Download The genetic basis of panic and phobic anxiety disorders

American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 148C:118– 126 (2008)
A R T I C L E
The Genetic Basis of Panic and Phobic
Anxiety Disorders
JORDAN W. SMOLLER,* ERICA GARDNER-SCHUSTER,
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. ß 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:118–126.
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
Jordan W. Smoller, M.D., Sc.D. is Associate
Professor of Psychiatry, Harvard Medical
School, Associate Professor in the Department of Epidemiology, Harvard School of
Public Health, Director, Psychiatric Genetics
Program in Mood and Anxiety Disorders,
Massachusetts General Hospital, Boston, MA
and co-Director, Genetics and Genomics Unit,
Clinical Research Program, Massachusetts
General Hospital, Boston, Massachusetts.
Ms. Gardner-Schuster is Clinical Research
Coordinator, Psychiatric Genetics Program in
Mood and Anxiety Disorders, Massachusetts
General Hospital, Boston, Massachusetts.
Ms. Covino is a Research Assistant in the
Psychiatric Genetics Program in Mood and
Anxiety Disorders, Massachusetts General
Hospital, Boston, Massachusetts.
*Correspondence to: Jordan W. Smoller,
M.D., Sc.D., Center for Human Genetic
Research, Simches Research Building, 185
Cambridge St., Boston, MA 02114.
E-mail: [email protected]
DOI 10.1002/ajmg.c.30174
ß 2008 Wiley-Liss, Inc.
1 month of at least one of the following:
persistent concern about having additional attacks, worry about the implications of the attack or its consequences,
or a significant change in behavior as a
result of the attacks. DSM-IV includes
three phobic disorders. The first, agoraphobia without a history of panic disorder
involves agoraphobia related to the fear
of developing panic-like symptoms.
Agoraphobia itself is defined by anxiety
about being in places or situations from
which escape might be difficult (or
embarrassing) or in which help may
not be available in the event of having an
unexpected or situationally predisposed
panic attack or panic-like symptoms.
Agoraphobia can occur as a complication of panic disorder (panic disorder with
agoraphobia) or alone (agoraphobia without
a history of panic disorder). Social anxiety
disorder (aka social phobia) is characterized
by marked fear and avoidance of one or
more social or performance situations.
Affected individuals recognize that their
fear is excessive and experience significant impairment as a result of their
anxiety and avoidance. The symptoms of
specific phobia are the same but the focus
of the fear and avoidance is on a specific
object (e.g., animals) or non-social
situation (e.g., being in closed spaces).
Panic and phobic anxiety disorders
are common disorders that are responsible for a substantial burden of suffering
and economic costs [Greenberg et al.,
1999]. In addition, both panic and
phobic anxiety have been linked to increased cardiovascular morbidity and
mortality [Albert et al., 2005; Smoller
et al., 2007]. Table I shows the estimated
lifetime prevalence and median age of
onset of these disorders. As shown, the
phobic disorders are more common than
panic disorder and tend to have an earlier
onset. It should be noted that while
panic attacks are a defining feature of
panic disorder, they may occur as symptoms of phobic disorders as well, in
which case they are precipitated by the
feared stimulus. Panic attacks may also
occur sporadically in the absence of
an anxiety disorder. The lifetime prevalence of isolated panic attacks has been
estimated at 22.7% [Kessler et al., 2006].
There has been controversy in the
literature about the relationship between
agoraphobia and panic disorder. The
prevailing view in American psychiatry,
as reflected in DSM-IV, has been that
agoraphobia (AG) is almost always a
complication of panic disorder (PD). An
alternative view, more closely allied with
European psychiatry and reflected in
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AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
[Noyes et al., 1986; Mendlewicz et al.,
1993; Goldstein et al., 1994; Fyer et al.,
1995, 1996; Horwath et al., 1995; Maier
et al., 1995], and have documented an
increased risk of PD (5–16%) among
relatives of affected individuals. Furthermore, early-onset PD appears to increase
the familial aggregation of PD: Goldstein et al. [1997] found a 17-fold increased risk of PD in first-degree
relatives of probands with onset by age
20 but only a 6-fold increase when
the proband’s onset was after age 20.
Based on a weighted summary of recurrence risks from these studies, first
degree relatives of PD probands have a
7-fold increased risk of the disorder
compared to relatives of unaffected controls. Family studies have also demonstrated the familial nature of phobic
disorders [Noyes et al., 1986; Fyer et al.,
1993, 1995; Stein et al., 1998]. As shown
in Table II, first-degree relatives of probands with each of the phobic disorders
have a six- to ninefold increased risk of
the disorder.
TABLE I. Prevalence and Age of Onset of Panic and Phobic Disorders
Disorder
Panic disorder (PD)
Agoraphobia without PD
Social anxiety disorder
Specific phobia
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].
ICD-10, is that agoraphobia is a distinct
disorder which may or may not follow
the onset of panic attacks. In ICD-10,
the diagnosis of panic disorder with
agoraphobia is given only if a primary
diagnosis of agoraphobia has been
excluded. Epidemiologic studies support the notion that AG can commonly
occur in the absence of panic disorder.
In the National Comorbidity Survey
Replication study, approximately 40% of
individuals with AG never met criteria
for PD [Kessler et al., 2006].
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.
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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
Six controlled family studies
that included probands with PD
have been reported, and have
documented an increased risk
of PD (5–16%) among
relatives of affected individuals.
Furthermore, early-onset PD
appears to increase the
familial aggregation of PD:
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 (4.4–11.3)
4.12 (2.1–7.9)
5.0 (2.5–9.7)
0 (0–4.6)
2.6
8.6
1.9
0
2.5 (1.1–5.8)
8.8 (4.2–19.6)
1.8 (0.19–8.2)
0 (0–7.5)
4.1
3.4
17.3
9.3
1.2 (0.69–2.2)
1.0 (0.43–2.2)
6.0 (3.7–9.8)
3.0 (0.87–8.0)
5.9
2.7
12.5
23.4
1.5 (0.71–1.8)
.50 (0.19–1.2)
2.6 (1.6–4.2)
5.6 (2.8–10.9)
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.
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proportion of the population variance
in disorder risk attributable to genes
(i.e., heritability). Twin studies of panic
and phobic disorders have indeed
demonstrated that these phenotypes are
moderately heritable. A meta-analysis of
high-quality twin studies by Hettema
et al. [2001] estimated heritabilities of
0.43 for PD and 0.20–0.39 for phobic
disorders. In a more recent analysis of
the Virginia Adult Twin Study of
Psychiatric and Substance Use Disorders, comprising more than 5,000
twins, Hettema et al. [2005] reported
heritabilies of 0.28 for PD, 0.36 for
agoraphobia, 0.10 for social anxiety
disorder and 0.24 for specific phobias.
Thus, genes contribute to these disorders, but environmental influences are
substantial. Multivariate modeling of
twin data suggest little contribution of
common shared environment (e.g.,
experiences and familial factors common to both twins) with most of
the variance attributable to individualspecific environment (which also includes measurement error) [Hettema
et al., 2001, 2005].
Linkage Studies
Having established that genetic factors
influence panic and phobic disorders,
several groups have undertaken linkage
studies to map the relevant loci.
As shown in Table III, linkage analyses
of PD have implicated several chromosomal regions including 1q [Gelernter
Having established that
genetic factors influence panic
and phobic disorders, several
groups have undertaken linkage
studies to map the relevant l
oci. As shown in, linkage
analyses of PD have implicated
several chromosomal regions
including 1q, 2q, 7p, 9q, 12q,
13q, 15q, and 22q.
et al., 2001], 2q [Fyer et al., 2006],
7p [Knowles et al., 1998; Crowe
et al., 2001], 9q [Thorgeirsson et al.,
2003], 12q [Smoller et al., 2001], 13q
[Weissman et al., 2000; Hamilton et al.,
2003], 15q [Fyer et al., 2006], and 22q
[Hamilton et al., 2003]. Of note, the
strongest evidence of linkage has been
found when phenotype definitions
have been broadened beyond the
DSM boundaries of diagnosis. Strong
evidence for the 13q locus was found
ARTICLE
when the phenotype was defined as
a syndrome that included PD as well
as several other medical conditions
(mitral valve prolapse, serious headaches,
and/or thyroid problems) [Weissman
et al., 2000; Hamilton et al., 2003]. In
another study of multiplex Icelandic
families, Thorgeirsson et al. [2003]
observed a genomewide 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.
[2006] reported genomewide significant
linkage to 15q using a broad panic
phenotype that included sporadic and
limited symptom panic attacks in addition to PD. However, as is evident
in Table III there has been little consistency in linkage scans for PD and data
for phobic disorders has been quite
limited.
Association Studies
In recent years, it has become clear
that linkage analysis has limited power
to identify loci influencing complex
(non-Mendelian) traits. Association analyses, which examine the co-occurrence
of a phenotype with specific genetic
variants, have become the predominant
method for identifying susceptibility
loci for complex traits. However,
TABLE III. Results of Linkage Studies of Panic and Phobic Anxiety Disorders
Crowe et al. [2001]
Gelernter et al. [2001]a
Smoller et al. [2001]
Hamilton et al. [2003]
Thorgeirsson et al. [2003]
Gelernter et al. [2003]a
Gelernter et al. [2004]a
Fyer et al. [2006]
Kaabi et al. [2006]a
a
Families
Region of peak evidence
Phenotype
23
20
7p (Lod ¼ 2.2)
1q (Lod ¼ 2.1), 11p (Lod ¼ 2.0)
3q (NPL ¼ 2.75, P ¼ 0.005)
12q (NPL ¼ 4.96, P ¼ 0.006)
13q (HLod ¼ 3.57), 22q (HLod ¼ 4.11)
9q (Lod ¼ 4.18)
14q (Lod ¼ 3.70)
16q (P ¼ 0.0003, Lod ¼ 2.22)
15q (Lod ¼ 2.56; genomewide empirical P ¼ 0.05)
2q (HLod ¼ 4.19; genomewide empirical P ¼ 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
Panic/phobic cluster score
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.
ARTICLE
Association analyses, which
examine the co-occurrence of a
phenotype with specific genetic
variants, have become the
predominant method for
identifying susceptibility
loci for complex traits.
identifying true association requires that
the alleles studied include variants that
are either directly related to the phenotype or strongly correlated with (i.e., in
linkage disequilibrium with) such causal
variants. Two approaches to association
analysis are now feasible: (1) candidate
gene studies, in which loci hypothesized
to be causally related to the phenotype
based on prior biological or genomic
evidence are examined, and (2) whole
genome association studies, in which a
large number (e.g., 500,000 or more)
markers designed to capture genetic
variation across the entire genome, are
examined. The latter approach has been
used successfully in the past 2 years to
identify susceptibility loci underlying a
range of medical disorders. To date,
however, association studies of panic and
phobic disorders have been limited
to the candidate gene method. Many
association findings in anxiety disorders
and psychiatry more broadly have been
difficult to replicate. The limited understanding of the biology of these disorders
means hat the prior probability that any
candidate is an actual susceptibility locus
is small; thus many reported associations
are likely to be false positives. Furthermore, it is increasingly clear that very
large samples are needed to detect robust
associations given the modest effect sizes
of individual susceptibility loci. As a
result, it is likely that most studies to date
have been underpowered, raising the
risk of false negatives as well.
Association analyses of PD have
implicated several genes; few have been
supported by independent studies.
Genes reported to be associated with
PD in more than one sample include
catechol-o-methyl transferase (COMT)
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
[Hamilton et al., 2002; Domschke
et al., 2004; Woo et al., 2004; Rothe
et al., 2006], adenosine 2A receptor
(ADORA2A) [Deckert et al., 1998;
Hamilton et al., 2004], cholecystokinin
(CCK) [Wang et al., 1998; Hattori et al.,
2001; Maron et al., 2005], CCK-B
receptor (CCK-B) [Kennedy et al.,
1999], serotonin 2A receptor (HTR2A)
[Inada et al., 2003; Maron et al., 2005],
and monoamine oxidase A (MAO-A)
[Deckert et al., 1999; Maron et al., 2004;
Samochowiec et al., 2004]. However,
in some cases, different alleles of these
genes have been associated in different
studies, negative studies of these genes
have also been reported, and none has
been established as a PD susceptibility
gene. Fewer candidate gene studies
of phobic disorders have appeared,
though reports of association with
COMT [McGrath et al., 2004], MAOA [Samochowiec et al., 2004], and
the dopamine transporter (DAT1)
[Rowe et al., 1998] have appeared. To
date, however, no genes have been
associated with phobias in independent
samples.
BEYOND THE DSM
CATEGORIES
As reviewed above, genetic epidemiologic studies have shown that genes
contribute to the development of panic
disorder and the phobic disorders, but no
specific susceptibility genes have been
established to date. Genetic studies of
these phenotypes must confront two
formidable obstacles related to the complexity of the anxiety disorders. The first
issue relates to genetic complexity—that
is, these disorders are likely to reflect
the additive or interactive effect of
multiple loci of small individual effect.
Genetic studies of these
phenotypes must confront two
formidable obstacles related to
the complexity of the anxiety
disorders. The first issue relates
to genetic complexity—that is,
121
these disorders are likely to
reflect the additive or interactive
effect of multiple loci of small
individual effect.
As a result, association studies will
require much larger sample sizes than
have been studied to date. The second
challenge is phenotypic complexity—
that is, while the DSM-defined disorders
have been useful for clinical purposes, it
is not clear that they are optimal for
the purposes of gene finding. Indeed,
evidence from a range of studies suggests
that genetic influences transcend the
boundaries of the DSM categories.
The second challenge is
phenotypic complexity—that
is, while the DSM-defined
disorders have been useful for
clinical purposes, it is not clear
that they are optimal for the
purposes of gene finding.
Indeed, evidence from a range
of studies suggests that genetic
influences transcend the
boundaries of the
DSM categories.
As shown in Table I, family studies
suggest that relatives are at greatest
risk for the proband’s anxiety disorder.
However, there is also evidence of
significant familial co-aggregation of
panic and phobic disorders. In their
analysis of the large Virginia twin
sample, Hettema et al. [2005] found that
the structure of genetic and environmental influences on the anxiety disorders were not isomorphic with the
clinically defined categories. Using
structural equation modeling, they
identified two genetic factors underlying
the disorders: one factor primarily predisposing to PD, agoraphobia, and GAD
and the second primarily influencing
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specific phobias. Social phobia was influenced by both broad factors.
Molecular genetic studies have supported this evidence that genetic effects
on panic and phobic disorders transcend
diagnostic boundaries [Smoller et al.,
2001; Kaabi et al., 2006]. Smoller et al.
found suggestive 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. [2006] observed
significant linkage on chromosome 4q
for a phenotype comprising PD, agoraphobia, social phobia and specific
phobia. In addition, several candidate
genes (e.g., COMT, MAO-A) have been
associated with both panic and phobic
anxiety [Deckert et al., 1999; Woo et al.,
2002; Domschke et al., 2004; McGrath
et al., 2004; Samochowiec et al., 2004],
and the glutamic acid decarboxylase 1
(GAD1) gene was reported to show
association with a genetic liability
underlying PD, GAD, phobias, MDD,
and the anxiety-related personality trait
of neuroticism [Hettema et al., 2006a].
These and other studies have suggested that genes that influence anxietyrelated traits may underlie multiple
anxiety disorders. Fear-conditioining, a
trait central to the development of phobic
disorders, is itself heritable (estimated
heritability 0.35–0.55), although the
genes influencing fear conditioning
appear to be distinct from those underlying phobic fears [Hettema et al., 2003,
2007]. The personality traits introversion
(low extraversion) and neuroticism
have an estimated heritability of 0.30–
0.50 and are elevated among individuals
with panic and phobic anxiety disorders
and may underlie the comorbidity of
these disorders and major depression
[Bienvenu et al., 2001]. Introversion is
characterized by low levels of sociability,
high levels of arousal, and a relatively
low propensity to experience positive
emotions, while neuroticism indexes
negative affectivity or the tendency to
experience negative emotions (anxiety,
sadness, anger). While neuroticism appears to be non-specifically associated
with a range of anxiety disorders and
depression [Hettema et al., 2006b], introversion may be more directly related to
social phobia and agoraphobia. [Bienvenu et al., 2004]. In a large twin sample,
Bienvenu et al. [2007] examined genetic
In a large twin sample,
Bienvenu et al. examined
genetic correlations between
phobic disorders and two
anxiety-related personality
traits: neuroticism and
introversion (low extraversion).
They found that the genetic
determinants of these
personality traits entirely
accounted for the genetic
influences on social phobia
and agoraphobia.
correlations between phobic disorders
and two anxiety-related personality traits:
neuroticism and introversion (low extraversion). They found that the genetic
determinants of these personality traits
entirely accounted for the genetic influences on social phobia and agoraphobia. In other words, there were no
genetic risk factors for these phobias over
and above those underlying the personality traits. In contrast, the genes influencing animal phobia (a specific
phobia) appeared to be largely distinct
from those influencing the personality
traits. The anxiety-related trait of harm
avoidance has also been implicated in
panic and phobic disorders. Individuals
scoring high on harm avoidance are
fearful, socially inhibited, easily tired,
and pessimistic [Cloninger, 1986]. Harm
avoidance is elevated among patients with
anxiety disorders [Starcevic et al., 1996;
Lyoo et al., 2001; Rettew et al., 2006;
Faytout et al., 2007] and in their relatives
[Stein et al., 2001].
The possibility that these anxietyrelated traits represent ‘‘intermediate
phenotypes’’ that are more proximal to
gene effects than are the complex clinical
diagnoses has motivated linkage and
association studies of these phenotypes.
ARTICLE
The possibility that these
anxiety-related traits represent
‘‘intermediate phenotypes’’
that are more proximal to gene
effects than are the complex
clinical diagnoses has motivated
linkage and association studies
of these phenotypes.
Linkage has been reported for neuroticism to five chromosomal regions,
including a region on chromosome 1q
syntenic with a region of mouse chromosome 1 that has been strongly linked to anxiety/fear behavior [Fullerton
et al., 2003], and harm avoidance has
been linked to regions on chromosome
8p [Cloninger et al., 1998; Zohar
et al., 2003; Dina et al., 2005]. Several
candidate gene association studies have
implicated specific genetic variants in
neuroticism or harm avoidance, including the short allele of the serotonin
transporter 5HTTLPR polymorphism.
However, three meta-analyses of these
studies [Schinka et al., 2004; Sen et al.,
2004; Munafo et al., 2005] have reached
conflicting conclusions. A recent genomewide association study failed to detect
any loci explaining more than 1% of
the variance in the trait [Shifman et al.,
2007].
The temperamental profile known
as behavioral inhibition to the unfamiliar
(BI) has been implicated as a familial and
developmental risk factor for panic and
phobic disorders (see Hirshfeld-Becker
The temperamental profile
known as behavioral inhibition
to the unfamiliar (BI) has
been implicated as a familial
and developmental risk
factor for panic and phobic
disorders.
ARTICLE
et al., this issue). BI is observable in
laboratory-based assessments as early as
infancy and consists of a stable tendency
to be cautious, quiet, and behaviorally
restrained in situations of novelty [Kagan
et al., 1988]. Longitudinal and crosssectional studies that have supported the
conclusion that BI is a developmental
risk factor for social phobia, panic and
other anxiety disorder symptomatology
[Kochanska and Radke-Yarrow, 1992;
Hayward et al., 1998; Mick and Telch,
1998; Schwartz et al., 1999; Wittchen
et al., 1999; Muris et al., 2001].
Estimates of the heritability of BI have
ranged from 0.41 to 0.76, with estimates
as high as >0.9 for extreme BI [Matheny,
1989; Robinson et al., 1992; Plomin
et al., 1993; DiLalla et al., 1994; Goldsmith and Lemery, 2000; Eley et al.,
2003]. A series of studies have demonstrated elevated rates of BI among
offspring of parents with panic disorder
with or without agoraphobia [Rosenbaum et al., 1988; Rosenbaum et al.,
2000] and an elevated risk of social
phobia, multiple anxiety disorders, and
chronicity of anxiety disorders among
parents of children with BI [Rosenbaum
et al., 1991, 1992]. Longitudinal studies
have demonstrated that BI is a developmental risk factor for social phobia
[Schwartz et al., 1999; Hirshfeld-Becker
et al., 2007]. Neurobiologic correlates of
BI include evidence of sympathetic and
HPA axis activation, EEG evidence
of right frontal cortical activation, and
amygdala hyper-reactivity to novelty
[Schwartz et al., 2003; Fox et al.,
2005a]. Genetic association studies have
begun to implicate several genes that
may influence the BI phenotype, including the corticotropin releasing hormone
gene (CRH) [Smoller et al., 2005] and
the serotonin transporter (SLC6A4)
[Fox et al., 2005b]. Animal models
suggest that the BI phenotype is
observed across phylogenies, including
rodents and primates [Kalin, 2004;
Willis-Owen and Flint, 2006]. Genetic
studies of mouse models of anxious
temperament have suggested candidate
loci relevant to anxious temperament. In
particular, the gene encoding regulator
of G-protein signaling 2 (Rgs2) has been
identified as a quantitative trait gene
AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS)
influencing BI-like phenotypes in mice
[Yalcin et al., 2004]. Smoller et al. [2008]
recently provided evidence that the
human ortholog RGS2 is associated
with BI and other intermediate phenotypes underlying social phobia. Alleles of
markers spanning RGS2 were strongly
associated with childhood BI (OR ¼
2.99) and were also associated with
introversion in adults and with increased
limbic activation (insular cortex and
amygdala) during emotion processing
(brain phenotypes correlated with social
phobia). Such findings suggest that
translational studies bringing together
insights from comparative genomics, as
well as behavioral and neuroimaging
intermediate phenotypes may help
unravel the genetic basis of anxiety
disorders.
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
phenotypes that reflect fundamental
components of panic and phobic disorders and that are under genetic
influence [Etkin and Wager, 2007;
Munafo et al., 2007; Smoller et al.,
2008]. These advances provide cause for
optimism that the coming years will see
significant progress in understanding the
genetic basis of panic and phobic anxiety
disorders.
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