Enda M. Byrne

Internalising symptoms including depression, anxiety and somatic symptoms in adolescence are common. They can be transient, but they can also persist and progress to major depressive disorder (MDD) Polygenic risk scores for major depression (MD-PGS) may help identify which symptomatic adolescents are at greatest risk of later disorder. In a mega-analysis of two longitudinal population-based cohorts from Brisbane, Australia, we investigated whether polygenic liability to depression improves risk stratification among adolescents with elevated internalising symptoms. Internalising symptoms were assessed at age 14, lifetime MDD was assessed in young adulthood using the Composite International Diagnostic Interview, and MD-PGS were generated using summary statistics from the latest Psychiatric Genomics Consortium major depression genome-wide association study, excluding Australian cohorts. Analyses focused on comparisons between individuals in the top decile of risk and those in the remaining 90% of each cohort. A total of 302 cases with lifetime MDD and 1693 controls were included. Compared with adolescents outside the highest decile of internalising symptoms, those in the top decile at age 14 had a more than two-fold increased odds of lifetime MDD (OR = 2.56, 95% CI 1.92–3.49, p = 5.4 × 10 ^-10 ). Individuals in the top decile of MD-PGS also showed increased odds of lifetime MDD compared with the remaining 90% (OR = 3.45, 95% CI 2.53–4.71, p = 4.4 × 10 ⁻ ¹⁵). Adolescents who were simultaneously in the top decile of both internalising symptoms and MD-PGS had an approximately eight-fold increased odds of lifetime MDD compared with individuals outside the top decile for both risk factors (OR = 8.58, 95% CI 4.04–18.26, p = 1.2 × 10 ⁻ ⁵). These findings indicate that polygenic risk scores for depression may have particular clinical utility for stratifying risk among adolescents already presenting with elevated internalising symptoms, identifying a subgroup at very high risk for later major depressive disorder.

Adolescence marks a critical window for the emergence of mental health problems and reproductive maturation. Menstrual cycle characteristics - including pubertal timing, cycle regularity, menstrual pain, and premenstrual symptoms -may capture biological and experiential processes relevant to psychopathology. However, evidence linking menstrual features to a broad range of mental health outcomes, including ADHD symptoms, remains limited. Using data from the Adolescent Brain Cognitive Development (ABCD) Study (v6.1 N = 5,678 biological females; 17,567 post-menarche observations across 7 waves), we examined associations between reproductive timing, menstrual characteristics and symptoms of attention-deficit/hyperactivity disorder (ADHD), depression, and anxiety symptoms across repeated assessments in early adolescence using linear mixed-effects models with crossed random intercepts for site, family, and participant. Two co-primary model specifications were used: without BMI (M1, full sample) and with BMI (M2). False discovery rate correction was applied across outcomes. Earlier age at menarche was specifically associated with higher depression symptom scores (B = -0.087, p FDR < 0.001), with attenuation after BMI adjustment. Greater gynaecologic age (time since menarche TSM) also associated with higher depression scores (B = + 0.118, p FDR < 0.001) independent of chronological age and pubertal timing. Among girls with established cycles (TSM ≥ 2 years), irregular cycles were associated with higher depression and anxiety, whereas associations with ADHD did not remain after BMI adjustment. Long cycles were associated with anxiety only. Severe menstrual pain and premenstrual symptom severity showed dose-response associations with depression, anxiety, and ADHD that were robust to BMI adjustment. The association between irregular cycles and depression, and between long cycles and depression and anxiety, strengthened significantly with increasing gynaecologic age, while symptom burden associations were consistent throughout the post-menarcheal period. Menstrual symptom burden particularly severe pain and premenstrual distress and earlier menarche were consistently associated with higher levels of psychiatric symptoms in adolescent girls. These findings highlight menstrual health as a potentially informative dimension of adolescent mental health assessment. When girls present with significant menstrual symptoms, assessment of emotional wellbeing may be warranted.

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.

Background: Anxiety disorders show striking sex differences in prevalence, symptoms, and clinical characteristics, shaping how they manifest and are experienced. Methods: 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: 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: 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.

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.

Depression is accompanied by considerable comorbidity and excess mortality. We examined multimorbidity data using the validated pharmacy-based Rx-Risk Comorbidity Index and examined healthcare costs associated with chronic illness burden in the Australian Genetics of Depression Study (AGDS). Australian Pharmaceutical Benefits Scheme (PBS) record linkage for 15,890 AGDS participants was available from 01/07/2013-31/12/2017. Forty-six health morbidities were inferred by mapping the prescription data using Anatomical Therapeutic Chemical Classification System codes and PBS Item Codes. Morbidity prevalence rates were then compared with an unselected 10% Australian representative population sample (10PCT) with PBS claims data available from 01/07/2010-31/12/2014. The average number of inferred comorbidities was higher among AGDS participants (4.6 ± 2.9) than 10PCT individuals (3.0 ± 3.0). Excluding depression, 89.1% of AGDS participants had one or more inferred comorbidity, most commonly pain (51.0%), inflammation/pain (40.3%), and anxiety (32.3%). In the AGDS, the number of comorbidities was higher among women compared to men and positively correlated with participant age, BMI, number of depressive episodes experienced, and annual health care costs. Compared to participants with no inferred comorbidities, the median annual health care costs were ∼65% higher among those with 2-3 comorbidities. This study highlights the patterns of health morbidities experienced by individuals living with depression and shows that this chronic disease burden is significantly associated with increased health costs to the individual and the health system.

Purpose: This study tested whether adverse mood effect of the oral contraceptive pill (OCP) is associated with reproductive depressive episodes, including peripartum depression (PPD), premenstrual dysphoric disorder (PMDD), and perimenopausal depression. Method: In a sample of 3,547 OCP users from the Australian Genetics of Depression Study, who reported a lifetime depression diagnosis, logistic regression was used to test the association of PPD, PMDD, and perimenopausal depression with OCP adverse mood effect. Polygenic scores (PGS) for major depression (MD) were also tested for association with adverse mood effect. Sensitivity analyses tested for modification of these associations by a history of depression prior to first OCP use (prior depression), or by depression onset before the age of twenty (child/teen depression onset). Results: Adverse mood effect was reported by 1,342 OCP users (38%). PPD, PMDD, prior depression and child/teen depression onset were significantly associated with adverse mood effect (PPD: Relative Risk (RR) = 1.66,CI=[1.4–2.0], P = 2.0 × 10 ^− 6 ; PMDD: RR = 3.78,CI=[2.4-6.0], P = 2.2 × 10 ^− 8 ; prior depression: RR = 1.32,CI=[1.1–1.5], P = 5.9 × 10 ^− 4 ; child/teen depression onset: RR = 1.56,CI=[1.3–1.8], P = 1.1 × 10 ^− 7 ). The association of PPD with adverse mood effect remained significant for women with no prior or child/teen depression onset (RR = 1.77,CI=[1.3–2.4], P = 4.6 × 10 ^− 4 ), but was not significant for women with both prior and child/teen depression onset. Adverse mood effect was significantly associated with PGS for MD: full sample: RR = 1.18,CI=[1.1–1.3], P = 3.6 × 10 ^− 5 ); no prior or child/teen depression onset: RR = 1.27,CI=[1.1–1.4], P = 3.1 × 10 ^− 4 . Conclusions: Participants who experience an adverse mood effect with OCP use are likely to have higher genetic vulnerability for depression, and experience child/teen depression onset, as well as reproductive depressive episodes such as PPD.

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.

The major anxiety disorders (ANX; including generalized anxiety disorder, panic disorder and phobias) are highly prevalent, often onset early and cause substantial global disability. Although distinct in their clinical presentations, they probably represent differential expressions of a dysregulated threat–response system. Here, we present a genome-wide association meta-analysis comprising 122,341 European ancestry ANX cases and 729,881 controls. We identified 58 independent genome-wide significant risk variants and 66 genes with robust biological support. In an independent sample of 1,175,012 self-report ANX cases and 1,956,379 controls, 51 out of the 58 associations replicated. As predicted by twin studies, we found substantial genetic correlation between ANX and depression, neuroticism and other internalizing phenotypes. Follow-up analyses demonstrated enrichment in all major brain regions and highlighted GABAergic signaling as one potential mechanism implicated in ANX genetic risk. These results advance our understanding of the genetic architecture of ANX and prioritize genes for functional follow-up studies.