Transporter-facilitated uptake of serotonin (5-hydroxytryptamine or 5-HT) has been implicated in anxiety in humans and animal models and is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs. Human 5-HT transporter (5-HTT) gene transcription is modulated by a common polymorphism in its upstream regulatory region. The short variant of the polymorphism reduces the transcriptional efficiency of the 5-HTT gene promoter, resulting in decreased 5-HTT expression and 5-HT uptake in lymphoblasts. Association studies in two independent samples totaling 505 individuals revealed that the 5-HTT polymorphism accounts for 3 to 4 percent of total variation and 7 to 9 percent of inherited variance in anxiety-related personality traits in individuals as well as sibships.

https://science.sciencemag.org/content/sci/274/5292/1527.full.pdf

Association of Anxiety-Related Traits with a Polymorphism in the Serotonin Transporter Gene Regulatory Region

OBJECTIVE: The authors conducted a meta-analysis of relevant data from primary studies of the genetic epidemiology of major depression.METHOD: The authors searched MEDLINE and the reference lists of previous review articles to identify relevant primary studies. On the basis of a review of family, adoption, and twin studies that met specific inclusion criteria, the authors derived quantitative summary statistics. RESULTS: Five family studies met the inclusion criteria. The odds ratios for proband (subjects with major depression or comparison subjects) versus first-degree relative status (affected or unaffected with major depression) were homogeneous across the five studies (Mantel-Haenszel odds ratio=2.84, 95% CI=2.31–3.49). No adoption study met the inclusion criteria, but the results of two of the three reports were consistent with genetic influences on liability to major depression. Five twin studies met the inclusion criteria, and their statistical summation suggested that familial aggregation was due ...

https://ajp.psychiatryonline.org/doi/pdfplus/10.1176/appi.ajp.157.10.1552

Genetic Epidemiology of Major Depression: Review and Meta-Analysis

OBJECTIVE: The authors conducted meta-analyses of data from family and twin studies of panic disorder, generalized anxiety disorder, phobias, and obsessive-compulsive disorder (OCD) to explore the roles of genetic and environmental factors in their etiology. METHOD: MEDLINE searches were performed to identify potential primary studies of these disorders. Data from studies that met inclusion criteria were incorporated into meta-analyses that estimated summary statistics of aggregate familial risk and heritability for each disorder. RESULTS: For family studies, odds ratios predicting association of illness in first-degree relatives with affection status of the proband (disorder present or absent) were homogeneous across studies for all disorders. The calculated summary odds ratios ranged from 4 to 6, depending on the disorder. Only for panic disorder and generalized anxiety disorder could the authors identify more than one large-scale twin study for meta-analysis. These yielded heritabilities of 0.43 for pa...

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A review and meta-analysis of the genetic epidemiology of anxiety disorders.

The ascendance of emotion theory, recent advances in cognitive science and neuroscience, and increasingly important findings from developmental psychology and learning make possible an integrative account of the nature and etiology of anxiety and its disorders. This model specifies an integrated set of triple vulnerabilities: a generalized biological (heritable) vulnerability, a generalized psychological vulnerability based on early experiences in developing a sense of control over salient events, and a more specific psychological vulnerability in which one learns to focus anxiety on specific objects or situations. The author recounts the development of anxiety and related disorders based on these triple vulnerabilities and discusses implications for the classification of emotional disorders.

Unraveling the mysteries of anxiety and its disorders from the perspective of emotion theory.

Background: The causes of obsessive-compulsive disorder (OCD) are as yet unknown. Evidence of familial aggregation is one approach for investigating the role of genetics in the etiology of this condition. The current study was conducted to determine if OCD is familial and to investigate possible familial subtypes. Methods: Eighty case probands were identified in 5 specialty OCD clinics and 73 community control probands were identified by random-digit dialing. These probands and their first-degree relatives (343 case and 300 control relatives) were blinded to group and evaluated by psychiatrists and doctoral-level clinical psychologists using semistructured instruments. Final diagnoses were assigned by a blinded-consensus procedure. The results were analyzed using logistic regression by the method of generalized estimating equations. Results: The lifetime prevalence of OCD was significantly higher in case compared with control relatives (11.7% vs 2.7%) (P,.001). Case relatives had higher rates of both obsessions and compulsions; however, this finding is more robust for obsessions. Age at onset of obsessive-compulsive symptoms in the case proband was strongly related to familiality (odds ratio, 0.92; confidence interval, 0.85-0.99) (P = .05); no case of OCD symptoms was detected in the relatives of probands whose age at onset of symptoms was 18 years or older. Probands with tics or obsessive-compulsive personality disorder were not more likely to have relatives with OCD than those without these features. Conclusions: Obsessive-compulsive disorder is a familial disorder. Obsessions are more specific to the phenotype than are compulsions. Age at onset of OCD is valuable in characterizing a familial subtype. Arch Gen Psychiatry. 2000;57:358-363

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/205690/yoa9236.pdf

A family study of obsessive-compulsive disorder.

The genetics of six neurotic disorders: a twin study.

A genetic analysis was conducted on trait neuroticism and symptoms of anxiety and depression in a five-wave study of 462 twin pairs. Models that assessed the relative importance of genetic and environmental factors to the lability (within-individual variability over time) of these measures were fitted to the data. Previous results concerning the substantial genetic involvement in the level of neuroticism and symptoms were confirmed. However, it was found that neither genes nor the shared environment of the twins was a significant cause of lability of these measures. An attempt was therefore made to identify aspects of individuals' environments that might be responsible for lability of neuroticism and symptoms. Adverse life events were found to predict variability of symptoms, but not of neuroticism. The availability of close social ties or having affectionless control in childhood did not contribute to lability.

A. S. Henderson

Papers

The genetics of six neurotic disorders: a twin study.

Genetic and environmental determinants of the lability of trait neuroticism and the symptoms of anxiety and depression.