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A R T I C L E
AND
JENNIFER COVINO
Panic disorder and phobic anxiety disorders are common disorders that are often chronic and disabling. Genetic
epidemiologic studies have documented that these disorders are familial and moderately heritable. Linkage
studies have implicated several chromosomal regions that may harbor susceptibility genes; however, candidate
gene association studies have not established a role for any specific loci to date. Increasing evidence from family
and genetic studies suggests that genes underlying these disorders overlap and transcend diagnostic boundaries.
Heritable forms of anxious temperament, anxiety-related personality traits and neuroimaging assays of fear
circuitry may represent intermediate phenotypes that predispose to panic and phobic disorders. The identification
of specific susceptibility variants will likely require much larger sample sizes and the integration of insights from
genetic analyses of animal models and intermediate phenotypes. 2008 Wiley-Liss, Inc.
KEY WORDS: panic; anxiety disorders
How to cite this article: Smoller JW, Gardner-Schuster E, Covino J. 2008. The genetic basis of panic
and phobic anxiety disorders. Am J Med Genet Part C Semin Med Genet 148C:118126.
INTRODUCTION
Although panic and phobic anxiety were
described well before the 20th century, it
was not until the publication of DSM-III
in 1980 that the modern definitions
of panic and phobic anxiety disorders
formally entered psychiatric nosology.
According to DSM-IV, panic disorder is
defined by recurrent, unexpected panic
attacks that are associated with a least
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LTP (%)
AAO (years)
4.7
1.4
12.1
12.5
24
20
13
7
LTP, lifetime prevalence; AAO median age of onset. Data from Kessler et al. [2005].
GENETIC EPIDEMIOLOGY
OF PANIC AND PHOBIC
ANXIETY DISORDERS
Family and twin studies of panic disorder
and phobic disorders have provided
consistent evidence that these phenotypes are familial and heritable. As
discussed below, there is also evidence
that genetic influences on these disorders
overlap to some degree.
119
Family Studies
Family studies examine whether a
phenotype aggregates in families by
comparing the prevalence of the
phenotype among relatives of affected
probands to the prevalence among
relatives of unaffected controls. Six controlled family studies that included
probands with PD have been reported
Twin Studies
Although family studies have clearly
documented that panic and phobic
disorders aggregate in families, they
are unable to distinguish genetic and
environmental contributions. Twin studies, by comparing concordance rates of
genetically identical (MZ) versus nonidentical (DZ) twins, can estimate the
TABLE II. Weighted Summary Risks From Controlled Family Studies of Panic and Phobic Disorders
PD
Proband
diagnosis
PD
AWOPD
SAD
SP
Risk to
relatives (%)
10.6
6.6
7.9
0.0
AWOPD
SAD
SP
Risk to
Risk to
Risk to
OR (95% CI) relatives (%) OR (95% CI) relatives (%) OR (95% CI) relatives (%) OR (95% CI)
7.0 (4.411.3)
4.12 (2.17.9)
5.0 (2.59.7)
0 (04.6)
2.6
8.6
1.9
0
2.5 (1.15.8)
8.8 (4.219.6)
1.8 (0.198.2)
0 (07.5)
4.1
3.4
17.3
9.3
1.2 (0.692.2)
1.0 (0.432.2)
6.0 (3.79.8)
3.0 (0.878.0)
5.9
2.7
12.5
23.4
1.5 (0.711.8)
.50 (0.191.2)
2.6 (1.64.2)
5.6 (2.810.9)
PD, panic disorder; AWOPD, agorpahobia without a history of panic disorder; SAD, social anxiety disorder; SP, specific phobia.
a
Risk to first degree relatives of affected probands.
b
Odds ratio and 95% confidence interval for risk to first degree relatives of affected vs. control probands. Weighted summary data from
Noyes et al. [1986], Fyer et al. [1993, 1995, 1996], Mendlewicz et al. [1993], Goldstein et al. [1994], Horwath et al. [1995], Maier et al.
[1995], and Stein et al. [1998]. Bolded values indicate significant familial aggregation of phenotypes.
120
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TABLE III. Results of Linkage Studies of Panic and Phobic Anxiety Disorders
Families
Phenotype
23
20
7p (Lod 2.2)
1q (Lod 2.1), 11p (Lod 2.0)
3q (NPL 2.75, P 0.005)
12q (NPL 4.96, P 0.006)
13q (HLod 3.57), 22q (HLod 4.11)
9q (Lod 4.18)
14q (Lod 3.70)
16q (P 0.0003, Lod 2.22)
15q (Lod 2.56; genomewide empirical P 0.05)
2q (HLod 4.19; genomewide empirical P 0.02 with
sex-specific recombination fractions)
4q (genomewide P < 0.05)
PD AG
PD
AG
PD AG
PD syndrome
PD
Simple phobia
Social phobia
Severe panic attack or PD
1
60
25
14
17
120
19
Same family sample; Lod, logarithm of odds; PD, panic disorder; AG, agoraphobia; PD syndrome, phenotype of PD with or without
bladder/kidney problems, mitral valve prolapse, migraine headache, thyroid problems.
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121
122
social phobia and agoraphobia. [Bienvenu et al., 2004]. In a large twin sample,
Bienvenu et al. [2007] examined genetic
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CONCLUSIONS
It is clear that genetic factors influence
risk for panic and phobic disorders, but
identifying the specific genes involved
has been challenging given the genetic
and phenotypic complexity of these
conditions. The recent discovery of
susceptibility genes for other complex
medical disorders (e.g., diabetes, rheumatoid arthritis, heart disease, and
inflammatory bowel disease) provides
important proof that genes can be
found despite such complexity. However, these successes required genomewide association methods and much
larger samples than have been included
in studies of anxiety disorders. In
addition to the need for such large-scale
studies, genetic investigations of panic
and phobic anxiety disorders should
exploit the particular opportunities that
exist relevant to these disorders: namely,
the availability of well-characterized
animal models and putative intermediate
phenotypes that have been robustly
associated with the development and
biology of anxiety disorders. Gene
mapping and gene targeting studies
in mice have implicated specific genes
influencing anxious temperament
and conditioned fear behavior [Finn
et al., 2003; Willis-Owen and Flint,
2006], and human studies have identified behavioral and neuroimaging
123
REFERENCES
Albert CM, Chae CU, Rexrode KM, Manson JE,
Kawachi I. 2005. Phobic anxiety and risk of
coronary heart disease and sudden cardiac
death among women. Circulation 111:480
487.
Bienvenu OJ, Brown C, Samuels JF, Liang KY,
Costa PT, Eaton WW, Nestadt G. 2001.
Normal personality traits and comorbidity
among phobic, panic and major depressive
disorders. Psychiatry Res 102:7385.
Bienvenu OJ, Samuels JF, Costa PT, Reti IM,
Eaton WW, Nestadt G. 2004. Anxiety and
depressive disorders and the five-factor
model of personality: A higher- and lowerorder personality trait investigation in a
community sample. Depress Anxiety 20:
9297.
Bienvenu OJ, Hettema JM, Neale MC, Prescott
CA, Kendler KS. 2007. Low extraversion
and high neuroticism as indices of genetic
and environmental risk for social phobia,
agoraphobia, and animal phobia. Am
J Psychiatry 164:17141721.
Cloninger C. 1986. A unified biosocial theory of
personality and its role in the development
of anxiety states. Psychiatr Dev 3:167226.
Cloninger CR, Van Eerdewegh P, Goate A,
Edenberg HJ, Blangero J, Hesselbrock V,
Reich T, Nurnberger J Jr, Schuckit M,
Porjesz B, Crowe R, Rice JP, Foroud T,
Przybeck TR, Almasy L, Bucholz K, Wu W,
Shears S, Carr K, Crose C, Willig C, Zhao J,
Tischfield JA, Li TK, Conneally PM,
Begleiter H. 1998. Anxiety proneness linked
to epistatic loci in genome scan of human
personality traits. Am J Med Genet 81:313
317.
Crowe RR, Goedken R, Samuelson S, Wilson R,
Nelson J, Noyes R Jr. 2001. Genomewide
survey of panic disorder. Am J Med Genet
105:105109.
Deckert J, Nothen M, Franke P, Delmo C, Fritze
J, Knapp M, Maier W, Beckmann H,
Propping P. 1998. Systematic mutation
screening and association study of the A1
and A2a adenosine receptor genes in panic
disorder suggest a contribution of the A2a
gene to the development of disease. Mol
Psychiatry 3:8185.
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. 1999. Excess of high activity monoamine oxidase A gene promoter alleles in
female patients with panic disorder. Hum
Mol Genet 8:621624.
124
ARTICLE
ARTICLE
Genetic change and continuity from fourteen to twenty months: The MacArthur
Longitudinal Twin Study. Child Dev 64:
13541376.
Rettew DC, Doyle AC, Kwan M, Stanger C,
Hudziak JJ. 2006. Exploring the boundary
between temperament and generalized anxiety disorder: A receiver operating characteristic analysis. J Anxiety Disord 20:931945.
Robinson J, Kagan J, Reznick J, Corley R. 1992.
The heritability of inhibited and uninhibited
behavior: A twin study. Dev Psychol 28:
10301037.
Rosenbaum J, Biederman J, Gersten M, Hirshfeld
D, Meminger S, Herman J, Kagan J,
Reznick J, Snidman N. 1988. Behavioral
inhibition in children of parents with panic
disorder and agoraphobia: A controlled
study. Arch Gen Psychiatry 45:463470.
Rosenbaum J, Biederman J, Hirshfeld D, Bolduc
E, Faraone S, Kagan J, Snidman N, Reznick
J. 1991. Further evidence of an association
between behavioral inhibition and anxiety
disorders: Results from a family study
of children from a non-clinical sample.
J Psychiatr Res 25:4965.
Rosenbaum JF, Biederman J, Bolduc EA, Hirshfeld DR, Faraone SV, Kagan J. 1992.
Comorbidity of parental anxiety disorders
as risk for childhood-onset anxiety in
inhibited children. Am J Psychiatry 149:
475481.
Rosenbaum JF, Biederman J, Hirshfeld-Becker
DR, Kagan J, Snidman N, Friedman D,
Nineberg A, Gallery DJ, Faraone SV. 2000.
A controlled study of behavioral inhibition
in children of parents with panic disorder
and depression. Am J Psychiatry 157:2002
2010.
Rothe C, Koszycki D, Bradwejn J, King N,
Deluca V, Tharmalingam S, Macciardi F,
Deckert J, Kennedy JL. 2006. Association of
the Val158Met catechol O-methyltransferase genetic polymorphism with panic
disorder. Neuropsychopharmacology 31:
22372242.
Rowe D, Stever C, Gard J, Cleveland H, Sanders
M, Abramowitz A, Kozol S, Mohr J,
Sherman S, Waldman I. 1998. The relation
of the dopamine transporter gene (DAT1) to
symptoms of internalizing disorders in
children. Behav Genet 28:215225.
Samochowiec J, Hajduk A, Samochowiec A,
Horodnicki J, Stepien G, Grzywacz A,
Kucharska-Mazur J. 2004. Association studies of MAO-A, COMT, and 5-HTT genes
polymorphisms in patients with anxiety
disorders of the phobic spectrum. Psychiatry
Res 128:2126.
Schinka JA, Busch RM, Robichaux-Keene N.
2004. A meta-analysis of the association
between the serotonin transporter gene
polymorphism (5-HTTLPR) and trait anxiety. Mol Psychiatry 9:197202.
Schwartz C, Snidman N, Kagan J. 1999. Adolescent social anxiety as an outcome of
inhibited temperament in childhood. J Am
Acad Child Adolesc Psychiatry 38:1008
1015.
Schwartz CE, Wright CI, Shin LM, Kagan J,
Rauch SL. 2003. Inhibited and uninhibited
infants grown up: Adult amygdalar
response to novelty. Science 300:1952
1953.
125
Sen S, Burmeister M, Ghosh D. 2004. Metaanalysis of the association between a serotonin transporter promoter polymorphism (5HTTLPR) and anxiety-related personality
traits. Am J Med Genet Part B Neuropsychiatr Genet 127B:8589.
Shifman S, Bhomra A, Smiley S, Wray NR, James
MR, Martin NG, Hettema JM, An SS, Neale
MC, van den Oord EJ, Kendler KS, Chen X,
Boomsma DI, Middeldorp CM, Hottenga JJ,
Slagboom PE, Flint J. 2007. A whole genome
association study of neuroticism using DNA
pooling. Mol Psychiatry (in press).
Smoller JW, Acierno JS Jr, Rosenbaum JF, Biederman J, Pollack MH, Meminger S, Pava JA,
Chadwick LH, White C, Bulzacchelli M,
Slaugenhaupt SA. 2001. Targeted genome
screen of panic disorder and anxiety disorder
proneness using homology to murine QTL
regions. Am J Med Genet 105:195206.
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. 2005. The corticotropin-releasing hormone gene and behavioral inhibition in
children at risk for panic disorder. Biol
Psychiatry 57:14851492.
Smoller JW, Pollack MH, Wassertheil-Smoller S,
Jackson RD, Oberman A, Wong ND, Sheps
D. 2007. Panic attacks and risk of incident
cardiovascular events among postmenopausal women in the Womens Health
Initiative Observational Study. Arch Gen
Psychiatry 64:11531160.
Smoller JW, Paulus MP, Fagerness JA, Purcell S,
Yamaki L, Hirshfeld-Becker D, Biederman
J, Rosenbaum JF, Gelernter J, Stein MB.
2008. Influence of RGS2 on anxiety-related
temperament, personality, and brain function. Arch Gen Psychiatry (in press).
Starcevic V, Uhlenhuth EH, Fallon S, Pathak D.
1996. Personality dimensions in panic disorder and generalized anxiety disorder.
J Affect Disord 37:7579.
Stein MB, Chartier MJ, Hazen AL, Kozak MV,
Tancer ME, Lander S, Furer P, Chubaty D,
Walker JR. 1998. A direct-interview family
study of generalized social phobia. Am
J Psychiatry 155:9097.
Stein MB, Chartier MJ, Lizak MV, Jang KL. 2001.
Familial aggregation of anxiety-related
quantitative traits in generalized social
phobia: Clues to understanding disorder
heritability? Am J Med Genet 105:7983.
Thorgeirsson TE, Oskarsson H, Desnica N,
Kostic JP, Stefansson JG, Kolbeinsson H,
Lindal E, Gagunashvili N, Frigge ML, Kong
A, Stefansson K, Gulcher JR. 2003. Anxiety
with panic disorder linked to chromosome 9q
in iceland. Am J Hum Genet 72:12211230.
Wang Z, Valdes J, Noyes R, Zoega T, Crowe R.
1998. Possible association of a cholecystokinin promotor polymorphism (CCK36CT)
with panic disorder. Am J Med Genet
81:228234.
Weissman M, Fyer A, Haghighi F, Heiman G,
Deng Z, Hen R, Hodge S, Knowles J. 2000.
Potential panic disorder syndrome: Clinical
and genetic linkage evidence. Am J Med
Genet 96:2435.
Willis-Owen SA, Flint J. 2006. The genetic basis
of emotional behaviour in mice. Eur J Hum
Genet 14:721728.
126
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