Largest study of its kind finds 16 genetic variants linked to depression in women and eight in men
Women may be more genetically predisposed to depression than men, according to a major international study that has identified significant differences in the genetic architecture of the disorder between sexes.
The research, published in Nature Communications and led by Australia’s QIMR Berghofer Medical Research Institute, is the largest genetic study to date examining sex differences in major depressive disorder (MDD). It found 16 genetic variants associated with depression in women, compared with eight in men, suggesting that women carry a higher burden of genetic risk.
Dr Brittany Mitchell, a senior researcher at QIMR Berghofer’s genetic epidemiology laboratory, said the findings could help explain why women are twice as likely as men to experience depression during their lifetime. “We already know depression manifests differently from one person to another,” she said. “Until now, there hasn’t been much consistent research to explain why depression affects females and males differently — including the possible role of genetics.”
The study analysed DNA from more than 480,000 people across five international cohorts in Australia, the Netherlands, the United States, and the United Kingdom. Of these, 130,471 women and 64,805 men had been diagnosed with major depression, while 159,521 women and 132,185 men formed the control group.
While many of the genetic variants were shared between sexes, researchers found evidence of female-specific variants that may partly explain women’s greater susceptibility. These differences, the authors suggested, could be a “key component of the biological mechanisms underlying sex disparities in depression”.
The study also revealed that genetic links between depression and metabolic traits — such as body mass index (BMI) and metabolic syndrome — were stronger in women. Lead researcher Dr Jodi Thomas said these correlations might explain why women with depression more frequently experience metabolic symptoms, including weight changes, fatigue, and energy fluctuations.
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Beyond genetics, the researchers emphasised that environmental, behavioural, and social factors still play major roles. Men, for instance, are often less likely to seek help for mental health issues, leading to underdiagnosis, while women are more frequently exposed to sexual abuse, interpersonal violence, and chronic stress, which increase vulnerability to depression.
“These factors highlight the need for a multifaceted approach to understanding depression,” the authors wrote. “However, our findings suggest that differences in genetics form an important part of the puzzle.”
The researchers acknowledged limitations, noting that the study’s participants were exclusively of European ancestry, which means the results may not generalise across other populations. They also pointed out that roughly twice as many women as men were included among those diagnosed with depression, although statistical analyses were conducted to ensure the findings were not simply due to sample size differences.
Independent experts have hailed the study as a breakthrough in understanding why depression affects the sexes differently. Professor Philip Mitchell, from the University of New South Wales, who was not involved in the research, said the findings provide “strong evidence” that biology plays a larger role than previously believed.
“There has been a longstanding debate about why depression is more common in females, with most theories focused on social and psychological explanations,” he said. “This large-scale genetic study provides compelling evidence that biological factors also contribute significantly. The discovery of more risk regions in female genomes than in males, and the limited overlap between them, suggests sex-specific mechanisms may be at play.”
Professor Mitchell added that such discoveries could eventually lead to sex-specific treatments for depression. “As the biological systems coded by these genetic regions become better understood, it may be possible to tailor pharmacological therapies to target these differences,” he said.
The research offers new hope for improving diagnosis and treatment, while reaffirming that depression is not a uniform illness — but a complex condition shaped by an intricate balance of genetics, biology, and lived experience.