The results of a genome-wide meta-analysis of genetic data from more than two million individuals has linked 102 genetic variants and 269 genes with depression, and found associations between the psychiatric disorder and a number of behavioral traits. The researchers, headed by a team at the University of Edinburgh, say their study results offer new insights into the genetic basis of depression, and could lead to new treatment approaches.

“These findings are further evidence that depression is partly down to our genetics,” commented lead investigator Andrew McIntosh, PhD, professor of biological psychiatry and a senior clinical research fellow at the University of Edinburgh Centre for Clinical Brain Sciences. The international team, including scientists in the U.K., Europe, the U.S., and Australia, reported the findings in Nature Neuroscience, in a paper titled “Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of prefrontal brain regions.”

Depression is the leading cause of disability worldwide, and an estimated 1 in 6 people will develop depression during their lifetime, the authors wrote. While there is a heritable component to the disorder, depression is a polygenic trait that is influenced by many different genetic variants, each of which will only have a very small effect, they noted. “Therefore, to enable the detection of causal genetic variants associated with depression, there is a need to study very large numbers of individuals.”

To maximize their sample size, McIntosh, et al., carried out a genome-wide meta-analysis of depression using anonymized data from 807,553 individuals (246,363 cases and 561,190 controls) in the three largest available study resources: the UK Biobank, 23andMe, and the Psychiatry Genomics Consortium. Their initial analyses identified 102 independent genetic variants that were independently linked with depression, and which were validated in an independent sample of another 1,507,153 individuals.

Depression often occurs in parallel with other diseases, and the study results indicated genetic correlations between depression and 41 other behavioral and disease traits, including schizophrenia, bipolar disorder, coronary artery disease, body fat, and waist-to-hip ratio. While many of the genetic correlations had been reported previously, “a novel genetic correlation was observed for age at menopause,” the team commented, “potentially indicating a shared genetic architecture between depression and earlier female reproductive life events.” Novel genetic correlations were also observed between depression and Crohn’s disease, and depression and starting smoking at an earlier age. Using a statistical approach known as Mendelian randomization to assess causation between these relationships, the team found a significant causal effect of neuroticism on depression, indicating that neuroticism may lead people to become depressed.

“There is an ever-growing body of evidence that there are shared genetic components between behavioral and psychiatric disorders,” the team commented. “… using the meta-analyzed results in the current study, this notion was evidenced by significant genetic correlations for depression with neuroticism, anorexia nervosa, attention deficit hyperactivity disorder (ADHD), schizophrenia,  and bipolar disorder.”

Further genetic and gene set analyses using the genetic analysis tool MAGMA identified 269 putative genes and 15 gene sets that were associated with depression. Interestingly, enrichment analysis and the gene set analysis also provided evidence that prefrontal brain regions may play a significant role in depression.

Subsequent evaluation of the 269 depression-linked genes for interactions with prescribed drugs in the Drug Gene Interaction Database identified hundreds of interactions between 57 genes and 514 drugs. The researchers pointed out that the drug interaction findings suggest that there are many already available drugs that could target the genetic component of depression, or which may provide unpredicted benefits or have adverse effects in people with the disorder. “Further, our work highlights other potential druggable genes associated with depression that are not, to our knowledge, currently associated with antidepressant treatment or mood-associated adverse effects,” they noted.

“These findings advance our understanding of the underlying genetic architecture of depression and provide novel avenues for future research,” the researchers concluded. “This large study is an important advance in understanding how genetic variability might contribute to risk for depression, stated Raliza Stoyanova, senior portfolio developer for neuroscience and mental health at The Wellcome Trust, which, together with the Medical Research Council, provided funding for the study. “Given that current treatments work for only half of those who need them, the study provides some intriguing clues for future research to follow up—for example, that biological pathways involved in developing the condition may not be the same as those involved in responding to treatment.”

“The power of this big genetic study is that it can point to systems in the brain which adds to our currently limited understanding in this area,” added Sophie Dix, who wasn’t involved in the reported work but is research director at mental health charity MQ. “This study adds to the weight of evidence that genes are one of the key risk factors in depression, which is also impacted by life events such as social environment and trauma. The value of this could really be seen when looking into the development of personalized treatments … We have seen very little advancement in nearly 50 years for people living with depression and right now the avenues available are not working for everyone … By increasing our understanding of these systems, and how the social environment affects biological risk factors, we can begin to identify new targets for treatments that could help the millions of people worldwide affected by depression.”

The University of Edinburgh team is now inviting people with depression in Scotland to take part in the Genetic Links to Anxiety and Depression (GLAD) study. “We hope that by launching the GLAD study, we will be able to find out more about why some people are more at risk than others of mental health conditions, and how we might help people living with depression and anxiety more effectively in future,” McIntosh explained.

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