Recent research has identified a substantial genetic overlap between the risk of developing major depressive disorder and the biological regulation of testosterone levels. The analysis suggests that the hereditary factors influencing total testosterone and a specific protein that transports sex hormones share a negative correlation with the genetic risk for depression. These findings were published in the journal BMC Psychiatry.

Depression is a pervasive mental health condition marked by persistent sadness and a loss of interest in daily activities. While environmental and psychological stressors play a role in its development, biological factors are also primary drivers. Researchers have observed that depression occurs roughly twice as often in women as in men. This disparity has led scientists to suspect that sex hormones may influence the disorder. Testosterone is one of the primary sex hormones in humans. It affects various aspects of physical and mental health.

Previous observational studies have attempted to link testosterone levels to depression, but the results have been inconsistent. Some data suggest that low testosterone in men correlates with depressive symptoms. Other studies indicate that high testosterone in premenopausal women is associated with depression. This contradiction makes it difficult to determine if the hormone causes the mood disorder or if the two simply co-occur due to other factors.

To address this uncertainty, researchers are increasingly looking at the genetic blueprints that dictate both hormone levels and depression risk. By examining DNA, scientists can bypass the fluctuations of daily hormone levels to see if the underlying biological architecture is shared. Wen Lu, a researcher at The First Affiliated Hospital of Xi’an Jiaotong University in China, served as the first author on a study investigating this genetic connection. The correspondence for the study was addressed to Jian Yang, a researcher at the same institution.

The team focused on three specific traits related to testosterone. The first trait was total testosterone, which refers to the aggregate amount of the hormone in the blood. The second trait was sex hormone-binding globulin, or SHBG. This is a protein that latches onto testosterone and transports it throughout the body. When testosterone is bound to SHBG, the body cannot immediately use it. The third trait was bioavailable testosterone. This represents the fraction of the hormone that is either free-floating or loosely bound, making it easily accessible for the body’s tissues to use.

The researchers utilized data from genome-wide association studies to conduct their analysis. A genome-wide association study involves scanning the genomes of many people to find genetic variations associated with a particular disease or trait. For the depression data, Lu and colleagues used a massive dataset from the Psychiatric Genomics Consortium. This dataset included genetic information from hundreds of thousands of individuals of European ancestry. For the testosterone and SHBG data, they accessed the UK Biobank, a similarly large biomedical database.

The team employed a statistical method known as linkage disequilibrium score regression to estimate genetic correlations. This technique allows researchers to determine if the genetic variants associated with one trait correlate with the variants associated with another. They also used a method called MiXeR. This tool helps estimate the total number of genetic variants shared between two traits, regardless of whether the correlation is positive or negative.

The analysis revealed a negative genetic correlation between major depressive disorder and total testosterone. This means that the genetic variants associated with higher levels of total testosterone tend to be associated with a lower risk of depression. A similar negative correlation appeared between depression and SHBG. However, the researchers found a negligible genetic correlation between depression and bioavailable testosterone. This lack of connection for the bioavailable form was unexpected given the other results.

Beyond simple correlations, the study uncovered an extensive polygenic overlap. The term polygenic refers to a trait that is influenced by many different genes rather than just one. The researchers estimated that approximately 49 percent of the genetic variants that influence total testosterone also influence the risk of major depressive disorder. For SHBG, roughly 32 percent of the variants overlapped with depression risk. This suggests that the biological pathways regulating these hormones are deeply intertwined with the pathways involved in mood regulation.

To identify the specific locations on the genome responsible for this overlap, the team used a statistical framework called the conjunctional false discovery rate. This method identified a range of 28 to 79 genomic loci shared between depression and the testosterone traits. A genomic locus is a specific fixed position on a chromosome where a particular gene or genetic marker is located.

One specific locus stood out in the analysis. A gene known as NT5C2 was simultaneously associated with total testosterone, SHBG, and major depressive disorder. NT5C2 encodes an enzyme that helps maintain the balance of nucleotides within cells. Nucleotides are the basic building blocks of DNA and RNA. Previous research has linked this gene to other psychiatric conditions, such as schizophrenia. Its presence here suggests it may play a broad role in brain function and mental health.

The researchers also performed a functional annotation to understand what these shared genes actually do in the body. They looked at the biological pathways where these genes are most active. A biological pathway is a series of actions among molecules in a cell that leads to a certain product or change. The analysis showed that the genes shared by depression and testosterone traits were predominantly enriched in immune-related pathways.

This connection to the immune system aligns with existing theories about depression. Scientists have long noted that people with depression often exhibit signs of inflammation and immune system activation. Glucocorticoids are steroid hormones that regulate immune responses. They are released by the hypothalamic-pituitary-adrenal axis, or HPA axis. The HPA axis is the body’s primary stress response system.

The study authors propose that the HPA axis acts as a bridge between testosterone regulation and depression. Long-term stress can dysregulate the HPA axis. This dysregulation leads to abnormal release of glucocorticoids. Testosterone acts as a negative feedback inhibitor for this system. This means testosterone helps tell the HPA axis to calm down. If the genetic factors regulating testosterone are faulty, the HPA axis may remain overactive. An overactive HPA axis is a known contributor to the development of depressive symptoms.

There are limitations to this study that require consideration. The genetic data used in the analysis came primarily from populations of European ancestry. Genetic associations found in one ancestral group do not always translate perfectly to others. The findings may not fully apply to populations in Asia, Africa, or other regions.

Another limitation involves the complexity of age and sex differences. The relationship between testosterone and mood can change as people age. It also differs fundamentally between males and females. The current genetic analysis pooled data in a way that makes it difficult to parse these specific demographic nuances.

The study also focused on genetic predisposition rather than real-time hormone levels. While genetics provide a blueprint, environmental factors heavily influence actual hormone levels and mental health status. Knowing that a genetic correlation exists does not predict with certainty who will develop depression based on their hormonal genetics.

Future research will need to explore the biological mechanisms of the identified genes. The discovery of the NT5C2 gene’s involvement provides a concrete target for laboratory experiments. Scientists must determine exactly how this gene influences both hormone transport and mood regulation in brain cells.

The findings also open new avenues for understanding why some patients do not respond to standard antidepressants. Current treatments primarily target neurotransmitters like serotonin. If a subset of depression cases is driven more by hormonal and immune dysregulation, different treatment strategies might be necessary.

This research reinforces the idea that mental health disorders are systemic issues involving the whole body. The separation between “brain” disorders and “hormonal” disorders is becoming increasingly blurred. By mapping the shared genetic architecture, scientists are slowly assembling a more complete picture of human physiology.

The study, “Exploring the shared genetic architecture between testosterone traits and major depressive disorder,” was authored by Wen Lu, Xiaoyan He, Huan Peng, Pu Lei, Jing Liu, Yuanyuan Ding, Bin Yan, Xiancang Ma, and Jian Yang.