byQIMR Berghofer Medical Research Institute

Miami plot of sex-stratified genome-wide association study (GWAS) meta-analysis of Major Depressive Disorder (MDD), with female and male meta-analyses shown on the top and bottom, respectively. Credit:Nature Communications(2025). DOI: 10.1038/s41467-025-63236-1

Important genetic differences in how females and males experience depression have been revealed for the first time in findings that could pave the way for more targeted intervention and treatments.

In the study,publishedinNature Communications, scientists found thatgenetic factorscontribute more todepressionrisk infemalesthan in males. The team discovered about twice as many genetic "flags" for depression in the DNA of females as they did in that of males.

"We already know that females are twice as likely to suffer from depression in their lifetime than males," said Dr. Brittany Mitchell, Senior Researcher at QIMR Berghofer's Genetic Epidemiology Lab. "And we also know that depression looks very different from one person to another. 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 team identified about 7,000 changes in the DNA that could cause depression in both sexes, and about a further 6,000 DNA changes (a total of 13,000) that could cause depression in females only.

Researcher Dr. Jodi Thomas said the study also pinpointed how depression could show up differently for females and males.

The team found that the genetic factors linked to depression overlap more with those associated with metabolic traits in females.

"We found somegenetic differencesthat may help explain why females with depression more often experience metabolic symptoms, such as weight changes or altered energy levels."

The global study is the largest of its kind to look at males and females in this way. Scientists analyzed DNA from hundreds of thousands of people with and without depression, including around 130,000 females and 65,000 males with depression. The changes in DNA the scientists have identified are genetic differences people are born with, not changes that happen because oflife experiences.

Traditionally, most drug trials and therapies are tested on males, but Drs Mitchell and Thomas hope their work will also translate to a greater clinical understanding of female depression.

"Unpacking the shared and unique genetic factors in males and females gives us a clearer picture of what causes depression—and opens the door to more personalized treatments," Dr. Thomas said.

The findings highlight the importance of considering sex-specific genetic influences in studying depression and other health conditions.

In the spirit of advancing scientific knowledge in this area, Drs. Thomas and Mitchell have also made their results publicly available, allowing other scientists to analyze them further.

More information: Jodi T. Thomas et al, Sex-stratified genome-wide association meta-analysis of major depressive disorder, Nature Communications (2025). DOI: 10.1038/s41467-025-63236-1 Journal information: Nature Communications

Provided by QIMR Berghofer Medical Research Institute