Researchers identify female-specific and male-specific genetic risks for anxiety

Men and women share much of the underlying genetic risk for anxiety, but researchers have now identified distinct genetic pathways specific to each sex. These biological differences help explain why females and males often experience and report anxiety in different ways. The findings were published in Psychological Medicine.

Anxiety disorders, which include generalized anxiety, panic disorders, specific phobias, and agoraphobia, are among the most common mental health conditions worldwide. They affect nearly a third of the global population at some point in their lives. Females are diagnosed with anxiety disorders at roughly twice the rate of males.

Men and women also tend to display different symptoms. Females more frequently report internalizing symptoms and experience depression alongside their anxiety. Males often exhibit externalizing behaviors and are more likely to use substances as a coping strategy.

Past research on these differences has often focused on cultural norms, hormonal fluctuations, or differences in brain activation. Studies examining the genetic roots of anxiety have yielded mixed results, with some suggesting stronger genetic influences in females and others finding equal risk. Previous genome-wide studies generally combined data from men and women, an approach that can hide genetic risks applying exclusively to one sex.

Lead authors Jihua Hu and Brittany L. Mitchell, researchers at the QIMR Berghofer Medical Research Institute and The University of Queensland in Australia, conducted a massive study to see if common genetic factors operate differently in men and women. They analyzed genetic and health data from 455,487 individuals of European ancestry using the UK Biobank and the All of Us research programs.

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The team first conducted a combined analysis of the entire group. They compared the genetic profiles of individuals with a history of anxiety against those without any mental distress diagnoses. In this group, the researchers identified 56 specific genetic variants associated with anxiety. Genetic variants are slight differences in the DNA sequence that occur naturally between individuals.

Following this initial analysis, the team separated the data to run distinct tests for males and females. The female group included 281,831 individuals, and the male group included 173,656 individuals. The researchers found 21 genetic variants associated with anxiety in females, compared to just five in males. Only a single genetic variant overlapped between the two groups.

The team then calculated the heritability of anxiety for both groups. They found that males exhibit a higher overall threshold for developing the disorder. This indicates that men generally require a greater accumulation of genetic vulnerability and environmental factors to cross the threshold into clinical anxiety. When calculating heritability based on real-world population prevalence, the overall genetic contribution appeared higher in females.

To understand the biological functions of these genetic variants, the researchers mapped them to specific genes. They discovered entirely different biological pathways associated with anxiety in men compared to women. In females, the identified genes were heavily involved in chromatin regulation and olfactory transduction.

Chromatin regulation is a cellular process that packages DNA and controls gene expression, which can influence how sensitive an individual is to environmental stressors. Olfactory transduction involves the body’s ability to process smells.

Evolutionarily, the sense of smell is tightly linked to threat detection and survival. Odor information is processed directly in the amygdala, a brain region central to stress responses. Previous psychological studies have shown that women with anxiety often report heightened sensitivity to smells, a finding that aligns with these genetic associations.

In males, the genes tied to anxiety were primarily involved in lipoprotein metabolism. Lipoproteins help transport and process fats in the body. When a person experiences stress, the body typically mobilizes energy resources, often increasing lipoprotein levels as part of a physical fight-or-flight response. Because male and female metabolisms process fats differently due to sex hormones, these genetic variations provide a biological rationale for why anxiety might manifest differently in men.

The researchers next compared the genetic risk for anxiety against the genetic profiles of 28 other mental and physical health conditions. They wanted to see if the genetic predisposition for anxiety overlaps with the predisposition for other traits. This analysis revealed several sex-specific correlations.

The genetic risk for anxiety in females was strongly correlated with the genetic risk for attention-deficit/hyperactivity disorder (ADHD) and a higher body mass index (BMI). In clinical settings, ADHD and anxiety frequently co-occur in females. The researchers noted that female ADHD might manifest predominantly as anxiety symptoms, which can sometimes result in ADHD being overlooked or misdiagnosed in women.

The link to general body mass index also aligns with past epidemiological studies showing that obesity and anxiety are more strongly linked in women, as well as neuroimaging research finding that higher BMI is associated with stronger stress-related brain responses in women. Conversely, the genetic risk for male anxiety showed a stronger association with waist-to-hip ratio adjusted for BMI. This metric reflects central body fat rather than overall weight.

Central fat distribution is more closely tied to insulin regulation and the specific lipoprotein metabolism pathways identified earlier in the male genetic data. In a final step, the researchers used the genetic variants to create polygenic scores, which are numerical estimates of a person’s genetic liability for a trait. They tested these scores in three independent cohorts, which included a general population group, a symptom-based group, and a clinical cohort of patients with depression.

A score generated from the female genetic data proved best at predicting anxiety in other women within the general population. When attempting to predict male anxiety, the female-derived score and the male-derived score performed similarly. Once the researchers mathematically matched the sample sizes to account for the smaller number of men, the only statistically significant difference was that the female-derived score predicted anxiety in women better than the male-derived score in the general population cohort; the other predictive differences between the male and female scores were not statistically significant.

The study does have a few limitations that require context. The male sample size was smaller than the female sample size, which reduces the statistical power to detect genetic variants in men. The researchers note that larger samples will be needed to clarify sex differences or commonalities.

The dataset also relied exclusively on individuals of European ancestry. As a result, the findings might not accurately reflect the genetic architecture of anxiety in other global populations. The researchers recommend that future genetic studies include larger and more diverse groups of people. By continuing to analyze male and female data separately, scientists can build a more accurate understanding of psychiatric conditions.

Standard approaches that blend male and female data run the risk of oversimplifying human biology and masking important genetic signals. The study, “Unravelling sex differences in the genetic architecture of anxiety,” was authored by Jihua Hu, Michelle K. Lupton, Enda M. Byrne, Nicholas G. Martin, David C. Whiteman, Catherine M. Olsen, Jodi T. Thomas, Sarah E. Medland, Katrina L. Grasby, and Brittany L. Mitchell.