A large international genetic study has concluded that men and women share much of the same risk for anxiety, but that distinct genetic pathways operate in each sex. Researchers identified sex-specific routes that could help explain why anxiety manifests and is reported differently by females and males. The work is published in Psychological Medicine.
The study analysed genetic and health data from 455,487 individuals of European ancestry drawn from the UK Biobank and the All of Us programmes. In a first combined analysis, the team compared people with a history of anxiety to those without mental distress and identified 56 genetic variants linked to anxiety.
Researchers then split the dataset by sex, with 281,831 women and 173,656 men. They found 21 variants associated with anxiety in women and five in men, with only a single variant overlapping between the two groups.
In assessing heritability, the scientists found that men appear to require a higher overall genetic and environmental burden before developing clinical anxiety, suggesting a higher threshold for expression. By contrast, when heritability was calculated based on population prevalence, the genetic contribution seemed greater in women.
Mapping the variants to genes revealed strikingly different biological pathways. In women, the anxiety-linked genes were heavily involved in chromatin regulation and olfactory transduction, the latter reflecting the biology of smell processing. Olfactory signals are processed in the amygdala, a brain region central to stress responses, a link that aligns with prior observations of heightened smell sensitivity in some women with anxiety.
Among men, the implicated genes primarily pertain to lipoprotein metabolism—how fats are transported and processed in the body. The researchers note that stress responses naturally mobilise energy resources, and sex hormones influence metabolic processing differently in men and women, offering a biological explanation for divergent anxiety presentations.
The team then examined how genetic risk for anxiety overlaps with other psychiatric and health traits. Female anxiety showed stronger correlations with attention-deficit/hyperactivity disorder (ADHD) risk and higher body mass index (BMI). Clinically, ADHD and anxiety often co-occur in women, and the authors suggest that some female ADHD presentations may primarily involve anxiety symptoms, potentially leading to underdiagnosis of ADHD in women.
For men, the genetic risk for anxiety correlated more strongly with waist-to-hip ratio adjusted for BMI, a measure of central fat distribution. This finding ties back to the earlier male-specific involvement of lipoprotein pathways and supports sex-differentiated metabolic links to anxiety.
To test predictive value, the researchers created polygenic scores based on the sex-specific data and tested them in three independent cohorts—a general population group, a symptom-based group, and a clinical cohort with depression. The female-derived score best predicted anxiety in women within the general population. In men, the female- and male-derived scores performed similarly, and when sample sizes were balanced to account for the smaller male group, the only statistically significant difference was that the female-derived score predicted anxiety in women more accurately than the male-derived one.
The authors acknowledge limitations. The male sample was smaller, reducing statistical power to detect male-specific variants, so larger studies are needed to clarify sex differences or commonalities. All data were limited to individuals of European ancestry, which may limit applicability to broader populations. The researchers advocate for more diverse cohorts and continued sex-stratified analyses to refine understanding of psychiatric genetics.
Overall, the study argues against merging male and female data in genetic analyses of anxiety, suggesting that separate analyses reveal important, sex-specific signals. The work, titled Unravelling sex differences in the genetic architecture of anxiety, was led by Jihua Hu and Brittany L. Mitchell, with colleagues from the QIMR Berghofer Medical Research Institute and The University of Queensland, Australia.
