Megan Skelton

Twin studies reveal high genetic overlap between anxiety disorders and depression, contributing to the internalising spectrum. Some genetic specificity for fear-based anxiety disorders (fear), distinct from general anxiety and depression (distress), has also emerged. Limited datasets with detailed phenotyping across anxiety disorders have restricted most genome-wide association studies (GWAS) to “any anxiety diagnosis”. Additional genome-wide evidence to discern genetic differences between fear and distress is required. We conducted GWAS meta-analyses of fear (panic, agoraphobia, specific phobia, social anxiety disorder) and generalised anxiety disorder (GAD), measured using brief single-item and detailed symptom-based diagnoses from three datasets. We explored two control group criteria: phenotype-specific (fear/GAD) or broader anxiety/depression screening. We identified one independent genome-wide significant locus and three gene-level associations with fear (up to 35,523 N _cases ; 157,447 N _controls ). Four genome-wide significant loci and three gene-level associations were identified for GAD (up to 60,879 N _cases ; 117,064 N _controls ). The genetic correlation between fear and GAD was significantly different from unity only when excluding a depression-enriched dataset and using phenotype-specific control screening (r _g = 0.87; P = 9.32 × 10 ⁻³ ). Most complex traits had statistically similar genetic correlations with fear and GAD, including depression. Exceptions included general cognitive ability, educational attainment, and coronary artery disease, showing statistically stronger genetic correlations with fear than GAD, while bipolar disorder type I, anorexia nervosa, and neuroticism displayed the opposite pattern. Our findings partially support a distress-fear genetic distinction, but show stronger evidence for an overarching genetic liability to internalising psychopathology driving comorbidity across anxiety disorders and depression.

Anxiety is heritable and exists on a continuum, with symptoms ranging from adaptive threat response to clinical disorder. Here we performed a genome-wide association meta-analysis of generalized anxiety symptom severity in 693,869 individuals of European ancestry from 14 cohorts. We identified 80 independent genome-wide significant variants within 74 loci, 39 of which were newly associated with anxiety. SNP-based heritability was 5.9% (posterior s.d. = 0.15%). Polygenic scores were significantly associated with anxiety symptom severity and disorder in European, African and South Asian ancestry samples ( R ² = 1.2–2.9%). Significant genetic correlations ( r _g ) were estimated with mental and physical health traits, including case–control anxiety, neuroticism and depression ( r _g = 0.71–0.85), irritable bowel syndrome ( r _g = 0.57), coronary artery disease, endometriosis and migraine ( r _g = 0.20–0.27). Gene-based and pathway analyses implicated synaptic and axonal processes, with enriched expression in the brain. These findings highlight the discovery power gained from analysing a quantitative trait rather than a case–control phenotype in anxiety genetics.

Background: Depression and anxiety are common mental health conditions in the UK. NHS Talking Therapies offers evidence-based therapies and is the largest provider of treatment, yet, only 50% of patients recover. Accurate outcome prediction could identify those at risk of poor outcomes and support more personalised care. This study aimed to develop and internally validate multivariable prediction models using routinely collected data from a large, ethnically diverse sample to enable fair, data-driven treatment decisions. Methods: Data included 30,999 adults who completed high-intensity therapy at a single NHS trust between 2018 and mid-2024. Seven NHS post-treatment outcomes were modelled: reliable improvement, recovery, and reliable recovery for both depression and anxiety, and also functional impairment at the end of treatment. Predictors measured at baseline included sociodemographic and clinical characteristics. Models were developed using elastic net logistic regression and internally validated using bootstrap resampling. Results: The sample was predominantly female (73%) with a median age of 34; 57% identified as White and 22% as Black. Models showed moderate to good discrimination (AUC 0.63–0.77) and strong calibration. Key predictors aligned with clinical expectations, including baseline symptom severity, unemployment, benefit receipt, reporting a disability or long-term condition, psychotropic medication use among other sociodemographic factors. Conclusions: This study highlights the potential of data-driven tools to inform clinical decisions and treatment stratification in NHS Talking Therapies. Early identification of patients less likely to benefit from standard care could support timely review, monitoring, or tailored interventions. External validation and implementation research are needed to ensure generalisability and equity in care.

Twin studies reveal high genetic overlap between anxiety disorders and depression, contributing to the internalising spectrum. Some genetic specificity for fear-based anxiety disorders (fear), distinct from general anxiety and depression (distress), has also emerged. Limited datasets with detailed phenotyping across anxiety disorders have restricted most genome-wide association studies (GWAS) to “any anxiety diagnosis”. Additional genome-wide evidence to discern genetic differences between fear and distress is required. We conducted GWAS meta-analyses of fear (panic, agoraphobia, specific phobia, social anxiety disorder) and generalised anxiety disorder (GAD), measured using brief single-item and detailed symptom-based diagnoses from three datasets. We explored two control group criteria: phenotype-specific (fear/GAD) or broader anxiety/depression screening. We identified one SNP-based independent locus and three gene-level genome-wide significant (GWS) associations with fear (up to 35,523 N _cases ; 157,447 N _controls ). Four GWS SNP-based loci and three gene-level loci were associated with GAD (up to 60,879 N _cases ; 117,064 N _controls ). The genetic correlation between fear and GAD was significantly different from unity only when excluding a depression-enriched dataset and using phenotype-specific control screening (r _g = 0.87; P = 9.32 × 10 ⁻³ ). Most complex traits had statistically similar genetic correlations with fear and GAD, including depression. Exceptions included general cognitive ability, educational attainment, and coronary artery disease, showing statistically stronger genetic correlations with fear than GAD, while bipolar disorder type I, anorexia nervosa, and neuroticism displayed the opposite pattern. Our findings partially support a distress-fear genetic distinction, but show stronger evidence for an overarching genetic liability to internalising psychopathology driving comorbidity across anxiety disorders and depression.

Background: Functional impairment in daily activities, such as work and socializing, is part of the diagnostic criteria for major depressive disorder and most anxiety disorders. Despite evidence that symptom severity and functional impairment are partially distinct, functional impairment is often overlooked. To assess whether functional impairment captures diagnostically relevant genetic liability beyond that of symptoms, we aimed to estimate the heritability of, and genetic correlations between, key measures of current depression symptoms, anxiety symptoms, and functional impairment. Methods: In 17,130 individuals with lifetime depression or anxiety from the Genetic Links to Anxiety and Depression (GLAD) Study, we analyzed total scores from the Patient Health Questionnaire-9 (depression symptoms), Generalized Anxiety Disorder-7 (anxiety symptoms), and Work and Social Adjustment Scale (functional impairment). Genome-wide association analyses were performed with REGENIE. Heritability was estimated using GCTA-GREML and genetic correlations with bivariate-GREML. Results: The phenotypic correlations were moderate across the three measures (Pearson’s r = 0.50–0.69). All three scales were found to be under low but significant genetic influence (single-nucleotide polymorphism-based heritability [h²_SNP] = 0.11–0.19) with high genetic correlations between them (r_g = 0.79–0.87). Conclusions: Among individuals with lifetime depression or anxiety from the GLAD Study, the genetic variants that underlie symptom severity largely overlap with those influencing functional impairment. This suggests that self-reported functional impairment, while clinically relevant for diagnosis and treatment outcomes, does not reflect substantial additional genetic liability beyond that captured by symptom-based measures of depression or anxiety.

Evidence-based psychological treatments for anxiety and depression are widely used, yet roughly half of those treated do not respond. Treatment response prediction could help to optimize patient outcomes and use of clinical resources. However, existing longitudinal studies with potentially valuable predictors are unlikely to include comprehensive, prospective measures of symptoms throughout therapy. Single-item patient ratings of helpfulness and improvement are a potentially cost-effective and efficient alternative, but their relationship with typically used change score measures is unknown. Data were analyzed from 135 participants (124 female sex; 120 female gender; 127 White) who received cognitive-behavioral therapy. Anxiety symptoms (Generalized Anxiety Disorder-7), depression symptoms (Patient Health Questionnaire-9), and impairment (Work and Social Adjustment Scale) questionnaire scores were obtained before therapy (assessment), before each session, and 1-month posttreatment (follow-up). Helpfulness (binary) and improvement (continuous) ratings were collected at follow-up. Linear regression models assessed the relationship between helpfulness and improvement ratings and questionnaire change scores from the first to the last session. Logistic regressions modeled the relationships between single-item measures and National Health Service Talking Therapies outcomes, derived from questionnaire change scores. Helpfulness and improvement showed significant associations with questionnaire change scores as well as National Health Service Talking Therapies outcomes. In a joint model, improvement retained significant associations while helpfulness became nonsignificant. Improvement, and to a lesser extent helpfulness, patient ratings may be a cost-effective alternative for establishing treatment efficacy and outcome. The items' wording and response scales may underlie observed differences. While not equivalent to change score-based measures, they may be adequate for studies requiring large sample sizes. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

We performed a genome-wide association meta-analysis of generalised anxiety symptom severity in 696,563 individuals of European ancestry from 14 cohorts. We identified 82 independent genome-wide significant variants within 76 loci, 41 of which were novel for anxiety. SNP-based heritability was 5.9% (SE = 0.19%). Polygenic scores were significantly associated with anxiety symptom severity and disorder in European, African, and South Asian ancestry samples (r²=1.2%-3.4%). Significant genetic correlations were estimated with numerous mental and physical health traits, including case-control anxiety, neuroticism and depression (r_g=0.71-0.86), irritable bowel syndrome (r_g=0.57), coronary artery disease, endometriosis, and migraine (r_g=0.20-0.27). Gene-based and pathway analyses implicated synaptic and axonal processes, with enriched expression in the brain. These findings highlight the additional value of a dimensional approach in anxiety genetics.

Introductory paragraph: Panic attacks, sudden episodes of intense fear accompanied by physical and psychological symptoms, affect approximately 23% of the population ^1,2 . Panic disorder, diagnosed in 2– 4% ³ , involves recurrent attacks followed by persistent worry about further attacks, leading to functional impairment and avoidance behaviours ^1,2 . We conducted genome-wide association meta-analyses of panic attacks and panic disorder (61,746 and 29,775 cases, respectively, and 105,814 controls), identifying the first genome-wide significant variants for both traits (16 for panic attacks; 7 for panic disorder). Geneset analysis using single-cell RNA sequencing data implicated afferent neurons from the eye, heart, and lung in panic attacks, suggesting a critical role for sensory processing and interoceptive awareness. Further analyses suggested that these associations generalize to other psychiatric disorders. These findings offer novel insights into the biological mechanisms underlying panic, the role of afferent neurons, and may inform the development of more targeted and effective interventions.

Background Functional impairment in daily activities, such as work and socialising, is part of the diagnostic criteria for major depressive disorder (MDD) and most anxiety disorders. Despite evidence that symptom severity and functional impairment are partially distinct, functional impairment is often overlooked. To assess whether functional impairment captures diagnostically relevant genetic liability beyond that of symptoms, we aimed to estimate the heritability of, and genetic correlations between, key measures of current depression symptoms, anxiety symptoms and functional impairment. Methods In 17,130 individuals with lifetime depression or anxiety from the Genetic Links to Anxiety and Depression (GLAD) Study, we analysed total scores from the Patient Health Questionnaire-9 (PHQ-9; depression symptoms), Generalised Anxiety Disorder-7 (GAD-7; anxiety symptoms), and Work and Social Adjustment Scale (WSAS; functional impairment). Genome-wide association analyses were performed with REGENIE. Heritability was estimated using GCTA-GREML and genetic correlations with bivariate-GREML. Results Phenotypic correlations were moderate across the three measures (Pearson’s r = 0.50 - 0.69). All three scales were found to be under low but significant genetic influence (h2SNP = 0.11 - 0.19) with high genetic correlations between them (rg = 0.79 - 0.87). Conclusions Among individuals with lifetime depression or anxiety, the genetic variants that underlie symptom severity largely overlap with those influencing functional impairment. This suggests that self-reported functional impairment, while clinically relevant for diagnosis and treatment outcomes, does not reflect substantial additional genetic liability beyond that captured by symptom-based measures of depression or anxiety.