e-Neuroforum 2013 · 4:71–78DOI 10.1007/s13295-013-0044-2© Springer-Verlag 2013

K. DomschkeDepartment of Psychiatry, University of Wuerzburg, Wuerzburg

Anxiety disorders: genetic mechanisms

Introduction

According to the International Classifica-tion of Diseases (ICD-10) anxiety disor-ders comprise “phobic disorders”, i.e. ob-ject- or situation-specific anxiety disor-ders leading to avoidance behavior, and the so-called “other anxiety disorders” which do not relate to any specific object or situation (see . Fig. 1).

Phobic disorders encompass agora-phobia, i.e. fear of crowds, public places or travelling far from home; social pho-bia, i.e. excessive fear of social situations, public humiliation or embarrassment; and specific phobias, i.e. irrational fear of specific situations or objects like animals, small confined spaces, heights, airplanes or medical procedures involving needles and injections. Object- or -situation-un-specific anxiety disorders comprise panic disorder, characterized by sudden and un-expected severe panic attacks along with palpitations, tachycardia, chest pain, dizzi-ness and feelings of alienation (deperson-alization or derealization), fear of dying or losing control, as well as generalized anxi-ety disorder, characterized by free-floating anxiety, excessive worry about impending disaster, typically concerning close rela-tives and hyperarousal.

With a 12-month prevalence of 14% and about 61.5 million patients suffering from the disease, anxiety disorders are the most frequent mental disorders in Europe and, as the forth most expensive neuropsychi-atric disorder in that part of the world, confer a high socioeconomic burden.

Women are affected by anxiety dis-orders approximately two to three times more frequently than men.

The pathogenesis of anxiety disorders is—as is the case in hypertension, diabetes

mellitus or asthma—complex, with an in-teraction between biological factors, envi-ronmental factors (e.g. childhood trauma, recent negative life events) and psycholog-ical mechanisms (e.g. conditioning, psy-cho-physiological model of panic attacks, psychodynamic models). Of the biologi-cal factors, genetic factors—by exerting their impact on several levels such as: the expression of receptors or transporters, the neurotransmitter level, the neuronal network level, and neurophysiological or neuropsychological phenotypes—are of particular importance in the pathogenesis of anxiety disorders. Therefore, the pres-ent article focuses on reviewing the cur-rent state of knowledge regarding the role of genetic factors in the etiology of anxi-ety and anxiety disorders, with particular focus on clinical and molecular genetics research, gene–environment interaction studies (“G x E” studies), epigenetic anal-yses, imaging genetic studies, genetics of further intermediate phenotypes of anxi-ety disorders and finally pharmaco-/psy-chotherapy-genetic studies (see . Fig. 2). In addition, diagnostic and therapeutic implications as well as ethical aspects are discussed.

For a further and more detailed pre-sentation of this topic see [6] [10] and the relevant papers in the current edition con-

cerning the genetics of the neuronal anx-iety network (Wotjak and Pape, this edi-tion), the interaction of genetic and en-vironmental factors regarding the patho-genesis of fear (Sachser und Lesch, this edition), as well as the genetic risk factors of neuropsychological phenotypes such as context conditioning.

Clinical genetics

The contribution of genetic factors to the pathogenesis of a disease is investigat-ed by means of clinical genetic methods such as family studies, twin studies, adop-tion studies and segregation studies (see . Excursus 1).

Family studies report an approximate-ly three- to five-fold increased risk in first-degree relatives of patients with panic dis-order, generalized anxiety disorder and specific phobias to also suffer from an anxiety disorder [18, 28]. This aggrega-tion of anxiety disorders in families (“fa-miliality”) suggests genetic factors and/or shared environmental factors to contrib-ute to the disease risk. However, as fami-lies do not only share their genetic make-up but also common environmental fac-tors, such as certain educational styles or traumatic life events, increased familiality does not prove a genetic influence on the

Review article

Phobic Anxiety Disorders (ICD-10 F40.-)

object-/ situation-speci�c

object-/ situation-unspeci�c

Other Anxiety Disorders (ICD-10 F41.-)

chronic

acute

Generalized Anxiety Disorder

Panic Disorder

Agoraphobia

Social Phobia

Speci�c Phobias

Fig. 1 7 Classification of anxiety disorders ac-cording to the Interna-tional Classification of 

Diseases (ICD-10)

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pathogenesis of a certain disease. To fur-ther disentangle genetic and environmen-tal risk factors in the pathogenesis of anx-iety disorders, twin studies have been ap-

plied, revealing a considerable role of ge-netic factors in the pathogenesis of anxi-ety disorders with heritability estimates of between 32% and 67% (see . Tab. 1). The

respective remaining variance has been at-tributed to environmental factors [18].

It is important to note that the genet-ic risk of anxiety disorders does not fol-low a specific pattern of inheritance ac-cording to Mendelian rules, as in the case of monogenetic diseases such as Chorea Huntington. Anxiety disorders have rath-er been shown to be “complex-genetic” disorders with an interaction of multiple “vulnerability genes” or “risk genes” inter-acting with each other (“epistasis”) and/or with environmental factors.

Molecular genetics

These vulnerability/risk loci and genes are the target of molecular genetic stud-ies, such as linkage studies or association studies (see . Excursus 2).

Linkage studies have revealed sever-al potential risk loci within the human genome, which co-segregate with anx-iety disorders in families. For panic dis-order, risk loci have been identified on chromosomes 1p, 4q, 7p, 9q, 11p, 15q and 20p, on chromosome 3q for agorapho-bia and chromosomes 16q and 14p for so-cial and specific phobias, respectively (see . Fig. 3). These risk loci, however, are still

Excursus 1: Clinical genetics

Family studies investigate the so-called familiality of a disease of interest, i.e. the aggregation of a disease in families due to genetic and/or shared environmental factors, by comparing the disease risk in first-degree relatives of index patients with the disease risk in the general population. Twin studies compare so-called concordance rates, i.e. both individuals of a twin pair being affected by the same disease, between monozygotic and dizygotic twins and thereby provide heritability es-timates, i.e. approximations of the actual contribution of genetic factors for the disease of interest. Adoption studies evaluate the disease risk in biological children of affected patients in the adoptive family and thus allow for a differentiation between biological and social factors in the pathogenesis of a disease of interest. Finally, segregation studies analyze modes of inheritance of a particular dis-order according to Mendelian patterns.

Excursus 2: Molecular genetics

Linkage studies investigate the co-segregation of particular genetic markers across the genome with the disease of interest in pedigrees of affected families, which enables disease risk loci to be defined. However, given the expected small individual effects of a single gene in complex-genetic disorders such as anxiety disorders, the detection sensitivity of linkage studies in these phenotypes is rather low. In association studies, the allelic frequency of a particular marker in a priori candidate genes (e.g. functional candidate genes, positional candidate genes) is comparatively analysed in patients and healthy controls, allowing for the identification of risk alleles in disease vulnerability genes. The advantage of association studies is their high sensitivity to detect genetic markers with small overall effects (explaining 2%–3% of the variance); however, this renders association studies relatively prone to false positive results, necessitating replication in independent samples. Genome-wide association studies (GWAS) interrogate the entire genome for association with a disease of interest, applying a hypothesis-free approach. GWAS have been suggested to aid in the more robust identification of risk variants and at the same time in discerning novel vulnerability genes for complex-genetic disorders.

Fig. 2 8 Pathogenetics of anxiety disorders. Variants, e.g. in the catechol-O-methyltransferase (COMT), serotonin 1A receptor (HTR1A), monoamine oxidase A (MAO-A) and neuropeptide S receptor (NPSR1) genes have been reported to increase the risk for anxiety disorders—possibly via an intermediate epigenetic level—in interaction with environmental factors (G x E; “gene–environment interaction”) and to contribute to the pathogenesis of anxiety disorders on different levels, such as the cellular level (e.g. expression of receptors, transporters, neurotransmitters) and the neural network level (“imaging genetics”), and by influencing disease-related neurophysiological and neuropsychological characteristics (“intermediate phenotypes”). Further-more, genetic factors appear to determine the success of pharmacotherapy and psychotherapy in anxiety disorders (modified according to [2])

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very large and comprise up to hundreds of potential risk genes.

Association studies in anxiety disor-ders have mainly focussed on a priori defined candidate genes based on func-tional considerations emerging from an-imal models (e.g. knockout mice), prov-ocation studies [e.g. cholecystokinin (CCK4) challenge studies, caffeine chal-lenge studies] or psychopharmacological studies, e.g. of selective serotonin reup-take inhibitors (SSRIs) or monoamine oxidase A (MAO-A) inhibitors in anxi-ety disorders. Accordingly, the most ro-bust association findings in panic disor-der, which, however, have not yet been un-equivocally replicated, have been report-ed for polymorphisms in classical candi-date genes such as the adenosine A2A re-ceptor (ADORA2A), the cholecystokinin B (CCK-B) receptor, the MAO-A, the cat-echol-O-methyltransferase (COMT) and the serotonin 1A receptor (HTR1A). In de-tail, the more active alleles of the COMT val158met polymorphism and the MAO-A “variable number tandem repeat” (VN-TR) polymorphism, resulting in a lower availability of catecholamines and/or se-rotonin in the synaptic gap, have been found to be associated with panic disor-der. Interestingly, the more active COMT and MAO-A variants increase the genet-ic risk for panic disorder among women in particular, which could in part explain the higher prevalence of anxiety disorders in women as compared to men. However, the currently known risk variants—with few exceptions—are to be considered pre-liminary and confer only a small risk in-crease of a factor smaller than 2. Variation in genes coding for the dopamine trans-porter (DAT1), the serotonin 2A receptor (HTR2A), COMT and MAO-A have been found to be associated with social phobia, specific phobia or generalized anxiety dis-order (see [6] for an overview).

Beside the classical neurotransmit-ter systems, neuropeptides have recent-ly attracted much attention with regard to their potential role in the pathogene-sis of anxiety: the neuropeptide Y system and very convincingly the neuropeptide S (NPS) system. The latter has been suggest-ed to be crucially involved in the etiology of anxiety based on animal models. NPS is highly relevant in modulating noradren-

ergic neurotransmission via its expression in the locus coeruleus and has been pro-posed as a promising new candidate in the pathomechanism of anxiety and “arousal”, i.e. nervous hyperexcitability along with an increased level of attention, alertness and responsiveness. Animal studies have shown an anxiolytic, while at the same time “arousal-increasing” effect of NPS it-self, a 20-amino-acid peptide, as well as of agonists at the neuropeptide S recep-tor (NPSR). Reciprocally, knockout mice for NPSR displayed increased anxiety-re-lated behavior and at the same time re-duced exploratory behavior. In humans, the gene coding for the neuropeptide S re-ceptor (NPSR1) is located on the short arm of chromosome (7p14.3), a potential risk locus for panic disorder emerging from linkage studies. A so-called SNP (single nucleotide polymorphism) in the NPSR1 gene (rs324981 A/T) results in an amino acid exchange from asparagine to isoleu-cine (Asn/Ile), with the T allele (Ile) con-ferring increased NPSR expression and an up-to-tenfold increased effectiveness of NPS at the receptor. As the NPSR1 gene is to be regarded an excellent positional as well as functional candidate gene of anx-iety due to its chromosomal localization and based on findings in animal models, genetic variation in NPSR1 has been in-vestigated for its role in the pathogenesis of anxiety in humans. In several indepen-dent samples, the more active NPSR1 T al-lele was found to be associated with pan-ic disorder as well as with the dimensional phenotype of anxiety sensitivity in healthy probands [9], which might possibly corre-spond to the arousal-increasing effect of NPS in the animal model.

Furthermore, genome-wide associa-tion studies (GWAS) interrogating the en-tire genome for association with the dis-ease of interest using a hypothesis-free ap-proach point to novel vulnerability genes of anxiety disorders such as the trans-membrane protein 132D (TMEM132D). The more active variant of TMEM132D leads to increased expression of this pro-tein, e.g. in the frontal cortex. Corre-spondingly, animal models have shown that anxiety-related behavior in the mouse correlates with an overexpression of Tmem 132d mRNA in the anterior cin-gulum, a brain region relevant for the pro-

cessing of anxiety-related stimuli. These translational findings suggest TMEM132D as a promising novel risk gene of anxiety, which might be particularly relevant in the pathogenesis of panic disorder via a dysfunctional cortico–limbic interaction during emotional processing [13].

Gene–environment interaction studies

Given heritability estimates for anxiety disorders ranging from 32% to 67%, a considerable genetic contribution to the pathogenesis of anxiety disorders is as-sumed, while at the same time acknowl-edging that the remainder of the variance (~32%–70%) can be attributed to environ-mental factors such as recent negative life events (e.g. chronic or acute illness, losses, divorces, financial problems, etc.), as well as dramatic life events during childhood or early adolescence (emotional and/or physical abuse, emotional and/or physical neglect, sexual violence etc.). Reciprocal-ly, animal models have shown that the im-pact of negative life events on the devel-

Abstract

e-Neuroforum 2013 · 4:71–78DOI 10.1007/s13295-013-0044-2© Springer-Verlag 2013

K. DomschkeAnxiety disorders: genetic mechanisms

AbstractThe pathogenesis of anxiety disorders is mul-tifactorial with an interaction between genet-ic (heritability estimates: 32%–67%) and nu-merous environmental factors. Various chro-mosomal risk loci and potential risk-increas-ing genetic variants have already been iden-tified, with particular support for the neuro-peptide S receptor gene (NPSR1) as a prom-ising novel candidate. Gene–environment in-teraction and epigenetic studies provide ev-idence that genetic and psychosocial factors interactively influence the risk of anxiety dis-orders. Intermediate phenotypes of anxiety such as neural activation patterns or the star-tle reflex have been shown to be partly driv-en by genetic variants. Initial therapy-genetic studies have revealed a genetic influence on pharmaco- and psychotherapeutic interven-tions in anxiety disorders. Genetic research in anxiety disorders, while presently of no diag-nostic or predictive value yet, might contrib-ute to the development of innovative and in-dividually tailored therapeutic approaches.

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opment of the anxiety phenotype is sig-nificantly influenced by genetic predispo-sition (for more details, see Sachser and Lesch, this edition). Thus, in order to dis-entangle the complex-genetic pathomech-anism of anxiety disorders, molecular ge-netic approaches need to be complement-ed by so-called gene–environment inter-action (G x E) studies investigating the in-tricate interplay between genetic and en-vironmental factors. The shorter S allele of the serotonin transporter 5-HTTLPR gene variant and negative life events have been shown to interactively increase the risk for anxiety in general. This, in synop-sis with similar findings in rhesus mon-keys and serotonin transporter knockout mice, points to a pivotal role of the sero-tonin transporter gene together with ad-verse environmental influences in the pathogenesis of anxiety and anxiety dis-orders (for more details, see Sachser and Lesch, this edition). Generalized anxiety disorder seems to be interactively driven by neuropeptide Y (NPY) gene variation and exposure to traumatic life events. Fur-

thermore, the shorter S allele of the 5-HT-TLPR gene variant and the NPSR1 T risk allele have been reported to interact with childhood trauma or recent negative life events in order to increase the dimension-al phenotype of anxiety sensitivity predis-posing to anxiety disorders [24].

Epigenetics

It has recently been shown that genet-ic studies in anxiety disorders are ridden with high levels of inconsistency across studies and the failure to unequivocally replicate positive association findings. Al-so, the hitherto most robustly identified risk genes of anxiety disorders explain only a fraction of the expected heritabil-ity (~2%–3%), a phenomenon described as the “hidden heritability”. Beside low statistical power of the individual studies, ethnically differing sample compositions (population stratification), deficiency of the a priori candidate gene approach and high complexity of the clinically defined phenotype, epigenetic processes might

partly account for this hidden heritabili-ty (see . Excursus 3).

Specifically with regard to anxiety dis-orders in humans, only one study has been published so far reporting signifi-cant DNA hypomethylation of MAO-A predominantly in female patients with panic disorder. Under the assumption of increased gene expression conferred by demethylation, MAO-A hypomethylation could result in increased activity of MAO-A and consequently in decreased avail-ability of noradrenaline and serotonin, which is supposed to be pathomechanis-tically relevant in particular in anxiety and panic disorder. Additionally, a significant negative correlation between methyla-tion status and negative life events with-in 12 months before manifestation of the disease was detected, while positive life events correlated positively with meth-ylation status in patients and controls. This could suggest that negative environ-mental influences might increase the dis-ease risk via demethylation of vulnerabil-ity genes, while positive life events might confer resilience towards anxiety disor-ders by maintaining or restituting a “nor-mal” methylation status of risk genes [11].

Genetics of intermediate phenotypes

To date, most molecular genetic studies have been performed in samples of pa-tients suffering from categorical anxi-ety disorders operationally diagnosed ac-cording to American or European clas-sification systems (DSM-IV or ICD-10).

Fig. 3 9 Molecular genet-ics: linkage studies in anxi-ety disorders. Linkage stud-ies point to several chro-mosomal risk regions (“risk loci”) for anxiety disor-ders. To date, the most ro-bust risk loci for the differ-ent kinds of anxiety dis-orders are specified on the right side of the chro-mosomes. * Panic disor-der/panic attack, § pan-ic syndrome+agoraphobia, ° social phobia. (See also figure in [10])

Excursus 3: Epigenetics

Epigenetic processes comprise mechanisms co-determining the activity of genes or even entire chromosome segments, such as the methylation of the base cytosine (MeC) in cytosine/guanine-rich regions (“CpG islands”) in the control region of a gene (“promoter”) or the acetylation of his-tones, around which the DNA is packed. Methylation of a gene by DNA methyltransferases (DNMT) usually renders the DNA less readable, i.e. the DNA is transcribed into mRNA to a lesser extent (“si-lencing”). Acetylation of histones is believed to result in increased gene activity and consequently protein expression by “unpacking” the DNA strand, rendering it more accessible to RNA polymeras-es. Epigenetic processes are—in contrast to the static DNA itself—flexible and temporally dynamic mechanisms essentially influenced by environmental factors. Accordingly, epigenetic mechanisms could play a significant role at the interface of genetic risk factors and environmental factors in the development of complex-genetic diseases.

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These clinical phenotypes, however, are composed of a variety of different neuro-biological and neuropsychological charac-teristics and differ in clinical characteris-tics regarding onset, severity and duration of the illness, thus constituting rather het-erogeneous nosological entities. This im-pedes the identification of pathogenetic mechanisms, which most probably influ-ences only few neurobiological or neuro-psychological traits. Thus, it has been sug-gested that so-called intermediate pheno-types or endophenotypes, which comprise heritable neurobiological or neuropsycho-logical traits linked to the disease of inter-est, but which—in contrast to the hetero-geneous categorical disease phenotype—are dimensional, more precisely defined and therefore assumed to be closer to the underlying genetic risk factors [16]. Sever-al neuropsychological traits such as a va-riety of neurobiological markers [e.g. pe-ripheral sympathetic activity, carbon di-oxide (CO2) reactivity, response to CCK4 challenge, startle reflex etc.] as well as anx-iety-related neuropsychological measures such as behavioral inhibition, trait anxi-ety or harm avoidance or context condi-tioning (for more details, see Glotzbach-Schoon et al., this edition) have been sug-gested as valid intermediate phenotypes of anxiety disorders. For instance, increased sympathetic activity was associated with variation in the ADORA2A gene in blood–injection phobia and the function-al NPSR1 gene polymorphism in panic disorder. Greater acoustic startle respons-es—partly in response to unpleasant emo-tional stimuli in an affect-modulated star-tle or fear-potentiated startle paradigm—were found to be influenced by the func-tional COMT val158met polymorphism, a functional variant in 5-HTTLPR (e.g. [1]) and—in interaction with caffeine ad-ministration—by the ADORA2A variant [7]. Interindividual differences in CO2

reactivity were associated with functional variation in the serotonin transporter (5-HTT) gene, which also seems to contrib-ute to anxiety-related neuropsychological traits such as harm avoidance and neu-roticism in healthy probands. Behavior-al inhibition was found to be influenced by variation in the corticotrophin releas-ing hormone (CRH) gene.

The term “imaging genetics” refers to a research approach where results from imaging studies, e.g. applying function-al magnetic resonance imaging (fMRI) techniques, serve as intermediate pheno-types of the disorder of interest. With re-gard to anxiety disorders, imaging stud-ies have focussed in particular on exam-ining regions comprised by the neuronal anxiety network such as the amygdala, the anterior cingulum and the prefrontal/or-bitofrontal cortex (see Wotjak and Pape, this edition). Accordingly, imaging genet-ic studies in social phobia using positron emission tomography (PET) and fMRI re-vealed variations in the 5-HTT and tryp-tophan hydroxylase 2 (TPH2) genes to drive amygdala excitability during prov-ocation exercises (public speaking, pho-bia-relevant emotional stimuli [14, 15]). In panic disorder, variants in the COMT und HTR1A receptor genes were found to be associated with a cortico–limbic dys-function during emotional processing (for an overview see [5]). Recently, the NPSR1 A/T polymorphism—associated with panic disorder—was furthermore found to drive neural activation corre-lates of emotional processing (. Fig. 4). The more active NPSR1 T allele has been reported to increase amygdala activity in response to anxiety-relevant emotion-al stimuli in healthy probands and to de-crease pre-/orbitofrontal and cingulate re-sponsiveness to negative emotional stim-uli in panic disorder [3, 9].

Pharmaco-/psychotherapy genetics

Several pharmacotherapeutic and psy-chotherapeutic options have been shown to be highly effective in anxiety disor-ders such as SSRIs, serotonin and norepi-nephrine reuptake inhibitors (SNRIs) or the calcium channel modulator pregaba-lin, as well as cognitive-behavioral ther-apy. However, there is still a consider-able rate of about 30% of patients not re-sponding to an initial therapeutic inter-vention, leading to a longer duration of suffering for patients as well as to an in-creased socioeconomic burden. Potential reasons underlying initial non-response to pharmacotherapy in anxiety disorders comprise epidemiological or clinical fac-tors such as non-compliance, i.e. not tak-ing the medication or taking it irregular-ly, age, duration of illness, psychiatric and somatic comorbidity as well as personality traits. Furthermore, it has been suggested that psychotropic drug response and side effects may be influenced by genetic varia-tion in both a pharmacokinetic and phar-macodynamic way (“pharmacogenetics”). Regarding pharmacogenetic mechanisms in anxiety disorders, four exemplary stud-ies have reported genetic variation in the serotonin transporter gene to predict re-sponse to treatment with SSRIs in pan-ic disorder [36], social phobia and gen-eralized social anxiety disorder. Further-more, the HTR1A gene seems to modu-late response to paroxetine in panic disor-der and in generalized social anxiety dis-order. In generalized anxiety disorder, re-cent studies have reported several genes to drive antidepressant treatment response [e.g., HTR2A, COMT, corticotropin-re-leasing hormone receptor 1 (CRHR1), do-pamine D3 receptor (DRD3), member 1 of the nuclear receptor subfamily group C (NR3C1), phosphodiesterase 1A (PDE1A)] (e.g. [35]).

In analogy to pharmacogenetic analy-ses, recent studies have set out to inves-tigate the genetic underpinnings of re-sponse to psychotherapeutic interven-tions in anxiety disorders. These first psy-chotherapy-genetic studies suggest the 5-HTTLPR SS genotype and the nerve growth factor (NGF) rs6330 T allele to confer a better response to cognitive be-havioral therapy (CBT) in children with

Tab. 1  Heritability of anxiety disorders: the contribution of genetic factors (“heritability”) to the pathogenesis of anxiety disorders (according to [18])

  Heritability

Agoraphobia 67% (CI 24%–63%)

Social phobia 51% (CI 39%–64%)

Blood-injection phobia 59% (CI 43%–78%)

Panic disorder 48% (CI 41%–54%)

Generalized anxiety disorder 32% (CI 24%–39%)CI: 95% confidence interval.

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anxiety disorders. Similarly, in adult pa-tients with panic disorder, the functional COMT val158met polymorphism and the MAO-A VNTR have been found to drive response to CBT [27, 36].

Summary and outlook

Clinical genetic research has revealed a significant influence of genetic factors on the development of anxiety disor-ders with heritability estimates between 32% and 67%. Molecular genetic studies point to chromosomal risk loci as well as risk variants of anxiety disorders, such as loci on chromosomes 1p, 3q, 4q, 7p, 9q, 11p, 14p, 15q, 16q and 20p, as well as vari-ants in the genes for ADORA2A, CCK-B, MAO-A, COMT, HTR1A and NPSR1. Ini-tial GWAS suggest previously unknown

novel risk genes of anxiety disorders such as TMEM132D for panic disorder. Anxi-ety disorders, however, are not monoge-netic, but rather complex-genetic diseas-es, with a large number of genes each con-ferring only a small effect, contributing interactively to the disease risk. Further-more, in complex-genetic disorders such as anxiety disorders, genetic factors in-teract with numerous environmental fac-tors. Accordingly, gene–environment in-teraction studies provide early evidence of an interaction of stressful life events with variants in 5-HTT, NPY and NPSR1 genes in the pathogenesis of anxiety and anxi-ety disorders. Beyond the relatively stat-ic DNA level, dynamic epigenetic mech-anisms such as altered DNA methyla-tion of the MAO-A gene seem to play a role in the pathogenesis of anxiety in in-

teraction with environmental factors. The study of intermediate phenotypes of anx-iety disorders, e.g. applying an imaging genetics approach, points to a function-al impact of genetic risk factors on a neu-ral network level. For instance, variants in the genes for 5-HTT, the tryptophan hy-droxylase 2 (TPH2), COMT, HTR1A and NPSR1 could be linked to a dysfunction-al cortico–limbic interaction during emo-tional processing. Finally, pharmacoge-netic studies suggest an impact of e.g. the 5-HTT, HTR2A, COMT, CRHR1, DRD3, NR3C1 and PDE1A genes on an anxiolyt-ic pharmacotherapy with antidepressants. Correspondingly, first psychotherapy-ge-netic studies point to a genetic control of response to a cognitive behavioral ther-apeutic intervention (e.g. 5-HTT, NGF, COMT, MAO-A).

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10

a b

Fig. 4 8 “Imaging genetics”. a Neuropeptide S receptor (NPSR1) A/T polymorphism and neural correlates of emotional pro-cessing. Association of the more active NPSR1 T allele with increased amygdala activation in response to fearful face stimu-li in healthy probands [3]. b Association of the more active NPSR1 T allele with decreased activity of the dorsolateral prefron-tal cortex (DLPFC), the orbitofrontal cortex (OFC) and the anterior cingulum (ACC) in response to fearful face stimuli in patients with panic disorder [9]

76 |  e-Neuroforum 3 · 2013

Review article

On a molecular genetic level, future re-search into the genetics of anxiety disor-ders might want to expand candidate gene and genome-wide association studies to larger and clinically more detailed char-acterized collectives and to investigate the entire region of a candidate gene repre-sented by a set of so-called tagging SNP, epistatic, i.e. interactional effects of sever-al gene variants as well as the entire exome by applying next generation sequencing techniques, such as exome sequencing. Furthermore, the study of micro RNAs and “copy number variations” (CNV), i.e. deletions or duplications of larger parts of the genome, as well as “pathway anal-yses’” focusing on a chain of functionally interacting elements, such as a signal cas-cade from receptor to nucleus level, rep-resent future targets of genetic research in the field of anxiety disorders. Future G x E analyses are warranted in the context of a genome-wide G x E approach and may provide information on the suggested in-teractional effect of genetic risk factors and cumulative/specific critical life events on the pathogenesis of anxiety.

On a clinical level, further specifica-tion of intermediate phenotypes rele-vant for anxiety disorders, such as an in-creased interoceptive sensitivity or “pha-sic fear” (fast onset and offset of fear of well-specified stimuli) versus “sustained fear” (longer-lasting or anticipatory anx-iety elicited by non-specific and not read-ily predictable stimuli) might be of great value for future genetic studies. Despite the initial successes of genetic research in the field of anxiety disorders as present-ed above, it should be emphasized that the currently available findings are of no diag-nostic or predictive value, as the intricate complex-genetic underpinnings of anxi-ety disorders with an interplay between multiple genetic risk variants and risk-in-creasing life events is far from being un-derstood in a comprehensive way. There-fore, genetic research is currently mainly serving the purpose of better understand-ing the molecular mechanisms of anxiety and anxiety disorders. On this basis, it is hoped that genetic findings will neverthe-less be of practical clinical significance in the future, as they could contribute to the development of innovative and individ-ualized treatment approaches (see Wot-

jak and Pape, this edition). For example, based on animal models and genetic stud-ies in humans, the NPS system is suggest-ed as a promising candidate in the patho-genesis of anxiety disorders and is cur-rently under investigation for its potential as an innovative therapeutic target in a rat model of anxiety, with neuropeptide S administered intranasally indeed exerting an anxiolytic effect (e.g. longer stays in the open arms of the “plus maze”; [48]). Ad-ditionally, pharmacogenetic and psycho-therapy-genetic research might aid in the design of personalized and thus more ef-ficient therapeutic approaches individu-ally tailored to the patient’s constellation of genetic and environmental risk factors (“personalized medicine”); this could sub-stantially shorten the individual patient’s suffering and lower the socioeconomic burden of anxiety disorders. It should be noted, however, that advances in genetic methodology in the field of mental disor-ders may under no circumstances entail a selection of patients or subjects at risk and therefore need to be accompanied by strict national and international regula-tions about stigmatization, privacy confi-dentiality and data protection.

Corresponding address

Prof. Dr. Dr. K. DomschkeDepartment of Psychiatry,  University of WuerzburgFuechsleinstr. 15, 97080 WuerzburgGermanyDomschke_K@klinik.uni-wuerzburg.de

K. Domschke. Prof. Katharina Domschke, MA, MD, PhD, completed her studies in medicine and psychol-ogy at the University of Muenster, Germany, and Trini-ty College Dublin, Ireland (MD), as well as Boston Uni-versity, Boston, MA, USA (MA), and Maastricht Univer-sity, The Netherlands (PhD). After her board certifica-tion as a psychiatrist she worked as an attending physi-cian and associate professor at the Department of Psy-chiatry, University of Muenster, Germany, and was ap-pointed full professor of psychiatry at the University of Wuerzburg, Germany, in January 2012. Since 2000, Prof. Domschke has been actively involved in the field of biological psychiatric research with focus on genet-ics, epigenetics, imaging genetics and pharmacoge-netics of anxiety and depression. Her research activity is reflected to date by over 100 publications in interna-tional journals, one co-edited book and 13 book chap-ters and has been recognized by, e.g. the Research Award of the World Federation of Societies of Biologi-cal Psychiatry (WFSBP), a Fellowship by the World Psy-chiatric Association (WPA), the Travel Award of the In-

ternational Society of Psychiatric Genetics (ISPG), the Poster Award of the German Society of Psychiatry, Psy-chotherapy and Neurology (DGPPN), the Research Award of the German Association of Women in Med-icine (DÄB), the Ingrid-zu-Solms Research Award and membership in the Young Academy of the Nation-al Academy of Sciences Leopoldina. She is a full mem-ber of the International Society of Psychiatric Genet-ics (ISPG), the Society of Biological Psychiatry (SOBP), the European College of Neuropsychopharmacolo-gy (ECNP), the German Society of Biological Psychia-try (DGBP), the German Society of Psychiatry, Psycho-therapy and Neurology (DGPPN) and the German Soci-ety of Anxiety Research (GAF). She is a member of the editorial boards of the International Journal of Neuro-psychopharmacology, PLosONE, Progress in Neuropsy-chopharmacology & Biological Psychiatry, Acta Neuro-psychiatrica and Frontiers in Molecular Psychiatry and serves as a regular reviewer for over 30 SCI-listed inter-national journals.

Conflict of interest.  The corresponding author states that there are no conflicts of interest.

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78 |  e-Neuroforum 3 · 2013

Review article