Neuroticism and adversity dominate depression and anxiety risk in UK Biobank study

By Dr. Liji Thomas, MDReviewed by Lauren HardakerJun 25 2026

A 13-year UK Biobank analysis suggests that neuroticism, adversity, and other psychosocial pressures may explain more of the population burden of depression and anxiety than physiological risk factors alone.

Study: Associations of modifiable risk factors with depression and anxiety in women and men: evidence from the UK Biobank. Image Credit: manka_web / Shutterstock

Given the high global burden of depression and anxiety, it is important to understand the relative importance of modifiable risk factors. A recent 'Article in Press' in the journal Translational Psychiatry found that psychosocial factors had the largest estimated contribution to the population burden of depression and anxiety in both sexes.

Background

Approximately 332 million people are living with depression worldwide as of 2021, and 359 million with anxiety, across all age groups. Both disorders emerge in early life, are often chronic, and can impair social, educational, and occupational functioning, as well as reduce quality of life.

Their management costs are high, and they reduce economic and social productivity. However, they can be treated if diagnosed early, highlighting the need for early recognition and preventive strategies.

Multiple factors have been linked to the origin of these disorders, including physiological, psychosocial, metabolic, and female-specific reproductive factors. For instance, individuals with adverse childhood experiences (ACEs) are more likely to develop anxiety and depression.

Sex-specific differences have long been recognized in these conditions, with women being nearly twice as likely to be diagnosed, with more severe symptoms and earlier onset. These differences may partly reflect biological, hormonal, reproductive, social, and behavioral differences over the female life course.

In the current study, the researchers examined modifiable physiological, psychosocial, and female-specific reproductive factors for their influence on the long-term risk of depression and anxiety in women and men. They calculated the population-attributable fraction (PAF), the proportion of disease cases in a population that could theoretically be prevented if a particular risk factor were eliminated, assuming it caused the outcome, for each factor. This provides quantitative estimates of the impact of these factors at the population level, helping to shape policy priorities.

The study employed data from 87,648 UK Biobank participants followed up for a median of 13.7 years. Participants were free of depression or anxiety at baseline. Over the follow-up, 5.7% of women and 4.2% of men developed depression. For anxiety, the corresponding figures were 6% and 3.6%, respectively.

Psychosocial factors were the strongest contributors

Among the factors studied, neuroticism symptoms, meaning elevated neuroticism-related traits rather than a clinical diagnosis, showed the greatest potential contribution to the overall burden of depression, based on PAF estimates. The PAF for depression was 49%-60%, while for anxiety, the PAFs ranged from 52% to 54%.

Women with neuroticism symptoms were 2.6-fold more likely to develop depression, and men were 3.5-fold more likely. For anxiety, the corresponding figures were 2.8-fold and 2.9-fold, respectively. The authors suggest that, despite women being more prone to neuroticism, the association between neuroticism and depression was stronger in men, possibly because of a lower psychological threshold or reduced emotional regulation capacity.

Other important contributors were adverse experiences in childhood and adulthood. For depression, these had PAFs of about 18% to 25%, while for anxiety, their PAFs were lower, at about 11% to 14%. Such events could disrupt stress responses and cause emotional dysregulation, making the individual more prone to depression and anxiety. The authors note that the higher prevalence among women might reflect their increased exposure to such situations, especially at home, and their tendency to internalize such stress.

Unhealthy lifestyle habits such as poor sleep, smoking, and sedentary behavior also increased the risk of depression and anxiety, along with low socioeconomic status. These associations were more pronounced in men, perhaps reflecting the clustering of unhealthy behaviors and less frequent use of stress-reducing or help-seeking behaviors.

Taken together, psychosocial factors contributed 61% of the PAF for depression in women, and 67% for men. They contributed 60% of the PAF for anxiety in women, and 56.8% in men. Notably, psychosocial factors continued to contribute substantially to the PAF across all age groups.

Physiological factors

Among physiological factors, obesity had the largest contribution to the PAF for depression, at 15% in both sexes. It was associated with a 33% higher risk among obese women, versus 25% higher for men. This may reflect the two-pronged risk posed by obesity, in terms of both metabolic and psychosocial stress.

Obesity is also associated with chronic inflammation. It also contributes to insulin resistance and other adverse metabolic effects, all of which may mediate a higher depression risk.

Chronic inflammation was associated with increased risks of both depression and anxiety in women and men. The PAFs for depression ranged from 6%-7%, and from 3%-5% for anxiety. This agrees with evidence of central endocrine dysregulation and immune disruption with chronic inflammation, potentially contributing to depression or anxiety.

Diabetes also increased the risk of depression in both sexes, but with PAFs <3%.

Taken together, physiological factors contributed 21% to 22% of the PAF for depression, but less so to anxiety. Across age groups, obesity contributed most to depression burden among participants aged under 60, while chronic inflammation contributed across all age groups. For anxiety, physiological contributions were generally modest at younger ages but increased in later life. The combined PAFs for depression were higher in women aged 55-59 years and in men aged 60-64 years.

Women-specific reproductive factors

Hormone replacement therapy (HRT) showed the largest individual reproductive-factor PAFs, at 13% for depression and 9% for anxiety. However, this was reported as ever use, and more granular exposure data are essential before this can be properly interpreted.

Early menarche, a history of pregnancy termination, and early age at first birth were other notable contributors to depression. For anxiety, HRT remained the leading reproductive factor, while a history of pregnancy termination made a modest contribution.

The combined PAF for reproductive factors and depression was 19%, with the greatest impact being in later life. For anxiety, however, the combined reproductive-domain PAF was minimal, at 0.13%, suggesting that this domain was more relevant to depression than to anxiety.

Additive combined PAF

With all factors combined, the PAF for depression was 68% in women and 70% in men. For anxiety, the corresponding PAFs were 61% and 58%, respectively.

Health implications

These findings indicate the importance of considering sex-specific factors, as well as broad emotional traits, physiological parameters, and psychosocial factors, in assessing mental health risks. These findings suggest that targeting modifiable psychosocial, lifestyle, and physiological factors could potentially reduce the population burden of depression and anxiety, although the estimates are theoretical.

Potential strategies include interventions targeting trauma and socioeconomic stress, and screening for mental health in chronic disease, older age groups, and in women at transition points like menopause.

Strengths and limitations

The study used data from the large-scale prospective UK Biobank cohort with granular data on health and risk factors. The researchers incorporated a wide range of modifiable risk factors across multiple areas of health. They used PAF estimates to provide actionable population-level impact figures. They also stratified by age and sex to identify the most vulnerable groups.

That said, “the estimated PAFs should be interpreted as indicative of potential population-level relevance rather than as precise causal effects.”

The study has several limitations. Being observational, causal inferences cannot be derived. Multiple sources were used to assess depression and anxiety, potentially introducing misclassification error. Retrospective self-reporting of adverse childhood or adult experiences could also have led to recall bias.

A large proportion of participants did not provide complete data, reducing the sample size, which could have affected the final estimates and, perhaps, limited the generalizability of the findings.

The estimates were based on a yes/no categorization for several variables, which could have prevented the observation of dose-response relationships. Unmeasured confounding could still affect the final estimates. The large number of statistical comparisons increases the possibility of chance findings. The UK Biobank is not representative of the general population.

Conclusions

The study underlines the contribution of multiple modifiable physiological, psychosocial, and reproductive factors to the risk of depression and anxiety in middle-aged and older adults.

The findings revealed the substantial role of psychosocial factors, in particular neuroticism and adversity. Finally, combined PAFs of around 58% to 70% indicate the potential for prevention, if these risk factors can be effectively addressed. This would require using “sex-sensitive, life course-oriented strategies that integrate psychological, metabolic, and reproductive health considerations into mental health prevention and clinical practice.”

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