Researchers from Semmelweis University identified a possible link between depression, the sense of smell and the immune system, with their findings recently published in the journal Translational Psychiatry. The new study shows that certain gene variants in olfactory receptors and the immune system may lead to some people being predisposed to depression. More than 700,000 people commit suicide each year, and depression is a major global health burden. The latest findings could open up new and more targeted pathways in the treatment of depression. 

People with certain characteristics and gene variants could potentially respond to “smell training” in depression treatment – the new study suggests.

Using UK Biobank, Semmelweis researchers have analysed the data of 324,451 depressed and healthy individuals (174,572 women and 149,879 men), aiming to identify subgroups with higher and lower risk of developing depression.

They used a so-called two-step cluster analysis run separately in males and females, with neuroticism (a tendency to experience negative emotions), body fat percentage, and years spent in education as input variables. Then, genome-wide association analyses were conducted within each resulting cluster, with lifetime depression as the outcome. 

They found that a high body fat percentage and lower education were associated with a higher risk of depression in both sexes, with women also having a higher tendency to negative emotions (frequent anxiety, sadness, anger). In contrast, better-educated participants with lower body fat percentage who experienced negative emotions less often, were less prone to the condition.

According to the World Health Organisation, 5% of the adult population, around 280 million people, suffer from depression, and more than 700,000 people commit suicide globally each year. 

Depression is 50% more common in women than in men, according to WHO data.

“Major depressive disorder (MDD) is a common and heavily debilitating psychiatric condition, with high rates of treatment resistance, which poses an urgent need for the identification of reliable biomarkers that characterise distinct subgroups of patients with distinct therapeutic needs” – the study says.

“We chose those four variables (sex, neuroticism, body fat percentage, education) because they have already been associated individually with the development of depression. However, their possible effects have not been examined together,” said Dr. Nóra Eszlári, assistant research fellow at Semmelweis University’s Department of Pharmacodynamics and the paper’s first author.

“Most research uses the symptoms of depressed patients as a starting point”, she adds. “We aimed to group participants from the general population (both healthy and depressed individuals) by characteristics that put them at risk of developing the disease. Therefore, our results may also be useful in preventing this debilitating condition.”

After identifying the high- and low-risk groups using a data-driven method, the researchers examined the genetics of depression in these groups. They discovered a link between some common gene variants and depression – but only in women, not in men.

For women in the higher-risk group (negative emotionality, high body fat percentage, lower education), specific gene variants in the immune system (e.g. rs526266 or rs7530503) showed an association with the development of depression. This means that if women in the higher-risk group also carry the identified gene variants, they are more likely to develop depression.

For women in the lower-risk group, a similar association has been found between specific olfactory gene variants (e.g. rs61957879) and depression. In other words, women who experience negative emotions less frequently, have a low body fat percentage with a higher education level, plus carry certain gene variants associated with smell – are also more likely to develop depression.  

“It has been known for some time that there may be a reciprocal, two-way relationship between depressive symptoms and olfactory function. There is even literature on the effects of so-called olfactory training on depression. However, research has shown mixed results. One study found that “smell training” was ineffective in depressed patients, but in other studies, such therapy improved symptoms in dementia patients and mildly depressed elderly people.

Our results may help identify a subgroup where olfactory training may effectively prevent or treat depression,

explains Dr Eszlári.

“Smell training” or olfactory training treats the loss of smell, most commonly after a viral infection. Patients retrain their brains by actively sniffing the same scents every day.

Another significant advantage of the study’s approach is that instead of using expensive tests and scans (brain imaging, electrophysiology, genetics) as a starting point, they grouped the participants based on quickly and cheaply assessable characteristics (questionnaire, body fat measurement) and then examined the genetics narrowing it down to the specific subgroups. If other research teams replicate the results in different samples, this approach could make it easier and more cost-effective to identify and treat patient groups in the future.

Photo: Balint Barta – Semmelweis University; Cover photo (illustration

Notes to editors:

UK Biobank is a large-scale biomedical database and research resource containing de-identified genetic, lifestyle and health information and biological samples from half a million UK participants. It is the most comprehensive and widely-used dataset of its kind, and is globally accessible to approved researchers who are undertaking health-related research that is in the public interest, whether they are from academic, commercial, government or charitable settings. UK Biobank is helping to advance modern medicine and enable better understanding of the prevention, diagnosis, and treatment of a wide range of serious and life-threatening illnesses – including cancer, heart disease and stroke. Over 30,000 researchers from more than 90 countries are registered to use UK Biobank and more than 10,000 peer-reviewed papers have been published as a result. UK Biobank is supported by Wellcome and the Medical Research Council, as well as the British Heart Foundation, Cancer Research UK, the UK Government’s National Institute for Health and Care Research and Department of Science, Innovation and Technology, Griffin Catalyst and Schmidt Futures.