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    J Korean Med Sci. 2011 Jun;26(6):701-710. English.
    Published online May 18, 2011.
    https://doi.org/10.3346/jkms.2011.26.6.701
    © 2011 The Korean Academy of Medical Sciences.
    Review

    The Genetic Basis of Panic Disorder

    Hae-Ran Na, Eun-Ho Kang, Jae-Hon Lee and Bum-Hee Yu
      • Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
    • Address for Correspondence: Bum-Hee Yu, MD. Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Korea. Tel: +82.2-3410-3583, Fax: +82.2-3410-6957, Email: bhyu@skku.edu
    Received January 19, 2011; Accepted March 22, 2011.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Panic disorder is one of the chronic and disabling anxiety disorders. There has been evidence for either genetic heterogeneity or complex inheritance, with environmental factor interactions and multiple single genes, in panic disorder's etiology. Linkage studies have implicated several chromosomal regions, but no research has replicated evidence for major genes involved in panic disorder. Researchers have suggested several neurotransmitter systems are related to panic disorder. However, to date no candidate gene association studies have established specific loci. Recently, researchers have emphasized genome-wide association studies. Results of two genome-wide association studies on panic disorder failed to show significant associations. Evidence exists for differences regarding gender and ethnicity in panic disorder. Increasing evidence suggests genes underlying panic disorder overlap, transcending current diagnostic boundaries. In addition, an anxious temperament and anxiety-related personality traits may represent intermediate phenotypes that predispose to panic disorder. Future research should focus on broad phenotypes, defined by comorbidity or intermediate phenotypes. Genome-wide association studies in large samples, studies of gene-gene and gene-environment interactions, and pharmacogenetic studies are needed.

    Keywords
    Panic Disorder; Genetics; Genome-Wide Association Study; Polymorphism

    INTRODUCTION

    Although more than a century has passed since panic symptoms were first described, panic disorder (PD) was not classified as a separate disorder entity until 1980. According to the DSM-IV, PD is defined by recurrent, unexpected panic attacks, for more than one month, in association with at least one of the following symptoms: persistent concern about having additional attacks, worry about the attacks' implications and/or consequences, or a significant change in behavior as a result of the attacks.

    Notably, while panic attacks are a defining feature of PD, they may also occur as symptoms of phobic disorders or sporadically in the absence of any anxiety disorder. The estimated lifetime prevalence of PD is 4.7%, and the median age of PD onset is 24 yr (1). However, the lifetime prevalence of isolated panic attacks has been estimated at 22.7% (2).

    PD causes substantial suffering and incurs economic costs to both patients and society at large (3). In addition, panic attacks are reportedly linked to increased cardiovascular morbidity and mortality (4). Therefore, researchers and clinicians should regard PD as an important psychiatric disease. However, no genetic basis for PD has been clearly defined, though interest and researches in this area are increasing. This article examines PD's genetic basis. We reviewed genetic studies of PD, focusing especially on genome-wide association studies (GWAS) that researchers have recently carried out regarding many psychiatric disorders, which have yielded novel genetic loci for additional research.

    GENETIC EPIDEMIOLOGY OF PANIC DISORDER

    For a long time, family and twin studies have suggested there are genetic influences on PD. Linkage analyses and association studies have become predominant, making up for several limitations of family and twin studies. However, they are still not sufficient for reaching a clear conclusion regarding PD's genetic basis.

    Family studies

    Researchers conducted family studies to examine whether a certain phenotype aggregates in some families, by comparing the phenotype prevalence among affected probands' relatives with that of unaffected controls' relatives. Early in the genetics-based research into PD, these studies were widely used to elucidate the disorder's genetic mechanism. Ever since psychiatrists knew PD as a family disease, six controlled family studies have documented an increased PD risk (5.7%-17.3%) among affected individuals' relatives (5-10). Furthermore, Goldstein et al. found a 17-fold increased PD risk in first-degree relatives of PD probands when their onset ages were below 20, whereas the study found only a 6-fold increased PD risk in first-degree relatives of probands when the onset age exceeded 20 yr (11). A meta-analytic report revealed the unadjusted aggregate risk for relatives of PD probands was 10.0%, compared with 2.1% for control subjects' relatives (12). Although family studies have clearly documented that PD aggregates in some families, these studies have some limitations, in that they did not distinguishing genetic contributions from environmental factors.

    Twin studies

    Twin studies, which supplement family studies, can provide additional information on the roles of genetic effects and of shared and unique environment effects. Twin studies of PD have demonstrated this phenotype is moderately heritable and that the concordance rate for monozygotic twins is higher than that for dizygotic twins. These findings indicate genetic factors contribute to PD's pathogenesis with an estimated heritability of 30%-40%. A meta-analysis of high-quality twin studies by Hettema et al. (12) estimated PD heritability at 0.43. A more recent analysis, by the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders, comprising more than 5,000 twins, showed a PD heritability of 0.28 (13). Thus, genes clearly contribute to the pathogenesis of PD, but environmental influences are also substantial.

    Multivariate modeling of twin data suggests little contribution by the shared environment (i.e., experiences and familial factors common to both twins), with most of the variance attributable to the individual-specific environment, which also includes the measurement error (12, 13). Although family and twin studies provided support for PD's genetic propensity, they did not provide clear evidence of Mendelian inheritance of PD, which suggested a single gene's individual effect may be minor.

    LINKAGE ANALYSES

    Linkage analysis is a method commonly used to map probable genetic loci for specific diseases through observing related individuals. Allelic heterogeneity does not affect linkage analysis, which applies to both monogenetic (parametric linkage) and complex disease (model-free or non-parametric linkage) including PD. A linkage study's advantage lies in the lack of any need for a priori hypothesis to identify risk loci for a particular disease. However, its detection sensitivity in complex genetic diseases is rather low, particularly given single genes' small individual effects in complex genetic diseases, such as PD. Several groups have undertaken linkage studies to map the relevant loci in PD, which have implicated several chromosomal regions, including 1q(14), 2q(15), 4q31-q34(16, 17), 7p(18, 19), 9q(17, 20), 12q(21), 13q(17, 22),14q(17, 23), 15q(15), and 22q(17, 24). However, linkage anlayses for PD have shown little consistency.

    ASSOCIATION STUDIES

    Although linkage analysis has yielded many implications regarding PD's genetic basis, such an analysis has limitations regarding complex (non-Mendelian) traits. Association analyses, which compare single-locus alleles or genotype frequencies (or, more generally, multilocus haplotype frequencies) between diseased subjects and healthy controls, have come to the forefront in genetic studies these days. Association analyses aim to identify the susceptibility loci. Most association studies of PD were limited to the candidate gene that was hypothesized to be causally related to the phenotype. In such a case, the candidate alleles should include variants that are either directly related to the phenotype or strongly correlated with (i.e., in linkage disequilibrium with) such causal variants. Association analyses of PD have implicated several genes that are essentially classical candidate genes, such as MAOA, COMT, ADORA2A, and CCK-BR. To date, association studies of PD have examined more than 350 candidate genes, but most results were inconsistent, negative, or not clearly replicated. Only the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene has been implicated in susceptibility to PD by several studies on independent samples. A recent meta-analysis confirmed this implication. Here, we review several PD candidate genes, based on monaminergic neurotransmitter systems. Fig. 1 shows various systems that may be related to PD.

    Fig. 1
    Brain systems that may be ralated to panic disorder. COMT, catechol-O-methyltransferase; 5-HT, 5-hydroxytryptamine; MAO, Monoamine oxidase; CCK, Cholecystokinin; GABA, γ-aminobutyric acid; NPY, neuropeptide Y.

    Catechol-O-methyltransferase (COMT)

    The COMT gene encodes the protein catechol-O-methyltransferase, an enzyme involved in the catabolic breakdown of catecholamines. Anxiety states associate with significantly elevated erythrocyte COMT activity (25). The COMT gene is located on chromosome 22q11.2. A single-nucleotide polymorphism (472G/A) in the COMT gene causes an amino acid change, at position 158, from valine to methionine. The gene harbors a DNA polymorphism, common across all human populations, that leads to alterations in the enzyme's activity. The COMT 158val allele confers higher COMT activity than the COMT 158met allele does (25). This polymorphism, variably called Val158Met or rs4680, has been examined in a number of studies, using both linkage and association paradigms, with samples ranging from as few as 29 cases to nearly 200 cases. Four of eight studies reported nominally significant findings among 255 cases, 249 controls, 163 trios, and 70 multiplex pedigrees (26-29) and negative results among 361 cases and 1,815 controls (30-33).

    Several of the positive associations appeared more pronounced in female subsets of the samples. One subset meta-analysis showed no consistent association but did suggest a heterogeneity between the findings, possibly driven by ethnicity (34). Another meta-analysis suggested the same general conclusion, but its authors argued ethnicity- and gender-specific analyses supported an association between the Val158Met polymorphism and PD (35). Given the multiple positive findings in case-control studies and family-based association studies, COMT seems to be one of the few consistent findings in PD genetics. However, the actual associated allele remains unknown, although previous studies have reported a prominent ethnic heterogeneity in the Val158Met SNP's DNA diversity pattern and the specific allele frequency (36). As mentioned above, the alleles of genes that some studies have defined, some different studies have implicated, while yet others have produced negative results, raising the risk of false negatives. So, although researchers have conducted a number of association studies, they have identified no specific gene as a susceptibility locus. This genetic variation's particular role in PD requires additional analysis, considering its gender- and ethnicity-dependent effect and putative impact on cognitive functions.

    Serotonergic (5-hydroxy-tryptamine [5-HT]) system

    The serotonergic 5-HT system plays an important role in both the pathophysiology and treatment of PD. Challenge studies with carbon dioxide-induced panic and brain imaging findings have shown that the 5-HT system has an association with panic symptoms. Also, selective serotonin-reuptake inhibitors are used as first-line pharmacological treatments for PD.

    Tryptophan hydroxylase (TPH), the rate-limiting enzyme in 5-HT biosynthesis, has two isoforms. TPH1 is mainly responsible for the synthesis of 5-HT in peripheral organs, and TPH2, in the central nervous system (CNS) (37). The TPH1 gene is located on chromosome 11p15.3-p14. Several studies showed no association between PD and the TPH1 218A/C SNP in intron 7 (38-40). The human TPH2 gene is located on chromosome 12q21. A German sample found no association between the disorder and the TPH2 SNPs rs4570625 and rs4565946 or their haplotypes (41). A study with a Korean sample, however, described a significant difference in rs4570625 allele frequency between patients and normal controls and showed this may have a gender-dependent effect on susceptibility to PD (42). A study of Estonian female patients with PD also observed an association with rs1386494 (43).

    The effects of serotonergic neurotransmission are mediated by at least 18 different serotonin receptors (5-HTR). Table 1 shows many of the studies that have produced conflicting results about the relationship between 5-HTR and PD.

    Table 1
    Genetic studies on serotonergic receptors in panic disorder

    The human serotonin transporter (5-HTT), a critical regulator of serotonergic function and the initial target of antidepressant drugs, is encoded by a single-copy gene (SLC6A4) located on chromosome 17q12. A 44-bp length variation in its upstream regulatory region (5-HTTLPR) modulates 5-HTT gene transcription, with a functional impact on serotonin transporter activity. While one study of an Estonian sample reported an association between PD and the 5-HTTLPR long allele (39), most studies, with samples from other populations, have observed no association between 5-HTTLPR and PD (44). One meta-analysis found no statistically significant association between 5-HTTLPR and PD (45). Recent evidence, however, suggests carriers of the 5-HTTLPR short allele might suffer from more severe panic and depressive symptoms (46) and that variants other than 5-HTTLPR might associate with PD (47). A functional polymorphism in the 5-HTT gene, which alters the balance of the two polyadenylation forms of 5-HTT (rs3813034), may be such a PD risk factor (48).

    Monoamine oxidase (MAO)

    MAO is a mitochondrial enzyme that catalyzes the degradation of several biogenic amines intracellularly. The human gene encoding MAOA is located on chromosome Xp11.3. Among its several polymorphisms, MAOA gene-linked polymorphic regions (MAOA-LPR, MAOA-uVNTR) modulate the MAOA gene's transcriptional activity and gender-specifically influence cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations (49). A study found the functionally-more-active, longer alleles (3.5, 4, and 5) significantly associated with PD in female subgroups of the study's German and Italian patients (50). However, a study of a Columbian family sample detected no genetic linkage or association between the functional promoter polymorphism in the MAOA gene and PD (51).

    Cholecystokinin (CCK)

    The gastrin-like neuropeptide, CCK neuro-modulator, is one of the most abundant neurotransmitter peptides in the brain. CCK plays an important role in PD's neurobiology, in both humans and animals, via interaction with dopamine and other neurotransmitters (52). CCK receptor agonists, such as the carboxy-terminal tetrapeptide of CCK-4, provoke panic attacks with significantly greater efficacy in patients than they do in controls.

    The human CCK gene is on the short arm of human chromosome 3. An initial study showed a positive association between PD and the promoter variant (-36C > T; rs1799923) in the CCK gene (53), but others did not replicate the results (54, 55). One study described the protective effects of the promoter variant (-36C > T; rs1799923) and an intron 1 polymorphism (IVS1-7C > G; rs754635) in the CCK gene against PD (56).

    CCK receptors differentiate into two subtypes, CCK A receptor (CCK-AR) and CCK B receptor (CCK-BR), based on their affinities for a structurally- and functionally-related peptide family. CCK-BR is widely distributed throughout the CNS, whereas CCK-AR is only found in circumscribed brain regions (57). The CCK-AR gene has been mapped to chromosome 4p15.2-15.1, which encompasses the dopamine D5 gene locus (58). Association studies on polymorphisms of the CCK-AR gene provided ambiguous results regarding the association between PD and CCK-AR -81A/G and -128G/T promoter polymorphisms in a Japanese sample (59) and negative findings regarding a polymorphism in the 3'-untranslated region of the CCK-AR gene and the PstI polymorphism in the boundary between intron 1 and exon 2 of the CCK-AR gene (60, 61). Another study described a two-marker haplotype (rs1800855/rs1800857) in the CCK-AR gene as protective against PD in women (56). The gene for CCK-BR, which contains a 1,356-bp open reading frame comprising five exons interspersed with four introns, has been located on chromosome 11p15.4 (62). The long alleles of the CCK-BR computed tomography repeat polymorphism showed a significant association with PD in two Caucasian samples (55, 60) but not in Asian or in other Caucasian samples (54, 63, 64). A missense mutation in the extracellular loop of exon 2 (1550 G > A, Val125 > Ile) of CCK-BR showed no association with PD in a Japanese sample (65).

    Other candidate systems

    Table 2 presents other studies on genetic effects regarding PD. A non-monoaminergic candidate system for association with PD is the GABA (γ-aminobutyric acid) neurotransmitter system. GABA is the most important inhibitory neurotransmitter, and GABAA receptor is the prime target of the anxiolytic benzodiazepines. However, there have been conflicting results regarding the GABA system's genetic effects on PD, including glutamate decarboxylase (GAD), the GABA receptor, and the GABA transporter.

    Table 2
    Genetic studies on other brain systems that may be associated with panic disorder

    Adenosine, the purine nucleoside, acts as another important inhibitory neuromodulator besides GABA. There have also been conflicting results regarding several adenosine receptors (ADORA) associations with PD.

    Reportedly, neuropeptide Y (NPY) is involved in the pathophysiology of anxiety and of PD in particular. There have been conflicting results regarding associations with PD.

    Brain-derived neurotrophic factor (BDNF) acts on certain neurons of the CNS, particularly serotonergic neurons, helping to support the survival of existing neurons and to encourage the growth and differentiation of new neurons and synapses. However, recent research has shown BDNF does not show genetic effects in regard to PD. The neuropeptide angiotensin is involved in the regulation of respiration, which has been suggested as a key mechanism in the development of panic attacks. However, the angiotensin system does not show genetic effects regarding PD, either. Table 2 shows selected BDNF and angiotensin results.

    PD studies on genes related to the hypothalamic-pituitary-adrenal (HPA) axis have had negative results. Other studies have focused on genes coding for sexual hormones, because of the marked gender difference in PD prevalence. Galanin (GAL), involved in the hypothalamic-hypophysiotropic signaling process, is co-secreted with luteinizing hormone-releasing hormone (LHRH), possibly acting as an estrogen mediator. The promoter region of GAL has been suggested as having genetic effects regarding PD.

    Genome-wide association study (GWAS)

    Since the first GWAS saw publication in March 2005 (66), researchers have used GWAS to identify associations between genetic loci-related traits and diseases. In 2009, the first GWAS of PD was published. It examined 200 Japanese patients and the same number of controls, using the GeneChip Human Mapping 500 K Array Set. The authors reported two findings regarding loci that reached significance using stringent statistical thresholds (i.e., P values < 5 × 10-8). One of these loci lies within an intron of the PKP1 gene, which encodes plakophilin 1, a protein involved in desmosome formation, and which, when mutated, leads to dermatologic syndromes in humans. The other locus lies within an intron of ANO2, which encodes anoctamin 2, a transmembrane protein that researchers recently found to function as a calcium-activated chloride channel in the olfactory epithelium. These researchers conducted a second replication analysis of PD, examining 558 Japanese patients and 566 controls using the DigTag2 assay and reported this analysis in 2010 (67). They tested 32 markers in the replication sample. In their results, they found no significant association, after correcting for multiple testing. However, they observed a difference at the nominal allele P value, < 0.05, for two SNPs (rs6733840 and rs132617). They also conducted haplotype analyses of SNPs in the APOL3 and CLU genes. However, no results showed any significant association with PD for these genes. If studies find specific GWAS genes underlying PD, this might alter the way psychiatrists understand PD's biology, and researchers and clinicians might approach anxiety disorders from a new viewpoint. Replication studies on reported variants and further studies with larger sample sizes are needed.

    CONSIDERATIONS IN THE GENETIC STUDIES OF PANIC DISORDER

    Although studies have achieved tremendous results regarding a genetic basis for PD so far, researchers have not reached a clear conclusion. Linkage analyses have suggested that several chromosomal regions associate with PD, but they have not yet identified a major gene for PD. Here, we discuss several limitations of genetic studies of PD, including considerations of current diagnostic problems with the DSM-IV criteria for PD.

    Small sample size

    A small sample size, typically fewer than 200 patients, raises the problem of a lack of statistical power. It seems to be one of the reasons for inconsistent results.

    Gender and ethnic specificity

    PD is approximately twice as prevalent in women as in men. Several studies suggest a gender-specific difference in the genetic susceptibility to PD. Three independent studies reported an association between PD and the high-activity COMT 158val allele in female patients (26, 28, 29). In addition, studies have observed associations between PD and the rs1386494 SNP of TPH2 (43) and between PD and MAOA gene variations (50), but only in the female patient subgroups. Furthermore, a meta-analysis showed PD's ethnic heterogeneity (35). Researchers have observed different associations between COMT and PD in Caucasian samples versus in Asian samples, showing PD associated with the COMT 158val allele (28, 29, 68) and the COMT 158met allele (27, 30), as the respective major alleles. Thus, future studies should consider ethnicity.

    Gene-gene interaction and gene-environment interaction

    Genetic complexity has a significant influence on PD, since it reflects the additive or interactive effects of multiple loci with small individual effects. Some preliminary evidence suggests gene-gene interactions. A study described a nominally significant interaction between the functional 5-HTR1A 1019C/G and COMT (472G/A = V158M) polymorphisms in PD (69). Also, gene-environment interactions should be considered in the etiology of PD. Researchers have observed significant associations between caffeine-induced anxiety and the ADORA2A polymorphism (70-72). A study reported a significant interaction between levels of childhood emotional (or physical) maltreatment and a serotonin transporter variant with regard to anxiety sensitivity (73), which clinicians consider a risk phenotype for PD.

    Multiple phenotypes

    Other factors accounting for the data inconsistency might relate to PD's phenotypic complexity; psychiatrists currently regard the definitions of adequate phenotypes and intermediate phenotypes as matters for discussion. The current psychiatric diagnostic systems, such as the DSM-IV, are not clearly optimal for gene studies' purposes. In the large Virginia twin sample, Hettema et al. (13) found that genetic and environmental influences on anxiety disorders were not isomorphic with the clinically-defined categories. Molecular genetic studies have supported the idea that genetic effects regarding PD transcend diagnostic boundaries (16, 21). Smoller et al. (21) found some evidence of linkage to a locus on chromosome 10q for a phenotype comprising PD and other anxiety disorders. In another linkage analysis, Kaabi et al. (16) observed a significant linkage between chromosome 4q and a phenotype comprising PD, agoraphobia, social phobia, and specific phobia. In addition, several candidate genes (e.g., COMT, MAOA) have shown associations with PD and phobic anxiety (27, 28, 50, 68). Reportedly the glutamic acid decarboxylase 1 (GAD1) gene shows an association with a genetic liability underlying PD, generalized anxiety disorder, phobias, major depressive disorder, and the anxiety-related personality trait of neuroticism (74). Notably, researchers have found the strongest evidence of linkage when using phenotype definitions broadened beyond the DSM-IV criteria's boundaries of diagnosis. Studies encountered strong evidence for the 13q locus when defining the phenotype as a syndrome including PD and several other medical conditions -mitral valve prolapse, serious headaches, and/or thyroid problems (22, 24). In another study, on multiplex Icelandic families, Thorgeirsson et al. (20) observed a genome-wide significant Lod score of 4.18, on chromosome 9q, for a phenotype that included comorbid anxiety disorders. In the largest linkage analysis to date, Fyer et al. (15) reported a genome-wide significant linkage to 15q, using a broad panic phenotype that included sporadic and limited-symptom panic attacks in addition to PD.

    Personality traits might have important correlations to PD, as well. One personality trait, introversion, is characterized by low levels of sociability, high levels of arousal, and a relatively low propensity to experience positive emotions. Another trait, neuroticism, reflects negative affectivity or the tendency to experience negative emotions (anxiety, sadness, anger). Introversion (low extraversion) and neuroticism have an estimated heritability of 0.30-0.50, which is elevated for individuals with PD. These traits may underlie PD and comorbid major depression, as well (75). In addition, harm avoidance, which comprises fearful, socially inhibited, easily tired, and pessimistic tendencies, has also been implicated in PD. High harm avoidance is frequently observed among patients with PD (76).

    The temperamental profile known as behavioral inhibition (BI) has been also implicated as a familial and developmental risk factor for PD. BI is observable in laboratory-based assessments as early as infancy. It consists of a stable tendency to be cautious, quiet, and behaviorally restrained in situations of novelty. Longitudinal and cross-sectional studies have supported the idea that BI is a developmental risk factor for PD (77, 78), social phobia (79), and other anxiety disorder symptomatologies (77, 80, 81). A series of studies have demonstrated elevated BI among offspring of parents with PD, with or without agoraphobia (82, 83). Neurobiological correlates of BI suggest sympathetic and HPA axis activation, right frontal cortical activation, and amygdala hyper-reactivity to novelty (84, 85). Genetic association studies have implicated several genes, including corticotrophin releasing hormone gene (86) and serotonin transporter (SLC6A4), which may influence the BI phenotype (87).

    CONCLUSION

    To identify specific genes involved in PD has been challenging because of PD's genetic and phenotypic complexity. GWAS replications with large samples, controlling for gender and ethnicity, are required. In addition, researchers conducting genetic investigations of PD should consider broad panic-relevant symptoms, including panic syndromes. Neuroimaging phenotypes may supplement the deficit in current genetic studies. We expect progress in the treatment of PD through deepening psychiatric knowledge regarding the genetic basis for this illness.

    AUTHOR SUMMARY

    The Genetic Basis of Panic Disorder

    Hae-Ran Na, Eun-Ho Kang, Jae-Hon Lee and Bum-Hee Yu

    Panic disorder is one of the chronic and disabling anxiety disorders. There has been evidence for either genetic heterogeneity or complex inheritance, with environmental factor interactions and multiple single genes, in panic disorder's etiology. However, to date no candidate gene association studies have established specific loci. Increasing evidence suggests genes underlying panic disorder overlap, transcending current diagnostic boundaries. In addition, an anxious temperament and anxiety-related personality traits may represent intermediate phenotypes that predispose to panic disorder. Future research should focus on broad phenotypes, defined by comorbidity or intermediate phenotypes. Genome-wide association studies in large samples, studies of gene-gene and gene-environment interactions, and pharmacogenetic studies are needed.

    References

      1. Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62:617–627.
      1. Kessler RC, Chiu WT, Jin R, Ruscio AM, Shear K, Walters EE. The epidemiology of panic attacks, panic disorder, and agoraphobia in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2006;63:415–424.
      1. Greenberg PE, Sisitsky T, Kessler RC, Finkelstein SN, Berndt ER, Davidson JR, Ballenger JC, Fyer AJ. The economic burden of anxiety disorders in the 1990s. J Clin Psychiatry 1999;60:427–435.
      1. Smoller JW, Pollack MH, Wassertheil-Smoller S, Jackson RD, Oberman A, Wong ND, Sheps D. Panic attacks and risk of incident cardiovascular events among postmenopausal women in the Women's Health Initiative Observational Study. Arch Gen Psychiatry 2007;64:1153–1160.
      1. Noyes R Jr, Crowe RR, Harris EL, Hamra BJ, McChesney CM, Chaudhry DR. Relationship between panic disorder and agoraphobia. A family study. Arch Gen Psychiatry 1986;43:227–232.
      1. Goldstein RB, Weissman MM, Adams PB, Horwath E, Lish JD, Charney D, Woods SW, Sobin C, Wickramaratne PJ. Psychiatric disorders in relatives of probands with panic disorder and/or major depression. Arch Gen Psychiatry 1994;51:383–394.
      1. Fyer AJ, Katon W, Hollifield M, Rassnick H, Mannuzza S, Chapman T, Ballenger JC. The DSM-IV panic disorder field trial: panic attack frequency and functional disability. Anxiety 1996;2:157–166.
      1. Horwath E, Wolk SI, Goldstein RB, Wickramaratne P, Sobin C, Adams P, Lish JD, Weissman MM. Is the comorbidity between social phobia and panic disorder due to familial cotransmission or other factors? Arch Gen Psychiatry 1995;52:574–582.
      1. Maier W, Lichtermann D, Minges J, Oehrlein A, Franke P. A controlled family study in panic disorder. J Psychiatr Res 1993;27 Suppl 1:79–87.
      1. Mendlewicz J, Sevy S, Mendelbaum K. Minireview: Molecular genetics in affective illness. Life Sci 1993;52:231–242.
      1. Goldstein RB, Wickramaratne PJ, Horwath E, Weissman MM. Familial aggregation and phenomenology of 'early'-onset (at or before age 20 years) panic disorder. Arch Gen Psychiatry 1997;54:271–278.
      1. Hettema JM, Neale MC, Kendler KS. A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry 2001;158:1568–1578.
      1. Hettema JM, Prescott CA, Myers JM, Neale MC, Kendler KS. The structure of genetic and environmental risk factors for anxiety disorders in men and women. Arch Gen Psychiatry 2005;62:182–189.
      1. Gelernter J, Bonvicini K, Page G, Woods SW, Goddard AW, Kruger S, Pauls DL, Goodson S. Linkage genome scan for loci predisposing to panic disorder or agoraphobia. Am J Med Genet 2001;105:548–557.
      1. Fyer AJ, Hamilton SP, Durner M, Haghighi F, Heiman GA, Costa R, Evgrafov O, Adams P, de Leon AB, Taveras N, Klein DF, Hodge SE, Weissman MM, Knowles JA. A third-pass genome scan in panic disorder: evidence for multiple susceptibility loci. Biol Psychiatry 2006;60:388–401.
      1. Kaabi B, Gelernter J, Woods SW, Goddard A, Page GP, Elston RC. Genome scan for loci predisposing to anxiety disorders using a novel multivariate approach: strong evidence for a chromosome 4 risk locus. Am J Hum Genet 2006;78:543–553.
      1. Maron E, Hettema JM, Shlik J. Advances in molecular genetics of panic disorder. Mol Psychiatry 2010;15:681–701.
      1. Knowles JA, Fyer AJ, Vieland VJ, Weissman MM, Hodge SE, Heiman GA, Haghighi F, de Jesus GM, Rassnick H, Preud'homme-Rivelli X, Austin T, Cunjak J, Mick S, Fine LD, Woodley KA, Das K, Maier W, Adams PB, Freimer NB, Klein DF, Gilliam TC. Results of a genome-wide genetic screen for panic disorder. Am J Med Genet 1998;81:139–147.
      1. Crowe RR, Goedken R, Samuelson S, Wilson R, Nelson J, Noyes R Jr. Genomewide survey of panic disorder. Am J Med Genet 2001;105:105–109.
      1. Thorgeirsson TE, Oskarsson H, Desnica N, Kostic JP, Stefansson JG, Kolbeinsson H, Lindal E, Gagunashvili N, Frigge ML, Kong A, Stefansson K, Gulcher JR. Anxiety with panic disorder linked to chromosome 9q in Iceland. Am J Hum Genet 2003;72:1221–1230.
      1. Smoller JW, Acierno JS Jr, Rosenbaum JF, Biederman J, Pollack MH, Meminger S, Pava JA, Chadwick LH, White C, Bulzacchelli M, Slaugenhaupt SA. Targeted genome screen of panic disorder and anxiety disorder proneness using homology to murine QTL regions. Am J Med Genet 2001;105:195–206.
      1. Weissman MM, Fyer AJ, Haghighi F, Heiman G, Deng Z, Hen R, Hodge SE, Knowles JA. Potential panic disorder syndrome: clinical and genetic linkage evidence. Am J Med Genet 2000;96:24–35.
      1. Middeldorp CM, Hottenga JJ, Slagboom PE, Sullivan PF, de Geus EJ, Posthuma D, Willemsen G, Boomsma DI. Linkage on chromosome 14 in a genome-wide linkage study of a broad anxiety phenotype. Mol Psychiatry 2008;13:84–89.
      1. Hamilton SP, Fyer AJ, Durner M, Heiman GA, Baisre de, Hodge SE, Knowles JA, Weissman MM. Further genetic evidence for a panic disorder syndrome mapping to chromosome 13q. Proc Natl Acad Sci USA 2003;100:2550–2555.
      1. Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM. Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 1996;6:243–250.
      1. Hamilton SP, Slager SL, Heiman GA, Deng Z, Haghighi F, Klein DF, Hodge SE, Weissman MM, Fyer AJ, Knowles JA. Evidence for a susceptibility locus for panic disorder near the catechol-O-methyltransferase gene on chromosome 22. Biol Psychiatry 2002;51:591–601.
      1. Woo JM, Yoon KS, Yu BH. Catechol O-methyltransferase genetic polymorphism in panic disorder. Am J Psychiatry 2002;159:1785–1787.
      1. Domschke K, Freitag CM, Kuhlenbäumer G, Schirmacher A, Sand P, Nyhuis P, Jacob C, Fritze J, Franke P, Rietschel M, Garritsen HS, Fimmers R, Nöthen MM, Lesch KP, Stögbauer F, Deckert J. Association of the functional V158M catechol-O-methyl-transferase polymorphism with panic disorder in women. Int J Neuropsychopharmacol 2004;7:183–188.
      1. Rothe C, Koszycki D, Bradwejn J, King N, Deluca V, Tharmalingam S, Macciardi F, Deckert J, Kennedy JL. Association of the Val158Met catechol O-methyltransferase genetic polymorphism with panic disorder. Neuropsychopharmacology 2006;31:2237–2242.
      1. Ohara K, Nagai M, Suzuki Y, Ochiai M. No association between anxiety disorders and catechol-O-methyltransferase polymorphism. Psychiatry Res 1998;80:145–148.
      1. Rotondo A, Mazzanti C, Dell'Osso L, Rucci P, Sullivan P, Bouanani S, Gonnelli C, Goldman D, Cassano GB. Catechol o-methyltransferase, serotonin transporter, and tryptophan hydroxylase gene polymorphisms in bipolar disorder patients with and without comorbid panic disorder. Am J Psychiatry 2002;159:23–29.
      1. Wray NR, James MR, Dumenil T, Handoko HY, Lind PA, Montgomery GW, Martin NG. Association study of candidate variants of COMT with neuroticism, anxiety and depression. Am J Med Genet B Neuropsychiatr Genet 2008;147B:1314–1318.
      1. Woo JM, Yoon KS, Choi YH, Oh KS, Lee YS, Yu BH. The association between panic disorder and the L/L genotype of catechol-O-methyltransferase. J Psychiatr Res 2004;38:365–370.
      1. Zintzaras E, Sakelaridis N. Is 472G/A catechol-O-methyl-transferase gene polymorphism related to panic disorder? Psychiatr Genet 2007;17:267–273.
      1. Domschke K, Deckert J, O'Donovan MC, Glatt SJ. Meta-analysis of COMT val158met in panic disorder: ethnic heterogeneity and gender specificity. Am J Med Genet B Neuropsychiatr Genet 2007;144B:667–673.
      1. Palmatier MA, Kang AM, Kidd KK. Global variation in the frequencies of functionally different catechol-O-methyltransferase alleles. Biol Psychiatry 1999;46:557–567.
      1. McKinney J, Knappskog PM, Haavik J. Different properties of the central and peripheral forms of human tryptophan hydroxylase. J Neurochem 2005;92:311–320.
      1. Kim W, Choi YH, Yoon KS, Cho DY, Pae CU, Woo JM. Tryptophan hydroxylase and serotonin transporter gene polymorphism does not affect the diagnosis, clinical features and treatment outcome of panic disorder in the Korean population. Prog Neuropsychopharmacol Biol Psychiatry 2006;30:1413–1418.
      1. Maron E, Lang A, Tasa G, Liivlaid L, Tõru I, Must A, Vasar V, Shlik J. Associations between serotonin-related gene polymorphisms and panic disorder. Int J Neuropsychopharmacol 2005;8:261–266.
      1. Yoon HK, Yang JC, Lee HJ, Kim YK. The association between serotonin-related gene polymorphisms and panic disorder. J Anxiety Disord 2008;22:1529–1534.
      1. Mössner R, Freitag CM, Gutknecht L, Reif A, Tauber R, Franke P, Fritze J, Wagner G, Peikert G, Wenda B, Sand P, Rietschel M, Garritsen H, Jacob C, Lesch KP, Deckert J. The novel brain-specific tryptophan hydroxylase-2 gene in panic disorder. J Psychopharmacol 2006;20:547–552.
      1. Kim YK, Lee HJ, Yang JC, Hwang JA, Yoon HK. A tryptophan hydroxylase 2 gene polymorphism is associated with panic disorder. Behav Genet 2009;39:170–175.
      1. Maron E, Tõru I, Must A, Tasa G, Toover E, Vasar V, Lang A, Shlik J. Association study of tryptophan hydroxylase 2 gene polymorphisms in panic disorder. Neurosci Lett 2007;411:180–184.
      1. Ishiguro H, Arinami T, Yamada K, Otsuka Y, Toru M, Shibuya H. An association study between a transcriptional polymorphism in the serotonin transporter gene and panic disorder in a Japanese population. Psychiatry Clin Neurosci 1997;51:333–335.
      1. Blaya C, Salum GA, Lima MS, Leistner-Segal S, Manfro GG. Lack of association between the Serotonin Transporter Promoter Polymorphism (5-HTTLPR) and Panic Disorder: a systematic review and meta-analysis. Behav Brain Funct 2007;3:41.
      1. Lonsdorf TB, Rück C, Bergström J, Andersson G, Ohman A, Schalling M, Lindefors N. The symptomatic profile of panic disorder is shaped by the 5-HTTLPR polymorphism. Prog Neuropsychopharmacol Biol Psychiatry 2009;33:1479–1483.
      1. Strug LJ, Suresh R, Fyer AJ, Talati A, Adams PB, Li W, Hodge SE, Gilliam TC, Weissman MM. Panic disorder is associated with the serotonin transporter gene (SLC6A4) but not the promoter region (5-HTTLPR). Mol Psychiatry 2010;15:166–176.
      1. Gyawali S, Subaran R, Weissman MM, Hershkowitz D, McKenna MC, Talati A, Fyer AJ, Wickramaratne P, Adams PB, Hodge SE, Schmidt CJ, Bannon MJ, Glatt CE. Association of a polyadenylation polymorphism in the serotonin transporter and panic disorder. Biol Psychiatry 2010;67:331–338.
      1. Jönsson EG, Norton N, Forslund K, Mattila-Evenden M, Rylander G, Asberg M, Owen MJ, Sedvall GC. Association between a promoter variant in the monoamine oxidase A gene and schizophrenia. Schizophr Res 2003;61:31–37.
      1. Deckert J, Catalano M, Syagailo YV, Bosi M, Okladnova O, Di Bella D, Nothen MM, Maffei P, Franke P, Fritze J, Maier W, Propping P, Beckmann H, Bellodi L, Lesch KP. Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder. Hum Mol Genet 1999;8:621–624.
      1. Hamilton SP, Slager SL, Heiman GA, Haghighi F, Klein DF, Hodge SE, Weissman MM, Fyer AJ, Knowles JA. No genetic linkage or association between a functional promoter polymorphism in the monoamine oxidase-A gene and panic disorder. Mol Psychiatry 2000;5:465–466.
      1. Vanderhaeghen JJ, Signeau JC, Gepts W. New peptide in the vertebrate CNS reacting with antigastrin antibodies. Nature 1975;257:604–605.
      1. Wang Z, Valdes J, Noyes R, Zoega T, Crowe RR. Possible association of a cholecystokinin promotor polymorphism (CCK-36CT) with panic disorder. Am J Med Genet 1998;81:228–234.
      1. Hamilton SP, Slager SL, Helleby L, Heiman GA, Klein DF, Hodge SE, Weissman MM, Fyer AJ, Knowles JA. No association or linkage between polymorphisms in the genes encoding cholecystokinin and the cholecystokinin B receptor and panic disorder. Mol Psychiatry 2001;6:59–65.
      1. Hösing VG, Schirmacher A, Kuhlenbäumer G, Freitag C, Sand P, Schlesiger C, Jacob C, Fritze J, Franke P, Rietschel M, Garritsen H, Nöthen MM, Fimmers R, Stögbauer F, Deckert J. Cholecystokinin- and cholecystokinin-B-receptor gene polymorphisms in panic disorder. J Neural Transm Suppl 2004:147–156.
      1. Koefoed P, Woldbye DP, Hansen TO, Hansen ES, Knudsen GM, Bolwig TG, Rehfeld JF. Gene variations in the cholecystokinin system in patients with panic disorder. Psychiatr Genet 2010;20:59–64.
      1. Mönnikes H, Lauer G, Arnold R. Peripheral administration of cholecystokinin activates c-fos expression in the locus coeruleus/subcoeruleus nucleus, dorsal vagal complex and paraventricular nucleus via capsaicin-sensitive vagal afferents and CCK-A receptors in the rat. Brain Res 1997;770:277–288.
      1. Huppi K, Siwarski D, Pisegna JR, Wank S. Chromosomal localization of the gastric and brain receptors for cholecystokinin (CCKAR and CCKBR) in human and mouse. Genomics 1995;25:727–729.
      1. Miyasaka K, Yoshida Y, Matsushita S, Higuchi S, Shirakawa O, Shimokata H, Funakoshi A. Association of cholecystokinin-A receptor gene polymorphisms and panic disorder in Japanese. Am J Med Genet B Neuropsychiatr Genet 2004;127B:78–80.
      1. Kennedy JL, Bradwejn J, Koszycki D, King N, Crowe R, Vincent J, Fourie O. Investigation of cholecystokinin system genes in panic disorder. Mol Psychiatry 1999;4:284–285.
      1. Ise K, Akiyoshi J, Horinouchi Y, Tsutsumi T, Isogawa K, Nagayama H. Association between the CCK-A receptor gene and panic disorder. Am J Med Genet B Neuropsychiatr Genet 2003;118B:29–31.
      1. Song I, Brown DR, Wiltshire RN, Gantz I, Trent JM, Yamada T. The human gastrin/cholecystokinin type B receptor gene: alternative splice donor site in exon 4 generates two variant mRNAs. Proc Natl Acad Sci USA 1993;90:9085–9089.
      1. Yamada K, Hattori E, Shimizu M, Sugaya A, Shibuya H, Yoshikawa T. Association studies of the cholecystokinin B receptor and A2a adenosine receptor genes in panic disorder. J Neural Transm 2001;108:837–848.
      1. Hattori E, Ebihara M, Yamada K, Ohba H, Shibuya H, Yoshikawa T. Identification of a compound short tandem repeat stretch in the 5'-upstream region of the cholecystokinin gene, and its association with panic disorder but not with schizophrenia. Mol Psychiatry 2001;6:465–470.
      1. Kato T, Wang ZW, Zoega T, Crowe RR. Missense mutation of the cholecystokinin B receptor gene: lack of association with panic disorder. Am J Med Genet 1996;67:401–405.
      1. Manolio TA, Collins FS. The HapMap and genome-wide association studies in diagnosis and therapy. Annu Rev Med 2009;60:443–456.
      1. Otowa T, Tanii H, Sugaya N, Yoshida E, Inoue K, Yasuda S, Shimada T, Kawamura Y, Tochigi M, Minato T, Umekage T, Miyagawa T, Nishida N, Tokunaga K, Okazaki Y, Kaiya H, Sasaki T. Replication of a genome-wide association study of panic disorder in a Japanese population. J Hum Genet 2010;55:91–96.
      1. Samochowiec J, Hajduk A, Samochowiec A, Horodnicki J, Stepień G, Grzywacz A, Kucharska-Mazur J. Association studies of MAO-A, COMT, and 5-HTT genes polymorphisms in patients with anxiety disorders of the phobic spectrum. Psychiatry Res 2004;128:21–26.
      1. Freitag CM, Domschke K, Rothe C, Lee YJ, Hohoff C, Gutknecht L, Sand P, Fimmers R, Lesch KP, Deckert J. Interaction of serotonergic and noradrenergic gene variants in panic disorder. Psychiatr Genet 2006;16:59–65.
      1. Alsene K, Deckert J, Sand P, de Wit H. Association between A2a receptor gene polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology 2003;28:1694–1702.
      1. Childs E, Hohoff C, Deckert J, Xu K, Badner J, de Wit H. Association between ADORA2A and DRD2 polymorphisms and caffeine-induced anxiety. Neuropsychopharmacology 2008;33:2791–2800.
      1. Rogers PJ, Hohoff C, Heatherley SV, Mullings EL, Maxfield PJ, Evershed RP, Deckert J, Nutt DJ. Association of the anxiogenic and alerting effects of caffeine with ADORA2A and ADORA1 polymorphisms and habitual level of caffeine consumption. Neuropsychopharmacology 2010;35:1973–1983.
      1. Stein MB, Schork NJ, Gelernter J. Gene-by-environment (serotonin transporter and childhood maltreatment) interaction for anxiety sensitivity, an intermediate phenotype for anxiety disorders. Neuropsychopharmacology 2008;33:312–319.
      1. Hettema JM, An SS, Neale MC, Bukszar J, van den Oord EJ, Kendler KS, Chen X. Association between glutamic acid decarboxylase genes and anxiety disorders, major depression, and neuroticism. Mol Psychiatry 2006;11:752–762.
      1. Bienvenu OJ, Nestadt G, Samuels JF, Costa PT, Howard WT, Eaton WW. Phobic, panic, and major depressive disorders and the five-factor model of personality. J Nerv Ment Dis 2001;189:154–161.
      1. Wachleski C, Salum GA, Blaya C, Kipper L, Paludo A, Salgado AP, Manfro GG. Harm avoidance and self-directedness as essential features of panic disorder patients. Compr Psychiatry 2008;49:476–481.
      1. Isolan LR, Zeni CP, Mezzomo K, Blaya C, Kipper L, Heldt E, Manfro GG. Behavioral inhibition and history of childhood anxiety disorders in Brazilian adult patients with panic disorder and social anxiety disorder. Rev Bras Psiquiatr 2005;27:97–100.
      1. Rosenbaum JF, Biederman J, Hirshfeld DR, Bolduc EA, Chaloff J. Behavioral inhibition in children: a possible precursor to panic disorder or social phobia. J Clin Psychiatry 1991;52 Suppl:5–9.
      1. Rotge JY, Grabot D, Aouizerate B, Pélissolo A, Lépine JP, Tignol J. Childhood history of behavioral inhibition and comorbidity status in 256 adults with social phobia. J Affect Disord 2011;129:338–341.
      1. Hirshfeld-Becker DR, Micco J, Henin A, Bloomfield A, Biederman J, Rosenbaum J. Behavioral inhibition. Depress Anxiety 2008;25:357–367.
      1. Rosenbaum JF, Biederman J, Bolduc-Murphy EA, Faraone SV, Chaloff J, Hirshfeld DR, Kagan J. Behavioral inhibition in childhood: a risk factor for anxiety disorders. Harv Rev Psychiatry 1993;1:2–16.
      1. Rosenbaum JF, Biederman J, Gersten M, Hirshfeld DR, Meminger SR, Herman JB, Kagan J, Reznick JS, Snidman N. Behavioral inhibition in children of parents with panic disorder and agoraphobia. A controlled study. Arch Gen Psychiatry 1988;45:463–470.
      1. Rosenbaum JF, Biederman J, Hirshfeld-Becker DR, Kagan J, Snidman N, Friedman D, Nineberg A, Gallery DJ, Faraone SV. A controlled study of behavioral inhibition in children of parents with panic disorder and depression. Am J Psychiatry 2000;157:2002–2010.
      1. Fox NA, Henderson HA, Marshall PJ, Nichols KE, Ghera MM. Behavioral inhibition: linking biology and behavior within a developmental framework. Annu Rev Psychol 2005;56:235–262.
      1. Schwartz CE, Wright CI, Shin LM, Kagan J, Rauch SL. Inhibited and uninhibited infants "grown up": adult amygdalar response to novelty. Science 2003;300:1952–1953.
      1. Smoller JW, Yamaki LH, Fagerness JA, Biederman J, Racette S, Laird NM, Kagan J, Snidman N, Faraone SV, Hirshfeld-Becker D, Tsuang MT, Slaugenhaupt SA, Rosenbaum JF, Sklar PB. The corticotropin-releasing hormone gene and behavioral inhibition in children at risk for panic disorder. Biol Psychiatry 2005;57:1485–1492.
      1. Fox NA, Nichols KE, Henderson HA, Rubin K, Schmidt L, Hamer D, Ernst M, Pine DS. Evidence for a gene-environment interaction in predicting behavioral inhibition in middle childhood. Psychol Sci 2005;16:921–926.
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    MeSH Terms
    Catechol O-Methyltransferase/genetics
    Cholecystokinin/genetics
    Genetic Loci
    Genome-Wide Association Study*
    Humans
    Monoamine Oxidase/genetics
    Panic Disorder/genetics*
    Metrics
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