Psychiatry · Medical Literature
Unravelling sex differences in the genetic architecture of anxiety.
Abstract
Anxiety disorders show striking sex differences in prevalence, symptoms, and clinical characteristics, shaping how they manifest and are experienced. Here, we report the first sex-specific meta-analysis of genome-wide association studies (GWAS) of anxiety, leveraging two of the largest biobank datasets, UK Biobank and All of Us, comprising 85,042 female cases with 196,789 controls and 36,732 male cases with 136,924 controls. Functional annotation, sex-specific polygenic scores (PGS), and genetic correlations were performed to assess genetic differences and functional implications. In females, 21 lead SNPs were significantly associated with anxiety, compared to five in males. Although the genetic correlation between sexes was high, it was significantly different from one, indicating partially distinct genetic architectures. In addition, both the SNP-based observed and liability-scale heritabilities (assuming a 2:1 female-to-male prevalence ratio) were significantly higher in females. Gene-based tests and functional prioritization identified different genes associated with anxiety in females and males. Moreover, genetic correlation analyses revealed stronger associations of female anxiety with attention-deficit/hyperactivity disorder (ADHD) and body mass index (BMI), whereas male anxiety showed stronger correlations with waist-hip-ratio-adjusted BMI. While the overall genetic architecture of anxiety is largely shared, our findings reveal distinct sex-specific genetic associations and correlations, highlighting the value of analyzing the sexes separately to uncover genetic signals that may be masked in sex-combined samples.
Clinical relevance
Does the genetic architecture of anxiety differ meaningfully between females and males, and can sex-stratified genome-wide association study (GWAS) meta-analysis identify sex-specific loci, heritability differences, and divergent genetic correlations with other traits? __SNAPSHOT__ {"studyDesign":"Sex-stratified GWAS meta-analysis (first sex-specific meta-analysis of anxiety GWAS)","setting":"Multi-national biobank; UK Biobank (United Kingdom) and All of Us Research Program (United States); research institute–based genomic analysis at QIMR Berghofer Medical Research Institute, Brisbane, Australia","sampleSize":"Total n=454,487 (European ancestry): females — 85,042 cases, 196,789 controls; males — 36,732 cases, 136,924 controls (as reported in the published abstract; note: the intermediate preprint v2 reported slightly different denominators of 85,014 female cases/130,817 controls and 36,724 male cases/117,044 controls — exact final figures should be verified in the full published text)","population":"Adults of European ancestry with lifetime anxiety (cases identified via self-reported diagnosis, relevant hospital diagnoses, and diagnostic criteria); controls defined as individuals without a history of anxiety","intervention":"Sex-stratified genome-wide association study meta-analysis; functional annotation, sex-specific polygenic scores (PGS), and LD-score regression genetic correlations performed as downstream analyses","comparator":"Female-specific GWAS vs. male-specific GWAS; cross-sex genetic correlation and PGS cross-prediction used to quantify similarity and difference","primaryOutcome":"Identification of genome-wide significant SNPs (lead SNPs) associated with lifetime anxiety in females and males separately; SNP-based heritability (observed and liability-scale); cross-sex genetic correlation; sex-specific genetic correlations with 28 external traits","followUp":"Not applicable (cross-sectional genetic association study)","fundingSource":"Government/non-profit: National Health and Medical Research Council of Australia (NHMRC) Investigator Grants and Research Excellence Grants; QIMR PhD scholarship. No industry funding declared. Authors declare no conflicts of interest."}
Key findings
In the published meta-analysis, 21 genome-wide significant lead SNPs were identified in females compared to 5 in males — a roughly 4-fold difference in the number of associated loci, likely reflecting greater statistical power in the female stratum given the larger sample size rather than necessarily indicating a biologically 4-fold richer genetic signal. The cross-sex genetic correlation was high but was statistically significantly different from 1.0, indicating that female and male anxiety share largely but not entirely the same common-variant genetic architecture. Both SNP-based observed and liability-scale heritabilities (estimated assuming a 2:1 female-to-male prevalence ratio) were significantly higher in females than in males. Gene-based tests and functional prioritization identified different sets of genes in females and males. Genetic correlation analyses with 28 external traits revealed 7 traits with statistically significant sex differences (Z-test p < 0.05): female anxiety showed stronger genetic correlations with ADHD, metabolic syndrome, BMI, and lower educational attainment, while male anxiety showed stronger correlations with bipolar disorder (overall, type I, and type II). Sex-specific PGS showed the expected directional pattern of stronger same-sex prediction, but these differences did not reach statistical significance across validation cohorts. Specific heritability point estimates, confidence intervals, and formal p-values for individual SNP associations are not reported in the abstract and were not available in the search results for this summary; they should be extracted from the full published text. NNT/NNH: not applicable (genetic association study).
Practice implications
This study establishes for the first time at a large biobank meta-analysis scale that the genetic architecture of lifetime anxiety is partially sex-differentiated: heritability is significantly higher in females, the cross-sex genetic correlation is significantly less than 1.0, distinct sets of genes are implicated in each sex, and genetic correlations with several comorbid conditions (notably ADHD, metabolic syndrome, and BMI in females; bipolar disorder in males) differ by sex. These findings provide molecular-genetic corroboration for the well-recognized clinical observation that anxiety disorders manifest differently in women and men. However, several important qualifications apply. First, the substantially larger female sample (≈4:1 case ratio) confers considerably greater power in the female stratum, and the greater number of significant female loci (21 vs. 5) may in part reflect this power imbalance rather than purely biological sex differences — a limitation the authors acknowledge. Second, this study does not establish that sex-specific genetic variants are clinically actionable or that polygenic risk scores should be sex-stratified in current clinical practice; PGS cross-sex predictive ability did not differ significantly. Third, all findings are restricted to individuals of European ancestry derived from biobank cohorts, which are not fully representative of the general population, limiting generalizability to other ancestral groups and to clinical populations. Fourth, anxiety was defined using a composite of self-report and ICD-based hospital diagnoses; the degree to which findings apply to specific DSM-5 anxiety disorder subtypes (GAD, panic disorder, social anxiety, etc.) is not established. Fifth, this is a published journal article based on what was available; only the abstract was fully accessible for this summary — the full paper should be consulted for complete statistical details. __LIMITATIONS__ Substantially smaller male sample relative to female sample markedly reduces statistical power in males, making direct comparison of locus counts between sexes difficult to interpret causally.,All analyses restricted to individuals of European ancestry from UK Biobank and All of Us; findings may not generalize to other ancestral populations or healthcare systems.,UK Biobank and All of Us are volunteer-based biobank cohorts with known healthy-volunteer bias, limiting representativeness of the general clinical population.,Anxiety phenotyping used a composite of self-report, hospital diagnoses, and diagnostic criteria across two different biobanks, introducing phenotypic heterogeneity and precluding disorder-specific conclusions (e.g., GAD vs. panic disorder vs. phobias).,PGS cross-prediction differences between sexes did not reach statistical significance, suggesting that genome-wide polygenic signal is largely shared — the identified differences may be driven by a small number of loci with heterogeneous effects.,Cross-sex genetic correlation significantly less than 1.0 is a necessary but not sufficient demonstration of clinically meaningful biological sex differences in anxiety genetics; effect sizes at individual loci may still be modest.,Liability-scale heritability estimates depend on assumed population prevalence ratios (2:1 female-to-male); misspecification of this assumption could affect conclusions about heritability differences.,Genetic correlations with external traits used sex-combined (not sex-specific) GWASs for most comparator traits, which may attenuate detection of sex-differentiated genetic relationships.,No independent replication cohort for sex-stratified results is described in the abstract; replication of the sex-specific loci is needed.,Causal inference is not possible from GWAS design; identified loci tag genomic regions and do not directly implicate specific biological mechanisms. __BOTTOM_LINE_CATEGORY__ potentially_practice_informing __BOTTOM_LINE__ This first large-scale sex-stratified GWAS meta-analysis of anxiety demonstrates that females and males share a largely but not entirely common genetic basis for anxiety, with females exhibiting significantly higher SNP heritability, more genome-wide significant loci, and distinct genetic correlations with ADHD, metabolic syndrome, and BMI compared to males, while males show stronger genetic links to bipolar disorder. These findings support a sex-differentiated approach to anxiety genetics research but do not yet warrant changes to clinical risk stratification, pharmacogenomic practice, or treatment selection. Replication in ancestrally diverse samples and disorder-specific analyses are needed before sex-stratified polygenic risk tools can be considered for clinical translation.