|
|
| PMID |
|
|
| TITLE |
|
| Unravelling sex differences in the genetic architecture of anxiety. |
|
| ABSTRACT |
|
| BACKGROUND |
NlmCategory: BACKGROUND |
| Anxiety disorders show striking sex differences in prevalence, symptoms, and clinical characteristics, shaping how they manifest and are experienced. |
| METHODS |
NlmCategory: METHODS |
| 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. |
| RESULTS |
NlmCategory: RESULTS |
| 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. |
| CONCLUSIONS |
NlmCategory: CONCLUSIONS |
| 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. |
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| DATE PUBLISHED |
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| HISTORY |
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| PUBSTATUS |
PUBSTATUSDATE |
| medline |
2026/06/11 12:41 |
| pubmed |
2026/06/11 06:38 |
| entrez |
2026/06/11 04:13 |
| pmc-release |
2026/06/11 |
|
| AUTHORS |
|
| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Hu J |
|
Hu |
Jihua |
J |
|
Brain and Mental Health Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. |
| Lupton MK |
|
Lupton |
Michelle K |
MK |
|
School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia. |
| Byrne EM |
|
Byrne |
Enda M |
EM |
|
Child Health Research Centre, University of Queensland, Brisbane, QLD, Australia. |
| Martin NG |
|
Martin |
Nicholas G |
NG |
|
Brain and Mental Health Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. |
| Whiteman DC |
|
Whiteman |
David C |
DC |
|
Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. |
| Olsen CM |
|
Olsen |
Catherine M |
CM |
|
Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. |
| Thomas JT |
|
Thomas |
Jodi T |
JT |
|
Brain and Mental Health Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. |
| Medland SE |
|
Medland |
Sarah E |
SE |
|
School of Psychology and Counselling, Queensland University of Technology, Brisbane, QLD, Australia. |
| Grasby KL |
|
Grasby |
Katrina L |
KL |
|
School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia. |
| Mitchell BL |
|
Mitchell |
Brittany L |
BL |
|
School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia. |
|
| INVESTIGATORS |
|
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| JOURNAL |
|
| VOLUME: 56 |
| ISSUE: |
| TITLE: Psychological medicine |
| ISOABBREVIATION: Psychol Med |
| YEAR: 2026 |
| MONTH: Jun |
| DAY: 11 |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 1469-8978 |
| ISSNTYPE: Electronic |
|
| MEDLINE JOURNAL |
|
| MEDLINETA: Psychol Med |
| COUNTRY: England |
| ISSNLINKING: 0033-2917 |
| NLMUNIQUEID: 1254142 |
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| PUBLICATION TYPE |
|
| PUBLICATIONTYPE TEXT |
| Journal Article |
| Meta-Analysis |
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| COMMENTS AND CORRECTIONS |
|
|
| GRANTS |
|
| GRANTID |
AGENCY |
COUNTRY |
| APP2017176 |
National Health and Medical Research Council |
|
| APP1173025 |
National Health and Medical Research Council |
|
| APP1172917 |
National Health and Medical Research Council |
|
| APP2025674 |
National Health and Medical Research Council |
|
| APP2026567 |
National Health and Medical Research Council |
|
| 1198304 |
National Health and Medical Research Council |
|
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| GENERAL NOTE |
|
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| KEYWORDS |
|
| KEYWORD |
| anxiety |
| genetics |
| genome-wide association study |
| polygenic risk scores |
| sex differences |
| sex-linked |
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| MESH HEADINGS |
|
| DESCRIPTORNAME |
QUALIFIERNAME |
| Female |
|
| Humans |
|
| Male |
|
| Anxiety |
genetics |
| Anxiety Disorders |
epidemiology |
| Attention Deficit Disorder with Hyperactivity |
genetics |
| Genetic Risk Score |
genetics |
| Genome-Wide Association Study |
genetics |
| Multifactorial Inheritance |
genetics |
| Polymorphism, Single Nucleotide |
genetics |
| Sex Characteristics |
genetics |
| Sex Factors |
genetics |
| United Kingdom |
epidemiology |
| United States |
epidemiology |
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| SUPPLEMENTARY MESH |
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| GENE SYMBOLS |
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| CHEMICALS |
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| OTHER ID's |
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