the total, because many more will have had too small an effect to be discovered in the latest study. “We know that thousands of genes are involved in depression with each having a very modest effect on a person’s risk,” said Lewis. “There is certainly no single gene for depression.”
Clinical depression is a debilitating condition the causes of which are still largely unknown. According to the World Health Organization, it is the leading cause of disability globally, costing the global economy as much as $1tn annually with no country on the planet immune. Sufferers can experience a range of “losses” – of appetite, mood, sleep, concentration, love, joy, enthusiasm, energy and serenity. As many as 3% of people with major depressive disorder attempt suicide. But there are few new treatments in the pipeline, as big pharmaceuticals companies have largely withdrawn from expensive research into the next generation of anti-depressants.
In the study, the researchers pooled seven separate datasets from the UK, the US, Iceland and Denmark, to glean genetic information on 135,000 people who reported having depression, and 345,000 mentally healthy individuals. The scientists then compared DNA across the groups to find gene variants that were more common in those with depression. The work, published in Nature Genetics, revealed a substantial overlap in the genetics that underpins depression and other mental disorders such as anxiety, schizophrenia and bipolar disorder, but also body mass index, where DNA that predisposes people to obesity also raises the risk of depression. As expected, many of the genes reported in the study have a role in how neurons grow, operate and send signals around the brain, where two regions are known as the prefrontal cortex, and the anterior cingulate cortex are the most important for depression. Gerome Breen, a co-author on the paper, said that some of the gene variants they found are linked to neurotransmitters such as serotonin, which existing antidepressants work on. But other gene variants point to new biological mechanisms that the next generation of drugs might target. “What we’ve had in recent decades is a shortage of new mechanisms that underlie depression and psychiatric disorders,” he said. “The hope is that in new data we identify new processes that can be targeted by newly developed types of drugs, which have different mechanisms of action to existing medications.”
It will take more research to confirm that the gene variants found in the study are linked to depression. Many of the participants involved in the research self-reported depression, which is far less reliable than a clinical diagnosis. This means that some of the gene variants the scientists link to depression could turn out not to be involved in the disorder. Jonathan Flint, who studies the genetics of depression at the University of California in Los Angeles said: “Our current treatments for depression are relatively ineffective – roughly speaking, only about half of patients improve – so we need better therapies. To discover new treatments and to deliver the ones we have more effectively, we need a better understanding of what causes depression. Finding genetic risk variants is a way to do just that – the risk variants point to genes that are involved in the disease, and thus provide clues to how depression arises.”
Credit: Ian Sample for The Guardian, 26 April 2018.