ABSTRACT Phenotypic heterogeneity of depression has been cited as one of the causes of the limited success to detect genetic variants in genome‐wide studies. The 7‐item Hospital Anxiety and Depression Scale (HADS‐D) was developed to detect depression in individuals with physical health problems. An initial psychometric analysis showed that a short version (“HADS‐4”) is less heterogeneous and hence more reliable than the full scale, and correlates equally strong with a DSM‐oriented depression scale. We compared the HADS‐D and the HADS‐4 to assess the benefits of using less heterogeneous phenotype measures in genetic analyses. We compared HADS‐D and HADS‐4 in three separate analyses: (1) twin‐ and family‐based heritability estimation, (2) SNP‐based heritability estimation using the software GCTA, and (3) a genome‐wide association study (GWAS). The twin study resulted in heritability estimates between 18% and 25%, with additive genetic variance being the largest component. There was also evidence for assortative mating and a dominance component of genetic variance, with HADS‐4 having slightly lower estimates of assortment. Importantly, when estimating heritability from SNPs, the HADS‐D did not show a significant genetic variance component, while for the HADS‐4, a statistically significant amount of heritability was estimated. Moreover, the HADS‐4 had substantially more SNPs with small P ‐values in the GWAS analysis than did the HADS‐D. Our results underline the benefits of using

Genetic and environmental influences in the determination of individual differences in self-reported symptoms of separation anxiety (SAD), overanxious disorder (OAD), and manifest anxiety (MANX) were evaluated in children and adolescents for three age groups (8-10, 11-13, and 14-16). Symptom counts for SAD and OAD were assessed for 1,412 twin pairs using the children's version of the Child and Adolescent Psychiatric Assessment, and MANX scores were based on child report from the Revised Children's Manifest Anxiety Scales. Despite significant age and gender differences in thresholds of liability for child reports of symptoms of SAD and OAD, additive genetic and environmental effects could be set equal across age and gender for these variables. For MANX, however, the best-fitting model was a common effects sex-limitation model with estimates of heritability varying dependent upon age and gender. Parameter estimates from the ACE models of OAD and SAD showed that additive genetic variation was a necessary component in the explanation of individual differences in child-reported symptoms of OAD (h2 = .37) across gender, but does not appear to be a major contributor to the explanation of individual differences in symptoms of SAD reported by children. Shared environmental effects (c2 = .40) were found to play a moderate role for SAD but could be dropped from the model for OAD and from all of the age groups for MANX, although the parameter approached significance among 11 yr to 13-yea

Caffeine, the main psychoactive component in coffee, has garnered significant attention for its potential impact on the most prevalent mental health conditions like anxiety and depression. This chapter comprehensively examines the neurobiological effects of caffeine, its influence on anxiety and depression, and relevant clinical studies. Caffeine exerts its psychostimulant effects primarily through antagonizing adenosine receptors, modulating neurotransmitter systems, and influencing intracellular calcium signaling in the brain. Caffeine exhibits dose-dependent effects. While moderate caffeine consumption is safe in healthy adults and may offer benefits for mental health, excessive intake is linked to adverse effects on neurological and psychiatric health and can aggravate symptoms, highlighting the importance of adjusting consumption patterns. High caffeine intake correlates with elevated anxiety levels, especially in individuals predisposed to anxiety disorders. However, the relationship between caffeine consumption and the risk of depression is intricate, with some studies suggesting a potential protective effect of moderate intake, while others find no significant association. Individual variations in caffeine metabolism, sensitivity, and genetic factors considerably impact responses to caffeine. The chapter also explores the therapeutic potential of caffeine as an adjunct treatment and outlines challenges and future research directions in elucidating caffeine's multiface

Specific phobia is a core anxiety disorder with a moderate genetic component, but its genetic background remains poorly understood. In the current study, the genetic correlations between specific phobia and other psychiatric disorders, including anxiety disorders, as well as intermediate phenotypes, were investigated. Large-scale genome-wide association study (GWAS) summary statistics for specific phobia, indicated by International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes during primary care visits or hospital admissions (n = 502,481); 12 psychiatric disorders, including panic disorder and anxiety disorders, from the UK Biobank (UKBB), which primarily consists of generalized anxiety disorder; and 23 intermediate phenotypes were utilized. Linkage disequilibrium score regression (LDSC) analyses were performed to estimate genetic correlations. We visualized the GWAS summary statistics for specific phobia, and no genome-wide significant loci were identified. We also performed a MAGMA tissue-enrichment analysis, and no significant tissue-specific gene expression enrichment was detected, although the brain cerebellum was the most nominally associated tissue (p = 0.059). We found that specific phobia exhibited a strong genetic correlation with panic disorder (rg = 0.78), followed by adjustment disorder (rg = 0.69), major depressive disorder (rg = 0.61), posttraumatic stress disorder (rg = 0.59), and anxiety disorders from the

Anxiety disorders are common mental disorders that often result in disability. Recently, large-scale genome-wide association studies (GWASs) have identified several novel risk variants and loci for anxiety disorders (or anxiety traits). Nevertheless, how the reported risk variants confer risk of anxiety remains unknown. To identify genes whose cis -regulated expression levels are associated with risk of anxiety traits, we conducted a transcriptome-wide association study (TWAS) by integrating genome-wide associations from a large-scale GWAS ( N = 175,163) (which evaluated anxiety traits based on Generalized Anxiety Disorder 2-item scale (GAD-2) score) and brain expression quantitative trait loci (eQTL) data (from the PsychENCODE and GTEx). We identified 19 and 17 transcriptome-wide significant (TWS) genes in the PsychENCODE and GTEx, respectively. Intriguingly, 10 genes showed significant associations with anxiety in both datasets, strongly suggesting that genetic risk variants may confer risk of anxiety traits by regulating the expression of these genes. Top TWS genes included RNF123 , KANSL1-AS1, GLYCTK, CRHR1, DND1P1, MAPT and ARHGAP27. Of note, 25 TWS genes were not implicated in the original GWAS. Our TWAS identified 26 risk genes whose cis -regulated expression were significantly associated with anxiety, providing important insights into the genetic component of gene expression in anxiety disorders/traits and new clues for future drug development.

Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder representing a serious burden to the healthcare system. IBS research is extremely challenging due to the multifactorial etiology of the disease and the heterogeneity of patients that present high comorbidity rates with mental disorders including anxiety and depression. Such highly comorbid disorders show substantial heritability and are partly determined by a genetic component. In the present study, we used data available from large pre-existing genome-wide association studies on IBS (n=455,321) and anxiety (n=117,751) to assess the genetic overlap and causal relationship between these comorbid disorders and found strong and positive genetic correlation between them (rg=0.713, se= 0.076, P= 3.6e-20). The multi-trait analysis of GWAS (MTAG) highlighted three new genome-wide significant loci for IBS located in, or nearby, genes related to synaptic transmission, nervous system development, neuroticism, and epigenetic modification of chromatin. We also used Mendelian randomization with a range of sensitivity analyses to clarify the causal relationship between these disorders and found consistent evidence for a causal effect of the genetic liability of IBS on anxiety (P=7.6e-05) but no evidence of causal effect was detected in the opposite direction. Our results are consistent with a shared common genetic background between IBS and anxiety, highlight the importance of common genetic factors in the risk of these

Abstract Background Temporomandibular disorders (TMD) show substantial clinical and genetic overlap with anxiety, yet it remains unclear whether TMD risk reflects shared anxiety-related liability or distinct anxiety-independent genetic mechanisms. Disentangling these components is essential for understanding TMD heterogeneity beyond symptom-based classifications. Methods We applied GWAS-by-subtraction using genome-wide summary statistics for TMD (20,799 cases and 479,549 controls; FinnGen Release 12) and anxiety disorders (74,973 cases and 400,243 controls), partitioning TMD heritability into two orthogonal latent components: an anxiety-dependent factor (F Anxiety ) and an anxiety-independent factor (F Non-Anxiety ). To delineate the mechanisms underlying each component, we integrated fine-mapping, transcriptome- and proteome-wide association analyses, genetic colocalization, brain imaging–genetics, and single-cell RNA sequencing from human embryonic temporomandibular joint tissue. Results Anxiety showed significant genetic correlation with TMD (rg = 0.4417, p = 1.98 × 10 − 1 9 ) and accounted for 19.50% of TMD heritable variance. F Anxiety yielded multiple genome-wide significant loci ( CNTNAP5 , PCLO , PRSS16 , BTN1A1 , RAB27B ), whereas F Non-Anxiety produced a single independent signal near GPNMB , demonstrating sharply divergent genetic architectures. Multi-omic integration identified RAB27B as a driver of the anxiety-related pathway, implicating synaptic vesicle traffic