Anxiety Disorders

D. S. Baldwin, B. E. Leonard

• Publisher: S. Karger
• Year: 2013
• ISBN:
  9783318024647
• Topic: Medicine
• Subtopic: Public Health, Administration & Care

Anxiety disorders are not uncommon and are often 'comorbid' with other forms of mental disorders. This publication provides an update on the origins and the causes of anxiety disorders and their related symptoms. Its focus is on neuroimaging and neuroinflammation and genetics as well as areas where an overlap may exist with abnormal cardiovascular physiology. Further it takes a closer look at the early phases of anxiety disorder and the potential effects of prolonged illness prior to diagnosis and also investigates recent research findings about the neuroimmunology of depression and the immunomodulatory effects of antidepressants. It also examines the neuroinflammatory hypothesis about anxiety disorders and concludes with the succinct but evidence-based and comprehensive reports on the value of pharmacological treatments used for generalized anxiety disorder, panic disorder, social anxiety disorder, posttraumatic stress disorder and obsessive-compulsive disorder. The topics covered in this publication will certainly make it essential reading for both novice and expert practitioners in psychiatric medicine, but its appeal should extend even further and include those researching the neuropsychobiology of anxiety or trying to improve our grasp of posttraumatic stress disorder or obsessive-compulsive disorder.

Baldwin DS, Leonard BE (eds): Anxiety Disorders.
Mod Trends Pharmacopsychiatry. Basel, Karger, 2013, vol 29, pp 24-46 (DOI: 10.1159/000351932)

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Genetic Factors in Anxiety Disorders

Katharina Domschke^a · Eduard Maron^b,c

^aDepartment of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany; ^bDepartment of Neuropsychopharmacology and Molecular Imaging, Imperial College London, London, UK; ^cDepartment of Psychiatry, University of Tartu, Tartu, Estonia

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Abstract

Presently available clinical genetic studies point to a considerable heritability of anxiety disorders (30-67%), with multiple vulnerability genes such as 5-HT_1A, 5-HTT, MAO-A, COMT, CCK-B, ADORA2A, CRHR1, FKBP5, ACE, RGS2/7 and NPSR1 suggested by molecular genetic association studies. These genes have been shown to partially interact with each other as well as with environmental factors to shape the overall disease risk in a complex genetic model. Additionally, recent studies have pointed out the crucial role of epigenetic signatures such as methylation patterns in modifying environmental influences as well as in driving the functional impact of anxiety disorder risk genes. On a systems level, vulnerability genes of anxiety disorders seem to confer some of the disease risk via intermediate phenotypes like behavioral inhibition, anxiety sensitivity or several neurobiological traits such as increased startle reactivity or dysfunctional corticolimbic activity during emotional processing. Finally, first pharmaco- and psychotherapy-genetic studies provide evidence for certain risk genes to confer interindividual variability in response to a pharmacological or psychotherapeutic intervention in anxiety disorders. Genetic research in anxiety disorders will be discussed regarding its potential to foster innovative and individually tailored therapeutic approaches for patients with anxiety disorders.

Copyright © 2013 S. Karger AG, Basel

The etiology of anxiety disorders has been proposed to be multifactorial with a complex interaction of neurobiological and environmental factors. Within the neurobiological pathomechanism of anxiety disorders, the role of genetic factors deserves particular attention. A significant contribution of genetic risk variants to the development of anxiety disorders has been suggested by clinical genetic studies such as family and twin studies.

Clinical Genetic Studies

Family studies report an up to 3-times increased disease risk in first-degree relatives of patients with panic disorder [1], generalized anxiety disorder and specific phobias [2] as well as posttraumatic stress disorder (PTSD) [3]. An increased familial risk seems to particularly apply to early-onset panic disorder with a 17-fold increased risk of panic disorder in relatives of patients with panic disorder onset at or before the age of 20 years [4]. This aggregation of anxiety disorders in families (‘familiality’) suggests genetic factors and/or shared environmental factors to contribute to the disease risk. To further disentangle genetic and environmental risk factors, twin studies compare concordance rates in monozygotic (100% genetic identity) and dizygotic (50% genetic identity) twins, which allows for an estimation of the actual contribution of genetic factors to a disease (‘heritability’). Heritability estimates for anxiety disorders range from ~30% for generalized anxiety disorder, simple phobias and PTSD over 48% (panic disorder), 51% (social phobia) and 59% (blood-injection phobia) to 67% for agoraphobia [2, 5, 6]. The genetic vulnerability towards anxiety disorders, however, does not follow a specific pattern of inheritance according to mendelian rules (e.g. dominant, recessive). Rather, anxiety disorders have been shown to belong to the group of so-called ‘complex-genetic’ disorders, where multiple susceptibility genes of only a small individual effect interact with each other as well as with environmental factors to constitute the overall disease risk [7].

Within the past ~20 years, much effort has been put into the search for specific genetic variants, which confer this increased genetic risk of anxiety disorders. Molecular genetic approaches such as linkage studies, cytogenetic studies and (genomewide) association studies have yielded several promising results with respect to potential anxiety risk loci and risk alleles, respectively.

Molecular Genetic Studies

Linkage Studies

Linkage studies analyzing the coinheritance of particular genetic markers with the disease of interest in affected families have revealed several potential risk loci for panic disorder (chromosomes 1p, 4q, 7p, 9q, 11p, 15q and 20p) [8-16] as well as for agoraphobia, specific phobias and social phobia (chromosomes 3q, 14p and 16q) [11, 17, 18]. A genome-wide linkage study of a broad anxiety phenotype yielded evidence for a risk locus on chromosome 14 [19]. Specific risk loci were identified for panic disorder with comorbid bipolar disorder (chromosomes 2, 12 and 18) [20, 21], for a ‘panic syndrome’ with concomitant interstitial cystitis, kidney/bladder dysfunction, migraine, mitral valve prolapse or thyroid conditions (chromosome 13q) [12, 22-24] and for panic disorder with early-onset susceptibility to anxiety (chromosome 1q) [25, for review see 26].

Cytogenetic Studies

In a cytogenetic study, duplication of a 17-Mb region on chromosome 15q24-26 (DUP25) spanning about 60 genes has been reported to be linked to a panic disorder subtype with joint laxity and mitral valve prolapse [27]. Additionally, a single nucleotide polymorphism in the 5’ untranslated region of the neurotrophin 3 gene located in this duplicated chromosomal region was found to be significantly associated with panic disorder [28]. However, the initial duplication finding could not be replicated in independent samples so far [29-32].

Association Studies

Association studies in anxiety disorders have investigated several hundred candidate genes so far, mostly selected based on results from animal studies, challenge experiments or psychopharmacological interventions in anxiety-related phenotypes or anxiety disorders. These ‘usual suspects’ comprise genes involved in the serotonergic, noradrenergic, dopaminergic, cholecystokininergic, adenosinergic, GABAergic and hypothalamus-pituitary-adrenal axis-related systems.

Serotonin/Norepinephrine System Genes

Serotonin function has been crucially implied in the pathogenesis and pharmacotherapy of anxiety disorders [33]. Consequently, genes coding for the serotonergic system have been considered prime candidate genes in the molecular genetic investigation of anxiety disorders. Most evidence has accumulated for the monoamine oxidase A (MAO-A) gene to be associated with panic disorder, particularly in female patients [34-36]. Furthermore, the serotonin 1A receptor (5-HT_1A) gene [37, 38], the serotonin 2A receptor (5-HT₂A) gene [39-42] and the tryptophan hydroxylase 2 (TPH2) gene [43, 44] have been suggested to contribute to the pathogenesis of panic disorder. The role of the serotonin transporter (5-HTT) gene is controversial with evidence for [36, 39, 45-47] as well as against association with panic disorder [48-51]. Social phobia has been found to be associated with variation in the 5-HT₂A gene [52], generalized anxiety disorder with a functional MAO-A gene polymorphism [53]. In PTSD, evidence has been provided for the 5-HTT [54-56] and the 5-HT₂A gene [57] to constitute potential risk factors. Finally, there is some support for variation in the norepinephrine transporter gene to be associated with panic disorder [58-60].

Dopamine System Genes

The probably best replicated vulnerability gene for panic disorder is the gene coding for the catechol-O-methyltransferase (COMT). Mostly in the subgroup of female patients, the functional val158met polymorphism has been found to be associated with the disease, potentially in an ethnically specific manner [61-66]. Association of COMT gene variation has also been reported in specific phobias [67]. Furthermore, the dopamine D1 receptor has been discerned to confer some vulnerability to panic disorder [39]. In social phobia and generalized anxiety disorder, variants in the dopamine transporter (DAT1) have been proposed to contribute to the disease risk [68]. In PTSD, association has been reported again for the COMT gene [69] and the dopamine D₂ receptor (DRD2) gene [70], with some support for DRD2 to specifically mediate severe comorbid psychopathology (anxiety, depression) and social dysfunction in PTSD subjects [71]. The DAT1 gene has also been found to be associated with PTSD, with, however, also contradictory reports of no association [72-75].

Cholecystokinin System Genes

Given accumulating evidence for cholecystokinin (CCK) in playing an important role with regard to neuroanatomical circuits and neurotransmitters involved in the pathophysiology of panic and anxiety [see 76, 77], molecular genetic studies have focused...