Download Genetics of anxiety disorders: the complex road from DSM to DNA

DEPRESSION
AND
ANXIETY 26 : 965–975 (2009)
Review
GENETICS OF ANXIETY DISORDERS: THE COMPLEX
ROAD FROM DSM TO DNA
Jordan W. Smoller, M.D. Sc.D., Stefanie R. Block, B.A., and Mirella M. Young, M.A.
Anxiety disorders are among the most common psychiatric disorders, affecting
one in four individuals over a lifetime. Although our understanding of the
etiology of these disorders is incomplete, familial and genetic factors are
established risk factors. However, identifying the specific casual genes has been
difficult. Within the past several years, advances in molecular and statistical
genetic methods have made the genetic dissection of complex disorders a feasible
project. Here we provide an overview of these developments, with a focus on their
implications for genetic studies of anxiety disorders. Although the genetic and
phenotypic complexity of the anxiety disorders present formidable challenges,
advances in neuroimaging and experimental animal models of anxiety and fear
offer important opportunities for discovery. Real progress in identifying the
genetic basis of anxiety disorders will require integrative approaches that make
use of these biologic tools as well as larger-scale genomic studies. If successful,
such efforts may yield novel and more effective approaches for the prevention
and treatment of these common and costly disorders. Depression and Anxiety
r 2009 Wiley-Liss, Inc.
26:965–975, 2009.
Key words: genetics; anxiety; genomewide association study; heritability
A
nxiety disorders are associated with an enormous
burden of suffering as well as billions of dollars in
direct and indirect economic costs. Although established treatments—including medications and cognitive-behavioral therapies—are effective for many
patients, there is an ongoing need for improved
treatment and prevention strategies. Progress in these
areas will require a more complete understanding of
the pathogenesis of these disorders. In light of the fact
that family history is one of the best established risk
factors for anxiety disorders, there has been great
interest in efforts to identify the genetic basis of these
conditions. Over the past two decades, molecular
genetic approaches, including linkage and association
analyses, have been applied to search for the relevant
genes, but the genetic and phenotypic complexity of
anxiety phenotypes has made progress difficult. In the
past 5 years, the prospects for genetic research on
complex disorders (including the anxiety disorders)
have substantially improved with the advent of more
powerful genomic approaches. Here, we will provide
an overview of the current status of anxiety genetics
with a focus on emerging issues in human and
experimental animal research that will likely guide the
research agenda in the coming years. Figure 1 outlines
r 2009 Wiley-Liss, Inc.
the successive research strategies used to explore the
genetic of psychiatric illness.
HOW DO WE KNOW THAT GENES
CONTRIBUTE TO ANXIETY
DISORDERS?
The earliest evidence that anxiety disorders might
have a genetic component came from family studies.
Psychiatric Genetics Program in Mood and Anxiety Disorders,
Department of Psychiatry, Massachusetts General Hospital,
Boston, Massachusetts
Presented in part at the Scientific Research Symposium on the
Genetics of Anxiety Disorders, 29th Annual Conference of the
Anxiety Disordes Association of America, Albuquerque, NM.
Correspondence to: Dr. Jordan W. Smoller, Department of
Psychiatry and Center for Human Genetic Research, Massachusetts
General Hospital, Simches Research Building, 185 Cambridge St.,
Boston, MA 02114. E-mail: [email protected]
DOI 10.1002/da.20623
Published online in Wiley InterScience (www.interscience.wiley.
com).
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Smoller et al.
Questions
Study Methods
Anxiety Disorders
Is the disorder familial?
Family study
Major Depression
Eating Disorders
How much do genes contribute? Twin and adoption studies
Alcohol Dependence
What genes are involved?
Linkage and association studies
What do the genes do?
Molecular biology and clinical
studies
Late Onset Alzheimer's disease
Attention Deficit Disorder
Bipolar Disorder
Figure 1. Chain of psychiatric genetic research.
Schizophrenia
Since 1970s, numerous family studies have documented
that the risk of specific anxiety disorders (including
panic and phobic disorders, obsessive-compulsive
disorder, and generalized anxiety disorder) is higher
in first degree relatives of affected probands compared
to relatives of unaffected controls.[1–16] Overall, firstdegree relatives have an approximately four- to six-fold
increased risk of the proband’s disorder.[17] Estimates of
the familiality of posttraumatic stress disorder (PTSD)
are more difficult to obtain because they would require
matching family members on trauma exposure.
Of course, the fact that anxiety disorders aggregate in
families does not necessarily mean that genes contribute as family members share both genes and
environmental exposures. One way to separately
estimate the genetic and environmental components
of disorder variance is to examine the phenotypic
similarity of twins. Twin studies compare the similarity
or concordance rate among identical (monozygotic)
twins and nonidentical (dizygotic) twins and ask: given
that one twin has the disorder, what’s the probability
that the second twin does? If the concordance for a
disorder is greater in the identical twins that suggests a
genetic contribution—that is, their greater phenotypic
similarity is attributable to their greater genetic
similarity. One caveat is that if identical twins are
treated more similarly by the environment that might
make them appear more similar for nongenetic reasons.
If the concordance rate for identical pairs, who are
essentially clones, is not 100%, there must be something above and beyond the genetic variation involved.
For the anxiety disorders, concordance rates have
typically been in the range of 12–26% for monozygotic
twins and 4–15% for dizygotic twins.[17]
Twin studies allow us to estimate the ‘‘heritability’’ of
a trait or disorder, an index of the proportion of
phenotypic variance in a population that is attributable
to genetic factors. That is, the heritability is an estimate
of the proportion of disease risk that is due to variation
in genes in a population. It is important to recognize
that it is a population measure and does not, for
example, measure what proportion of an individual’s
anxiety disorder is due to genetic factors. Heritability
can vary from 0 (no contribution of genetic variation to
disease risk) to 100% (entirely due to genetic variation).
For the anxiety disorders (including panic disorder,
phobic disorders, GAD, OCD, and PTSD), heritability
estimates from twin studies have consistently been in
Depression and Anxiety
0
50
Approximate Heritability
100
Autism
Figure 2. Approximate heritability of selected neuropsychiatric
disorders.
the range of 20–40%.[18–20] Thus, it is clear that
variations in genes contribute to the risk of developing
anxiety disorders. As shown in Figure 2, the heritability
of anxiety disorders is similar to that for major
depressive disorder, but less than a number of other
psychiatric disorders. However, the magnitude of the
heritability tells us little or nothing about the ‘‘genetic
architecture’’ of a disorder—that is how many genes are
involved or the magnitude of effects attributable to any
contributing genes. For example, a heritability of 75%
could represent the additive effects of three loci each
accounting for 25% of the variance or 100 loci each
accounting for 0.75%. As genetic architecture is the
crucial determinant of how easy or difficult it will be to
identify specific susceptibility genes, heritability offers
little help beyond confirming that there are genes to be
found.
WHERE ARE THE GENES?
As it has turned out, actually finding those genes
proved more difficult than some initially expected. The
root of this difficulty has to do with the fact that anxiety
disorders, and other common medical disorders, are
genetically ‘‘complex disorders’’ (Fig. 3). Many familiar
medical genetic disorders are due to highly penetrant
single gene mutations—for example, the autosomal
dominant triplet repeat mutation underlying Huntington disease or the recessive point mutations that cause
cystic fibrosis and sickle cell anemia. For such
disorders, inheritance of the disease-causing variant
produces illness with near certainty. In contrast,
common diseases including the anxiety disorders are
‘‘complex’’ in that they reflect the influence of several
or many genetic risk factors, each of which may have
individually small effects. Moreover, the risk genes may
require interactions with other genes (epistasis) or
environmental factors (gene–environment interaction).
In addition, there may be substantial genetic heterogeneity (different susceptibility genes segregating in
different families). Detecting such small and diverse
effects may be quite difficult.
Review: Genetics of Anxiety Disorders
Single Gene Disorder
Complex Disorder
Example: Huntington Disease
(dominant inheritance)
•
•
•
Single gene causes disease
•
Disease requires one copy of mutation
•
•
•
967
Not due to single gene
Several or many genes may
contribute
Each may have small effect by itself
Effects may depend on interaction
with environment
Figure 3. Single gene versus complex disorders.
In the 1980s and early 1990s, after the mapping and
later cloning of several important disease genes
(including those causing Huntington disease and cystic
fibrosis), there was great optimism that genes for
psychiatric disorders would soon be found. With the
recognition that the genetic architecture of psychiatric
disorders was likely to be quite complex, this era of
‘‘irrational exuberance’’ gave way to a period of near
hopelessness as researchers worried that mental illness
genes might simply be out of reach.
In general, efforts to localize and identify risk genes
for anxiety disorders have relied on two well-established strategies. The first, linkage analysis, examines
whether DNA markers spaced at intervals across the
genome are co-inherited with the illness within
families. Linkage analysis is well-suited to mapping
genes of major effect (and, in fact, was the initial
method that localized the genes for Huntington
disease, cystic fibrosis, and many other single-gene
medical genetic disorders). Essentially, this method
asks the question ‘‘where in the genome are the disease
genes located?’’ by determining whether markers in
specific chromosomal regions are transmitted along
with the phenotype more than expected by chance.
These regions or ‘‘loci’’ are then considered likely to
harbor susceptibility genes.
Linkage studies of the anxiety disorders have
implicated several chromosomal regions, although the
results have been largely inconclusive (reviewed in[21]).
Suggestive linkage for panic anxiety phenotypes has
been reported for regions on chromosomes 1q,[22]
2q,[23] 7p,[24,25] 9q,[26] 12q,[27] 13q,[28,29] 15q,[23] and
22q.[28] Gelernter et al. conducted linkage analyses of
phobic disorders in a set of pedigrees ascertained for
panic disorder and reported evidence implicating
chromosome 3q for agoraphobia,[22] 14q for specific
phobia,[30] 16q for social phobia.[31] For OCD,
suggestive evidence of linkage has been found for
3q27–q28,[32] 9p24,[33,34] 10p15,[35] and 14q.[36]
In recent years, association analyses have become far
more common than linkage for genetic studies of
complex disorders. Association studies ask ‘‘which
genes are involved?’’ by examining whether there is a
correlation between specific alleles and the phenotype
of interest. The most common design—the casecontrol study—is a standard epidemiologic design.
For example, a case-control study of smoking and
myocardial infarction (MI) would ascertain MI cases
and unaffected controls and compare the prevalence of
smoking between the two groups. If smokers are overrepresented among the cases (relative to controls), the
inference would be that smoking is a cause of MI. The
same approach is used in genetic association studies
except that instead of smoking, the risk factor of
interest is an allele or a genotype. Thus, we would ask,
‘‘are certain genotypes over-represented among cases?’’
To date, most association studies of anxiety disorders
have focused on ‘‘candidate genes’’—that is, genes that
are suspected to play a role in the disorder(s) based on
earlier biological evidence (biological candidates) or, in
some cases, because they are located within chromosomal regions previously implicated in linkage studies
(positional candidates). Among the widely-studied
biological candidate genes (sometimes referred to as
‘‘the usual suspects’’) are genes encoding receptors,
transporters, and synthetic enzymes involved in neurotransmitter systems that are the target of therapeutic
agents (e.g. serotonin, norepinephrine, glutamate,
dopamine) and neuropeptides implicated in animal
models of anxiety (e.g. the corticotropin releasing
hormone system, neuropeptide Y, brain-derived neurotrophic factor). Two types of variations in these loci
have been tested in most studies. The first are single
nucleotide polymorphisms or SNPs—variations in
single DNA bases. These are the most common form
of variation in the genome, occurring on average at a
frequency of 1 per 1000 bases of DNA sequence. The
second comprise short repeated sequences of two to
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four nucleotides that occur in stretches of variable
length in and around genes (sometimes referred to as
‘‘microsatellites’’).
In fact, the most extensively studied variant in
genetic studies of anxiety and mood disorders is a
di- (two-) nucleotide repeat that is present in the
promoter region of the serotonin transporter gene (the
so-called 5HTT promoter length polymorphism or
5HTTLPR). The serotonin transporter is the target of
the most widely used pharmacotherapy for anxiety
disorders—SSRI antidepressants. The ‘‘short‘‘ allele of
the 5HTTLPR, lacking 44 base pairs of dinucleotide
repeat sequence that are present in the ‘‘long’’ allele,
confers reduced transcriptional activity of the serotonin
transporter gene.[37] In addition, the polymorphism is
common; the ‘‘short’’ allele has a frequency of
approximately 45% among individuals of EuropeanAmerican ancestry.[38] These features have made the
variation particularly appealing as a target of association studies, and the short allele has been associated
with anxiety-related traits including neuroticism, harm
avoidance, and, in some studies, anxiety disorders
including social phobia, OCD, and PTSD.[39–44]
However, the validity of these associations is difficult
to establish. For example, there have been many
negative studies and nonreplications with anxiety
phenotypes. In addition, the polymorphism has been
so widely studied that it has been associated with an
implausibly large number of psychiatric and nonpsychiatric phenotypes, many of which are likely to be
false positives. In a recent study of panic disorder, Strug
et al.[45] reported association with an intronic SNP in
the serotonin transporter gene (SLC6A4) but no
association with the 5HTTLPR polymorphism.
A number of other genes have been reported to be
associated with anxiety disorders in multiple studies,
though in virtually all cases, nonreplications have also
been reported. Meta-analyses can be useful in providing a summary estimate of the evidence in favor a
putative susceptibility gene or variant and allow the
pooling of data to achieve the power needed to support
or reject a candidate gene. As shown in Table 1, a small
handful of genes have been associated with anxiety
disorders in multiple studies. Table 1 shows the only
specific variants for which the same allele has been
associated with a given anxiety disorders in more than
one study at a statistical threshold of Pr.01. Candidate
gene studies of gene–environment interaction have
begun to appear, but this remains an under-utilized
strategy for genetic studies of anxiety. Such analyses are
particularly relevant for understanding the pathogenesis of PTSD that, by definition, requires exposure to
an environmental trauma. Despite the fact that trauma
exposure is common, only a subset of victims develop
PTSD and it seems likely that genetic variation
contributes to this vulnerability. For example, Binder
et al.[46] recently reported that SNPs in the FKBP5,
which regulates glucocorticoid receptor sensitivity,
were associated with PTSD severity among victims of
child abuse (but not other trauma).
Candidate gene studies have been plagued by an
‘‘inconvenient truth’’: despite the claims made for the
importance of specific genes in anxiety or other
psychiatric disorders, it has been very difficult to
establish a role for them based on association studies.
There are likely several reasons for this. First, the
likelihood that a reported candidate gene association is
a true positive is related to the gene’s earlier probability
of association. There are more than 20,000 genes in the
human genome, and a substantial fraction are brainexpressed. Any of these could be considered a candidate
gene for neuropsychiatric phenotypes like the anxiety
disorders. However, the earlier probability is low that
the specific candidate gene selected for a given study is
in fact causally related to the disorder (as our understanding of the pathogenesis of anxiety disorders
remains limited). In this circumstance, an association
with a candidate gene in a single study is likely to be
a false positive. Other factors contributing to falsepositive reports of association include inadequate
correction for multiple testing, inadequate genotyping quality control, confounding due to population
stratification (differences in genetic background between cases and controls) and the ‘‘winner’s curse’’ (an
ascertainment bias in which the initial report of an
association effect size is likely to be inflated).[47] Given
TABLE 1. Candidate gene studies associated (at Pr.01) with specific anxiety disorders in at least two independent
studies
Disorder
PD
OCD
PTSD
Gene
Variant
Risk allele
] Positive studies/total studies
5HT2AR
COMT
COMT
COMT
DRD2
FKBP5
rs6313 (T102C)
rs4680 (val158met)
rs4680 (val158met)
rs4680 (val158met)
Taq1 (rs1800497)
rs3800373
C
G (Met)
A (Val)
G (Met)
A1
C
2/7
2/13
2/13
4/16
2/5
2/2
PD, Panic disorder; OCD, Obsessive-compulsive disorder; PTSD, Posttraumatic stress disorder.
Pr.01.
Meta-analysis has not supported an association with PD.[113]
Supported by recent meta-analysis.[114] Based on studies in English-language publications. References available upon request.
Depression and Anxiety
Review: Genetics of Anxiety Disorders
the explosive proliferation of genetic association
studies and the likelihood that a large proportion of
reported findings are false positives, replication in
adequately-powered independent samples has become
the sine qua non for establishing valid genotype–phenotype associations.[48]
At the same time, many association studies may be at
risk for Type II error—that is, missing true associations. Most complex disorders are believed to be highly
polygenic and common variants underlying these
disorders are expected to have very modest effect sizes
(e.g. odds ratios for susceptibility alleles on the order of
1.1–1.4).[49] Reliably detecting such effects requires
extremely large sample sizes—on the order of thousands of cases and controls—much larger than the
samples that have typically been examined in candidate
gene studies. In addition, studies may examine only a
fraction of the variants in a given candidate gene,
further increasing the risk of false-negative conclusions
about such genes.
WHY IT’S HARD TO GO FROM
DSM TO DNA
These methodological considerations have contributed to the difficulty in establishing susceptibility
variants for anxiety disorders and other psychiatric
disorders. But there are additional difficulties to
overcome (Fig. 4). The genetic complexity of these
disorders presents additional challenges, including the
existence of genetic heterogeneity, epistasis, and
gene–environment interactions (see earlier), all of
which increase the sample size requirements for
successful association studies. But there is another
important reason challenge that has made it difficult to
establish the specific genes that account for the
heritability of psychiatric disorders—that is, to go
‘‘from DSM to DNA.’’ The problem of ‘‘phenotypic
complexity’’ is a challenge that may be more daunting
for psychiatric genetics than for other fields of medical
genetics. As reviewed earlier,[21] the current definitions
of anxiety disorders are relatively recent, dating to
DSM-III in 1980, and the boundaries among them are
far from clear. Family studies have demonstrated
Challenge
• Genetic Complexity
p
y
– Multiple genes of small effect
– Gene–gene & gene–environment
interaction
• Phenotypic Complexity
– Limitations of diagnostic
categories
Strategy
⇑Sample Size and
Genomewide studies
⇑ Effect Size: Identity
more powerful phenotypes
Figure 4. Complex disorders: Why it’s hard to go from DSM to
DNA.
969
significant familial co-aggregation of DSM-IV anxiety
disorders (for review, see [21]). For example, relatives of
probands with social phobia have an increased risk of
agoraphobia and panic disorder in addition to social
phobia itself. Relatives of probands with generalized
anxiety disorder are at increased risk of both GAD and
panic disorder; and relatives of probands with OCD are
at increased risk for panic and phobic disorders as well
as OCD. Twin studies have confirmed that genes
contribute to the familial clustering of anxiety disorders.
In a large population-based twin sample, Hettema
et al.[18] identified two genetic factors underlying the
major anxiety disorders with one factor primarily
predisposing to PD, agoraphobia, and GAD and the
other primarily influencing specific phobias. Social
phobia showed overlapping influences of both factors.
Anxiety-related personality traits may underlie these
cross-disorder effects. For example, neuroticism and
introversion are heritable traits that are associated with
a range of anxiety disorders. Twin studies have shown
that, taken together, genetic influences on neuroticism
and introversion entirely account for genetic variation
in risk of social phobia and agoraphobia.[50]
GO BIG OR GO DEEP
Broadly speaking, investigators have pursued two
strategies to address the complexity of psychiatric
disorders and enhance the power to find susceptibility
genes. The first has been to vastly increase the scope of
genetic studies—both in terms of genes and sample
size. The second has been to try to maximize detectable
effect sizes by examining phenotypes that may be more
direct expressions of anxiety disorder genes than are the
disorders themselves.
The first strategy, that of ‘‘going big’’, has been
enabled by dramatic recent advances in our understanding of the genome (Fig. 5). Following the
sequencing of the human genome in 2001,[51] several
large-scale projects have provided key tools for
• Up to 1 million genetic
markers can be
examined
i lt
ly
simultaneous
• The “whole haystack”
contained on a single
gene “chip”
• Before 2006, only a handful
of genes had been found for
any common medical
disorders
di
d
Disease
Genes/Loci
Discovered 2006-2008
Diabetes
>25
Cardiovascular
>20
Inflammatory Bowel
Disease
>30
Autoimmune Disease
>20
Obesity
Cancer
>20
>30
Total
>400
Figure 5. Genomewide association studies: a major advance for
complex trait genetics.
Depression and Anxiety
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Smoller et al.
genomic analyses. The International HapMap project,[52] which cataloged genomic variation across
different populations, has provided a database of SNPs
that have made genomewide association analysis
(GWAS) feasible. Instead of limiting the search to
pre-specified candidate genes, GWAS analysis provides
a hypothesis-free (also called, unbiased) survey of the
entire genome in a single experiment. These studies
make use of the fact that the alleles of many SNPs are
strongly correlated—or, more technically, there is
extensive ‘‘linkage disequilibrium’’ across the genome.
Thus, a given SNP may provide information about
other (correlated) SNPs, so that common genetic
variation throughout the genome can be assayed
without having to genotype all of the millions of
individual SNPs that actually exist. By selecting a
reduced set of SNPs that efficiently ‘‘tag’’ nearby
genetic variants, the entire genome can be interrogated
using DNA chips that simultaneously assay up to one
million or more SNPs.[53] Because of the large number
of statistical tests involved, very large sample sizes and
stringent statistical measures to control false-positive
rates are needed. A consensus has emerged that a P
value threshold of at least 10 7 (or, more stringently,
5 10 8) is the appropriate genomewide correction to
account for the approximately 1 million independent
tests involved in surveying the entire genome.[54,55]
Nevertheless, the GWAS approach has already unequivocally identified several genes and variants that
influence complex disorders including diabetes, autoimmune disease, cardiovascular disorders, cancer, and
others.[56] Before 2006, only a handful of susceptibility
variants had been found for common medical disorders. In the last 3 years, largely through the
application of GWAS analysis, this number has
increased to several hundred.[57] In the past 2 years,
genomewide analysis of common SNPs and rare copy
number variations (deletions or duplications of typically 10 kilobases to a few megabases of DNA
sequence) have been strongly associated with psychiatric disorders including autism,[58,59] to bipolar disorder (BPD),[60] and SCZ.[61–65]
To date, few applications of GWAS methods to
anxiety phenotypes have been reported. The first
published GWAS of panic disorder examined 200 cases
and 200 controls of Japanese origin.[66] Seven SNPs in
or near genes met a threshold of Po10 6 (for a false
discovery rate of o.05). The strongest signals were
observed for SNPs in TMEM16B (top SNP 5
rs12579350, P 5 3.7 10 9), a gene on chromsome
12p13 whose function remains poorly understood, and
PKP1 (top SNP 5 rs860554, P 5 4.6 10 8), a gene on
1q32 involved in cytoskeleton/cell membrane interactions. None of the ‘‘usual suspect’’ candidate genes
showed evidence of association. These results await
replication. GWAS analyses of the anxiety-related trait
neuroticism have also appeared[67–69] though no loci
explaining more than 1% of the variance in the trait
have emerged. In one GWAS study, Van den Oord
Depression and Anxiety
et al.[69] reported moderate evidence of association for
SNPs in MAMDC1, a gene thought to be involved in
neuronal migration, with neuroticism in a US sample
that approached genomewide significance when combined with GWAS data from an independent German
sample. Overall, the results to date suggest that
neuroticism is likely to be highly polygenic and
identifying the genes that contribute to its overall
heritability may require very large samples.
The other major strategy for enhancing the power of
genetic studies has been to define phenotypes that may
be more proximal expressions of genes that confer
susceptibility to the target disorder (‘‘going deep’’).
These putative endophenotypes or intermediate phenotypes are familial or heritable traits that are thought
to underlie the clinically diagnosed disorders. The
hope is that genes that may have only modest effects on
the disorder would have larger effects on these more
elemental traits. It is here that genetic studies of anxiety
disorders have advantages over studies of many other
psychiatric disorders. In particular, research in neuroimaging and experimental animal models has identified
key elements of the neural circuitry and biological
pathways that mediate anxiety and fear behavior.
Functional MRI (fMRI) studies have shown that
anxiety disorders are associated with altered limbic
reactivity during emotion processing tasks. For example, a meta-analysis of fMRI studies[70] found increased
activity of amygdala and insula among individuals with
social and specific phobias and PTSD compared with
healthy controls. PTSD was further characterized by
reduced activity of the anterior cingulate and ventromedial prefrontal cortices. Such phenotypes provide
attractive targets for genetic studies because they
reflect the underlying functional biology that lies
between genetic variation and disorder risk. A number
of specific candidate polymorphisms have shown
evidence of association with brain measures of emotional reactivity related to anxiety. Of these, the most
widely studied has been the 5HTTLPR polymorphism
that was first associated with amygdala reactivity by
Harriri et al.[71] Since then several studies have
replicated an association between the short allele of
this variation and increased amygdala reactivity to
emotional stimuli. Further analysis has suggested that
short allele carriers exhibit reduced connectivity of the
anterior cingulated and amygdala, suggesting that this
variant may enhance fear reactivity by reducing cortical
inhibition of amygdala responses to threat.[72] A recent
meta-analysis of 14 studies (total N 5 339) supported
the association of the short allele with increased
amygdala reactivity (overall P 5.002).[73]
Animal models of anxiety-related traits have also
been used to characterize the neurobiologic basis of
fear and anxiety phenotypes. Several fear and anxietyrelated traits appear to be evolutionarily conserved
phenotypes that resemble primate and human anxiety.
Rodent assays of fear behavior are arguably, along with
substance abuse models, the best validated animal
Review: Genetics of Anxiety Disorders
models of human psychopathology. They also provide
powerful tools for dissecting the role of specific genes
in anxiety-related traits. For example, genetic mapping
in large-scale mouse crosses led to the localization and
ultimate identification of a quantitative trait gene, rgs2,
that influences murine anxious temperament.[74] Gene
targeting approaches, in which specific genes can be
inserted (transgenic mice) or deleted (knockout mice)
from the genome, have allowed researchers to examine
the effect of specific genes on anxiety-related behaviors.[75] As an example, mice in which the serotonin
1A receptor was deleted were found to exhibit
increased anxiety behaviors.[76] Using a tissue-specific
conditional rescue strategy, Gross et al.[77] found that
expression of the gene in the hippocampus and cortex
(but not in the raphe nuclei) is sufficient to rescue the
anxiety phenotype of the knockout mice. They further
showed that the timing of gene expression is crucial:
using a conditional knockout that inactivated the gene
in either early development or adulthood they demonstrated that function of the gene in the early postnatal
period determines anxiety-like behavior in the adult.
Such studies can demonstrate the neuroanatomic and
developmental importance of candidate genes. Of note,
human studies have implicated the 5HT1A receptor
gene and its expression in panic and phobic anxiety
disorders.[78–80]
Expression profiling in mouse brain tissue provides
another powerful tool for identifying genes relevant to
anxiety phenotypes. For example, Hovatta et al.[81]
compared mRNA expression levels of approximately
10,000 genes in limbic brain regions from mouse
strains that differed in anxiety-proneness. They identified 17 genes whose expression levels correlated with
anxiety behavior and went on to use gene targeting
methods to implicate two of these genes (glyoxylase 1
and glutathione reductase 1) as causally related to the
anxiety phenotypes. In a subsequent study, Donner
et al.[82] examined variants in the human orthologues
of these 17 genes in a sample of 321 cases and 653
controls form a population-based Finnish sample.
They observed nominally significant association
(Po.01) for social phobia (with variants in ALAD and
CDH2), panic disorder (EPB41L4Aa and PSAP),
and generalized anxiety disorder (PTGDS, DYNLL2,
and EPB41L4A).
Gene targeting methods in rodents also allow us to
go in the opposite direction—from human studies to
experimental animal models—to characterize the functional significance of risk alleles. Several studies have
suggested that the Val66Met polymorphism in the
brain derived neurotrophic factor (BDNF) gene is
associated with a variety of neuropsychiatric phenotypes relevant to mood and anxiety disorders. Chen
et al.[83] demonstrated that mice engineered to express
the human Met allele exhibit increased anxiety-related
behaviors and are resistant to SSRI treatment.
Primate models of anxious temperament have
also provided opportunities to examine genetic and
971
gene–environment effects on anxiety. Anxious temperament (behavioral inhibition) is heritable in rhesus
macaques and is associated with hyper-reactivity of
limbic brain circuits that have also been implicated in
human anxious temperament.[84,85] Furthermore, monkeys carrying the short allele of the rhesus 5HTTLPR
exhibit anxious temperament and altered stress hormone responses, particularly after early adversity.[86–88]
In an example of combining insights from animal
models and intermediate phenotypes, we have been
studying the effects of mouse anxiety genes on
behavioral and biological traits underlying social anxiety
disorder[89] with a focus on the temperamental profile
known as behavioral inhibition to the unfamiliar (BI).[90]
Several features of the BI phenotype make it particularly
attractive for studying the genetic basis of anxiety. BI is
observable in laboratory protocols as early as 14 months
of age and consists of a stable tendency to be cautious,
quiet, and behaviorally restrained in situations of
novelty. Longitudinal research has also demonstrated
that BI is a stable profile in childhood[91] and is a
familial and developmental risk factor for anxiety
disorders, particularly social anxiety disorder.[92–94]
Estimates of the heritability of BI (in the range of
40–75%) have exceeded those for the anxiety disorders
themselves,[95,96] and biologic features of BI have been
documented including evidence of sympathetic hyperreactivity,[97] activation of the HPA axis, and asymmetric
(right4left) frontal EEG activity.[97–100] Functional
MRI studies have shown that adults classified as
inhibited in early childhood exhibit increased amygdala
reactivity to novel and emotional stimuli.[101,102]
In addition, behavioral inhibition has also been
described and well-studied in animal models including
rodents and monkeys. Like children with BI, fearful
mice exhibit inhibition of behavior and autonomic
arousal in response to novel, unfamiliar, or threatening
environments.[103] As in humans, anxious temperament
appears to be highly heritable in rodent and primate
models.[85,104,105] As noted earlier, Rgs2 was identified
by positional mapping as a contributor to mouse
anxious temperament phenotypes resembling BI.[74]
The gene encodes a regulator of G-protein signaling
that accelerates the deactivation of G-proteins that are
second messengers for neurotransmitters including
norepinephrine and serotonin.[106]
We observed association between variants in the
human orthologue (RGS2) with BI in a family-based
sample in which children had undergone laboratorybased temperament assessments.[89] In particular, a
haplotype of SNPs spanning the gene conferred a
three-fold increased likelihood of inhibited temperament in these children. The same alleles were
associated with introversion, a trait for which BI is a
developmental precursor, in a sample of 744 adults.
Finally, we examined whether the gene is associated
with brain endophenotypes common to anxious temperament and anxiety disorders. The same allele of a
SNP (rs4606, previously associated with reduced RGS2
Depression and Anxiety
972
Smoller et al.
expression) that was associated with BI and introversion, also predicted increased amygdala and insula
response to emotional stimuli in a sample (N 5 55) of
adults who underwent fMRI. Taken together, these
results suggest that genetic variation associated with
reduced expression of RGS2 contributes to increased
reactivity of limbic brain structures modulating anxious
temperament and social anxiety. Although these findings require replication, they highlight the potential
utility of combining clues from behavioral and developmental research, neuroimaging, and animal models
for dissecting the genetic basis of anxiety disorders.
However, the role of RGS2 in the etiology of anxiety
disorders remains unclear as (nominal) association has
been reported for the rs4606 SNP and panic disorder,[107] PTSD,[108] and GAD,[109] but with the allele
opposite to that associated with BI.
CONCLUSIONS AND FUTURE
DIRECTIONS
Several conclusions have emerged from the past two
decades of research on the familial and genetic basis of
anxiety disorders. First, it is clear that all of the major
DSM-IV anxiety disorders run in families and are
heritable. In addition to motivating molecular genetic
studies, this provides evidence that the clinical diagnostic categories capture phenotypes that are under
genetic influence. However, the second conclusion that
can be drawn from family and twin studies is that the
familial and genetic boundaries among these disorders
are not sharply defined. They co-aggregate in families
and are genetically correlated, suggesting that the
genetic and environmental risk factors among subsets
of these disorders are shared. This creates a challenge
for efforts to define phenotypes for gene mapping
studies. We can also be confident that the anxiety
disorders, like other common psychiatric and medical
syndromes are genetically complex. It is likely that
many genes of modest effect contribute and that the
expression of anxiety disorder phenotypes involves
interactions among genes and between genes and
environmental influences. To date, molecular genetic
studies (linkage and association studies) have implicated several specific genes but few findings have been
robustly replicated. This is at least partly attributable
to the limited set of genes that have been examined and
the need for much larger studies to achieve sufficient
power to detect susceptibility genes.
How can we move the ball forward? Lessons from
other successful studies of other complex diseases suggest
a few directions. First, genetic association studies will
require much larger samples than have been examined to
date. While the underlying genetic architecture of the
anxiety disorders remains obscure, GWAS studies that
have established risk genes for diseases like diabetes,
autoimmune disease, and cardiovascular disease[110]
suggest that common risk alleles are likely to have very
Depression and Anxiety
small effect sizes. Indeed, identifying genes influencing
height, a highly heritable phenotype, required GWAS
studies of tens of thousands of cases and controls,[111]
with rigorous replication in independent samples.
Success in these other areas of medicine has required
extensive collaboration and the formation of research
consortia to achieve the kinds of power that are simply
impossible for individual research groups. Investigators
interested in the genetics of anxiety have recently formed
a collaborative network (the ANxiety Genetics Study
Team, or ANGST) that may provide such a resource for
identifying anxiety disorder genes.
Recent evidence from genomewide studies of schizophrenia and autism have highlighted the possibility that
the genetic architecture of complex psychiatric phenotypes involves a combination of common variants of small
effect and rarer variants of larger effect (e.g. copy number
variations). Genomewide analyses of copy number variation have not yet been undertaken for the anxiety
disorders. In the coming years, advances in highthroughput whole genome DNA sequencing will facilitate
genomewide studies of rare variants, but again, large
sample sizes will be needed for such analyses. Progress in
genomic biology is creating other exciting opportunities
for molecular studies of complex disease. For example,
epigenetic modification of DNA and associated proteins
appears to have important effects on gene expression that
may underlie environmental influences on disease risk.
Preclinical studies in rodents have suggested that early
adversity can exert lasting effects on stress responsivity
through such mechanisms.[112] The role of epigenetic
effects on human anxiety is a fertile area for research. In
any case, the strong likelihood that environmental factors
interact with genetic risk to confer vulnerability to anxiety
disorders underscores the need for further research on
gene–environment interaction. Unfortunately, precisely
measuring the relevant environmental variables is a much
more challenging task than assaying genotypes; further
efforts to examine the role of environmental exposures
and their developmental influence are needed. Finally, as
mentioned earlier, anxiety genetic research should capitalize on the genetic and neurobiologic insights that have
emerged from animal models, neuroimaging and molecular studies of the biology of anxiety.
REFERENCES
1. Black DW, Noyes Jr R, Goldstein RB, Blum N. A family study of
obsessive-compulsive disorder. Arch Gen Psychiatry 1992;49:
362–368.
2. Fyer A, Manuzza S, Chapman T, Lipsitz J, Martin L, Klein D.
Panic disorder and social phobia: effects of comorbidity on
familial transmission. Anxiety 1996;2:173–178.
3. Fyer AJ, Mannuzza S, Chapman TF, Martin LY, Klein DF.
Specificity in familial aggregation of phobic disorders. Arch Gen
Psychiatry 1995;52:564–573.
4. Goldstein RB, Weissman MM, Adams PB, Horwath E, Lish JD,
Charney D, Woods SW, Sobin C, Wickramaratne PJ, et al.
Psychiatric disorders in relatives of probands with panic disorder
and/or major depression. Arch Gen Psychiatry 1994;51:383–394.
Review: Genetics of Anxiety Disorders
5. Grabe HJ, Ruhrmann S, Ettelt S, et al. Familiality of obsessivecompulsive disorder in nonclinical and clinical subjects. Am J
Psychiatry 2006;163:1986–1992.
6. Hanna GL, Himle JA, Curtis GC, Gillespie BW. A family study
of obsessive-compulsive disorder with pediatric probands. Am J
Med Genet B Neuropsychiatr Genet 2005;134:13–19.
7. Horwath E, Wolk SI, Goldstein RB, et al. Is the comorbidity
between social phobia and panic disorder due to familial
cotransmission or other factors? Arch Gen Psychiatry 1995;52:
574–582.
8. Maier W, Minges J, Lichtermann D. The familial relationship
between panic disorder and unipolar depression. J Psychiatr Res
1995;29:375–388.
9. Mendlewicz J, Papdimitriou G, Wilmotte J. Family study of
panic disorder: comparison with generalized anxiety disorder,
major depression and normal subjects. Psychiatr Genet
1993;3:73–78.
10. Nestadt G, Samuels J, Riddle M, et al. A family study of obsessivecompulsive disorder. Arch Gen Psychiatry 2000;57:358–363.
11. Nestadt G, Samuels J, Riddle MA, et al. The relationship
between obsessive-compulsive disorder and anxiety and affective
disorders: results from the Johns Hopkins OCD Family Study.
Psychol Med 2001;31:481–487.
12. Newman SC, Bland RC. A population-based family study of
DSM-III generalized anxiety disorder. Psychol Med 2006;36:
1275–1281.
13. Noyes R, Clarksohn C, Crowe RR, Yates WR, McChesney CM.
A family study of generalized anxiety disorder. Am J Psychiatry
1987;144:1019–1024.
14. Noyes Jr R, Crowe RR, Harris EL, Hampa BJ, McChesney CM,
Chaudry DR. Relationship between panic disorder and
agoraphobia: a family study. Arch Gen Psychiatry 1986;43:
227–232.
15. Pauls D, Alsobrook II J, Goodman W, Rasmussen S, Leckman J.
A family study of obsessive-compulsive disorder. Am J Psychiatry
1995;152:76–84.
16. Stein M, Chartier M, Hazen A, et al. A direct-interview family
study of generalized social phobia. Am J Psychiatry 1998;155:
90–97.
17. Hettema JM, Neale MC, Kendler KS. A review and metaanalysis of the genetic epidemiology of anxiety disorders. Am J
Psychiatry 2001;158:1568–1578.
18. 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.
19. Kendler KS, Myers J, Prescott CA, Neale MC. The genetic
epidemiology of irrational fears and phobias in men. Arch Gen
Psychiatry 2001;58:257–265.
20. Scherrer JF, True WR, Xian H, et al. Evidence for genetic
influences common and specific to symptoms of generalized
anxiety and panic. J Affect Disord 2000;57:25–35.
21. Smoller JW, Gardner-Schuster E, Misiaszek M. Genetics of
anxiety: would the genome recognize the DSM? Depress Anxiety
2008;25:368–377.
22. Gelernter J, Bonvicini K, Page G, et al. Linkage genome scan for
loci predisposing to panic disorder or agoraphobia. Am J Med
Genet 2001;105:548–557.
23. Fyer AJ, Hamilton SP, Durner M, et al. A third-pass genome scan
in panic disorder: evidence for multiple susceptibility loci. Biol
Psychiatry 2006;60:388–401.
24. Crowe RR, Goedken R, Samuelson S, Wilson R, Nelson J,
Noyes Jr R. Genomewide survey of panic disorder. Am J Med
Genet 2001;105:105–109.
973
25. Knowles JA, Fyer AJ, Vieland VJ, et al. Results of a genome-wide
genetic screen for panic disorder. Am J Med Genet 1998;
81:139–147.
26. Thorgeirsson TE, Oskarsson H, Desnica N, et al. Anxiety with
panic disorder linked to chromosome 9q in iceland. Am J Hum
Genet 2003;72:1221–1230.
27. Smoller JW, Acierno Jr JS, Rosenbaum JF, et al. Targeted
genome screen of panic disorder and anxiety disorder proneness
using homology to murine QTL regions. Am J Med Genet
2001;105:195–206.
28. Hamilton SP, Fyer AJ, Durner M, et al. Further genetic evidence
for a panic disorder syndrome mapping to chromosome 13q.
Proc Natl Acad Sci USA 2003;100:2550–2555.
29. Weissman M, Fyer A, Haghighi F, et al. Potential panic disorder
syndrome: clinical and genetic linkage evidence. Am J Med
Genet Neuropsychiatr Genet 2000;96:24–35.
30. Gelernter J, Page GP, Bonvicini K, Woods SW, Pauls DL,
Kruger S. A chromosome 14 risk locus for simple phobia: results
from a genomewide linkage scan. Mol Psychiatry 2003;8:
71–82.
31. Gelernter J, Page GP, Stein MB, Woods SW. Genome-wide
linkage scan for loci predisposing to social phobia: evidence for a
chromosome 16 risk locus. Am J Psychiatry 2004;161:59–66.
32. Shugart YY, Samuels J, Willour VL, et al. Genomewide linkage
scan for obsessive-compulsive disorder: evidence for susceptibility loci on chromosomes 3q, 7p, 1q, 15q, and 6q. Mol
Psychiatry 2006;11:763–770.
33. Hanna GL, Veenstra-VanderWeele J, Cox NJ, et al. Genomewide linkage analysis of families with obsessive-compulsive
disorder ascertained through pediatric probands. Am J Med
Genet 2002;114:541–552.
34. Willour VL, Yao Shugart Y, Samuels J, et al. Replication study
supports evidence for linkage to 9p24 in obsessive-compulsive
disorder. Am J Hum Genet 2004;75:508–513.
35. Hanna GL, Veenstra-Vanderweele J, Cox NJ, et al. Evidence
for a susceptibility locus on chromosome 10p15 in earlyonset obsessive-compulsive disorder. Biol Psychiatry 2007;62:
856–862.
36. Samuels J, Shugart YY, Grados MA, et al. Significant linkage to
compulsive hoarding on chromosome 14 in families with
obsessive-compulsive disorder: results from the OCD collaborative genetics Study. Am J Psychiatry 2007;164:493–499.
37. Lesch K-P, Bengel D, Heils A, et al. Association of anxietyrelated traits with a polymorphism in the serotonin transporter
gene regulatory region. Science 1996;274:1527–1531.
38. Gelernter J, Kranzler H, Coccaro EF, Siever LJ, New AS.
Serotonin transporter protein gene polymorphism and personality measures in African American and European American
subjects. Am J Psychiatry 1998;155:1332–1338.
39. Furmark T, Tillfors M, Garpenstrand H, et al. Serotonin
transporter polymorphism related to amygdala excitability and
symptom severity in patients with social phobia. Neurosci Lett
2004;362:189–192.
40. Hasler G, Kazuba D, Murphy DL. Factor analysis of obsessivecompulsive disorder YBOCS-SC symptoms and association
with 5-HTTLPR SERT polymorphism. Am J Med Genet B
Neuropsychiatr Genet 2006;141:403–408.
41. Kilpatrick DG, Koenen KC, Ruggiero KJ, et al. The serotonin
transporter genotype and social support and moderation of
posttraumatic stress disorder and depression in hurricaneexposed adults. Am J Psychiatry 2007;164:1693–1699.
42. Lesch KP, Bengel D, Heils A, et al. Association of anxiety-related
traits with a polymorphism in the serotonin transporter gene
regulatory region. Science 1996;274:1527–1531.
Depression and Anxiety
974
Smoller et al.
43. Lin PY. Meta-analysis of the association of serotonin transporter
gene polymorphism with obsessive-compulsive disorder. Prog
Neuropsychopharmacol Biol Psychiatry 2007;31:683–689.
44. Sen S, Burmeister M, Ghosh D. Meta-analysis of the association
between a serotonin transporter promoter polymorphism
(5-HTTLPR) and anxiety-related personality traits. Am J Med
Genet B Neuropsychiatr Genet 2004;127:85–89.
45. Strug LJ, Suresh R, Fyer AJ, et al. Panic disorder is associated
with the serotonin transporter gene (SLC6A4) but not the
promoter region (5-HTTLPR). Mol Psychiatry 2008.
46. Binder EB, Bradley RG, Liu W, et al. Association of FKBP5
polymorphisms and childhood abuse with risk of posttraumatic
stress disorder symptoms in adults. J Am Med Assoc 2008;
299:1291–1305.
47. Xiao R, Boehnke M. Quantifying and correcting for the winner’s
curse in genetic association studies. Genet Epidemiol 2009;
33:453–462.
48. Chanock SJ, Manolio T, Boehnke M, et al. Replicating genotypephenotype associations. Nature 2007;447:655–660.
49. Ioannidis JP, Trikalinos TA, Khoury MJ. Implications of small
effect sizes of individual genetic variants on the design and
interpretation of genetic association studies of complex diseases.
Am J Epidemiol 2006;164:609–614.
50. Bienvenu OJ, Hettema JM, Neale MC, Prescott CA,
Kendler KS. Low extraversion and high neuroticism as
indices of genetic and environmental risk for social phobia,
agoraphobia, and animal phobia. Am J Psychiatry 2007;164:
1714–1721.
51. Lander ES, Linton LM, Birren B, et al. Initial sequencing and
analysis of the human genome. Nature 2001;409:860–921.
52. Altshuler D, Brooks LD, Chakravarti A, Collins FS, Daly MJ,
Donnelly P. A haplotype map of the human genome. Nature
2005;437:1299–1320.
53. de Bakker PI, Yelensky R, Pe’er I, Gabriel SB, Daly MJ,
Altshuler D. Efficiency and power in genetic association studies.
Nat Genet 2005;37:1217–1223.
54. Ioannidis JP, Thomas G, Daly MJ. Validating, augmenting and
refining genome-wide association signals. Nat Rev Genet 2009;
10:318–329.
55. Pearson TA, Manolio TA. How to interpret a genome-wide
association study. J Am Med Assoc 2008;299:1335–1344.
56. Hindorff LA, Sethupathy P, Junkins HA, et al. Potential etiologic
and functional implications of genome-wide association loci for
human diseases and traits. Proc Natl Acad Sci USA 2009;106:
9362–9367.
57. Hindorff L, Junkins H, Mehta J, Manolio T. 2009. A catalog of
published genome-wide association studies. Available at:
www.genome.gov/gwastudies.
58. Glessner JT, Wang K, Cai G, et al. Autism genome-wide copy
number variation reveals ubiquitin and neuronal genes. Nature 2009.
59. Wang K, Zhang H, Ma D, et al. Common genetic variants on
5p14.1 associate with autism spectrum disorders. Nature 2009.
60. Ferreira MA, O’Donovan MC, Meng YA, et al. Collaborative
genome-wide association analysis supports a role for ANK3 and
CACNA1C in bipolar disorder. Nat Genet 2008.
61. O’Donovan MC, Craddock N, Norton N, et al. Identification of
loci associated with schizophrenia by genome-wide association
and follow-up. Nat Genet 2008.
62. Stone JL, O’Donovan MC, Gurling H, et al. Rare chromosomal
deletions and duplications increase risk of schizophrenia. Nature
2008.
63. Purcell SM, Wray NR, Stone JL, et al. Common polygenic
variation contributes to risk of schizophrenia and bipolar
disorder. Nature 2009;460:748–752.
Depression and Anxiety
64. Shi J, Levinson DF, Duan J, et al. Common variants on
chromosome 6p22.1 are associated with schizophrenia. Nature
2009;460:753–757.
65. Stefansson H, Ophoff RA, Steinberg S, et al. Common variants
conferring risk of schizophrenia. Nature 2009;460:744–747.
66. Otowa T, Yoshida E, Sugaya N, et al. Genome-wide association
study of panic disorder in the Japanese population. J Hum Genet
2009;54:122–126.
67. Shifman S, Bhomra A, Smiley S, et al. A whole genome
association study of neuroticism using DNA pooling. Mol
Psychiatry 2007.
68. Terracciano A, Sanna S, Uda M, et al. Genome-wide association
scan for five major dimensions of personality. Mol Psychiatry
2008.
69. van den Oord EJ, Kuo PH, Hartmann AM, et al. Genomewide
association analysis followed by a replication study implicates a
novel candidate gene for neuroticism. Arch Gen Psychiatry
2008;65:1062–1071.
70. Etkin A, Wager TD. Functional neuroimaging of anxiety: a
meta-analysis of emotional processing in PTSD, social anxiety
disorder, and specific phobia. Am J Psychiatry 2007;164:
1476–1488.
71. Hariri AR, Mattay VS, Tessitore A, et al. Serotonin transporter
genetic variation and the response of the human amygdala.
Science 2002;297:400–403.
72. Pezawas L, Meyer-Lindenberg A, Drabant EM, et al.
5-HTTLPR polymorphism impacts human cingulate-amygdala
interactions: a genetic susceptibility mechanism for depression.
Nat Neurosci 2005;8:828–834.
73. Munafo MR, Brown SM, Hariri AR. Serotonin transporter
(5-HTTLPR) genotype and amygdala activation: a metaanalysis. Biol Psychiatry 2008;63:852–857.
74. Yalcin B, Willis-Owen SA, Fullerton J, et al. Genetic dissection
of a behavioral quantitative trait locus shows that Rgs2 modulates
anxiety in mice. Nat Genet 2004;36:1197–1202.
75. Smoller JW, Faraone SV. Genetics of anxiety disorders: complexities and opportunities. Am J Med Genet C Semin Med Genet
2008.
76. Ramboz S, Oosting R, Amara DA, et al. Serotonin receptor 1A
knockout: an animal model of anxiety-related disorder. Proc Natl
Acad Sci USA 1998;95:14476–14481.
77. Gross C, Zhuang X, Stark K, et al. Serotonin1A receptor acts
during development to establish normal anxiety-like behaviour in
the adult. Nature 2002;416:396–400.
78. Lanzenberger RR, Mitterhauser M, Spindelegger C, et al.
Reduced serotonin-1A receptor binding in social anxiety
disorder. Biol Psychiatry 2007;61:1081–1089.
79. Neumeister A, Bain E, Nugent AC, et al. Reduced serotonin type 1A
receptor binding in panic disorder. J Neurosci 2004;24:589–591.
80. Rothe C, Gutknecht L, Freitag C, et al. Association of a
functional 1019C4G 5-HT1A receptor gene polymorphism
with panic disorder with agoraphobia. Int J Neuropsychopharmacol 2004;7:189–192.
81. Hovatta I, Tennant RS, Helton R, et al. Glyoxalase 1 and
glutathione reductase 1 regulate anxiety in mice. Nature 2005.
82. Donner J, Pirkola S, Silander K, et al. An association analysis of
murine anxiety genes in humans implicates novel candidate genes
for anxiety disorders. Biol Psychiatry 2008;64:672–680.
83. Chen ZY, Jing D, Bath KG, et al. Genetic variant BDNF
(Val66Met) polymorphism alters anxiety-related behavior. Science
2006;314:140–143.
84. Fox AS, Shelton SE, Oakes TR, Davidson RJ, Kalin NH.
Trait-like brain activity during adolescence predicts anxious
temperament in primates. PLoS ONE 2008;3:e2570.
Review: Genetics of Anxiety Disorders
85. Rogers J, Shelton SE, Shelledy W, Garcia R, Kalin NH. Genetic
influences on behavioral inhibition and anxiety in juvenile rhesus
macaques. Genes Brain Behav 2008.
86. Barr CS, Newman TK, Shannon C, et al. Rearing condition and
rh5-HTTLPR interact to influence limbic-hypothalamic-pituitary-adrenal axis response to stress in infant macaques. Biol
Psychiatry 2004;55:733–738.
87. Kalin NH, Shelton SE, Fox AS, Rogers J, Oakes TR, Davidson RJ.
The serotonin transporter genotype is associated with intermediate
brain phenotypes that depend on the context of eliciting stressor.
Mol Psychiatry 2008;13:1021–1027.
88. McCormack K, Newman TK, Higley JD, Maestripieri D,
Sanchez MM. Serotonin transporter gene variation, infant abuse,
and responsiveness to stress in rhesus macaque mothers and
infants. Horm Behav 2009.
89. Smoller JW, Paulus MP, Fagerness JA, et al. Influence of RGS2
on anxiety-related temperament, personality, and brain function.
Arch Gen Psychiatry 2008;65:298–308.
90. Kagan J, Reznick J, Clarke C, Snidman N, Garcia-Coll C.
Behavioral inhibition to the unfamiliar. Child Dev 1984;55:
2212–2225.
91. 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.
92. Hirshfeld-Becker DR, Biederman J, Henin A, et al. Behavioral
inhibition in preschool children at risk is a specific predictor of
middle childhood social anxiety: a five-year follow-up. J Dev
Behav Pediatr 2007;28:225–233.
93. Rosenbaum JF, Biederman J, Bolduc-Murphy EA, et al. Behavioral inhibition in childhood: a risk factor for anxiety disorders.
Harv Rev Psychiatry 1993;1:2–16.
94. Schwartz C, Snidman N, Kagan J. Adolescent social anxiety as an
outcome of inhibited temperament in childhood. J Am Acad
Child Adolesc Psychiatry 1999;38:1008–1015.
95. DiLalla L, Kagan J, Reznick J. Genetic etiology of behavioral
inhibition among 2-year-old children. Infant Behav Dev
1994;17:405–412.
96. Eley TC, Bolton D, O’Connor TG, Perrin S, Smith P, Plomin R.
A twin study of anxiety-related behaviours in pre-school children.
J Child Psychol Psychiatry 2003;44:945–960.
97. Kagan J, Reznick S, Snidman N. Biological bases of childhood
shyness. Science 1988;240:167–171.
98. Calkins S, Fox N, Marshall T. Behavioral and physiological
antecedents of inhibited and uninhibited behavior. Child Dev
1996;67:523–540.
975
99. Fox NA, Henderson HA, Marshall PJ, Nichols KE, Ghera MM.
Behavioral inhibition: linking biology and behavior within a
developmental framework. Annu Rev Psychol 2004.
100. Schmidt L, Fox N, Rubin K, et al. Behavioral and neuroendocrine
responses in shy children. Dev Psychobiol 1997;30:127–140.
101. Perez-Edgar K, Roberson-Nay R, Hardin MG, et al. Attention
alters neural responses to evocative faces in behaviorally
inhibited adolescents. Neuroimage 2007;35:1538–1546.
102. 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.
103. Gershenfeld HK, Paul SM. Towards a genetics of anxious
temperament: from mice to men. Acta Psychiatr Scand Suppl
1998;393:56–65.
104. Trullas R, Skolnick P. Differences in fear motivated behaviors among
inbred mouse strains. Psychopharmacology 1993;111:323–331.
105. Williamson DE, Coleman K, Bacanu SA, et al. Heritability of
fearful-anxious endophenotypes in infant rhesus macaques: a
preliminary report. Biol Psychiatry 2003;53:284–291.
106. Neubig RR, Siderovski DP. Regulators of G-protein signalling
as new central nervous system drug targets. Nat Rev Drug
Discov 2002;1:187–197.
107. Leygraf A, Hohoff C, Freitag C, et al. Rgs 2 gene polymorphisms as modulators of anxiety in humans? J Neural Transm
2006;113:1921–1925.
108. Amstadter AB, Koenen KC, Ruggiero KJ, et al. Variant in RGS2
moderates posttraumatic stress symptoms following potentially
traumatic event exposure. J Anxiety Disord 2009;23:369–373.
109. Koenen KC, Amstadter AB, Ruggiero KJ, et al. RGS2 and
generalized anxiety disorder in an epidemiologic sample of
hurricane-exposed adults. Depress Anxiety 2009;26:309–315.
110. Altshuler D, Daly MJ, Lander ES. Genetic mapping in human
disease. Science 2008;322:881–888.
111. Weedon MN, Frayling TM. Reaching new heights: insights into
the genetics of human stature. Trends Genet 2008;24:595–603.
112. Meaney MJ, Szyf M, Seckl JR. Epigenetic mechanisms of
perinatal programming of hypothalamic-pituitary-adrenal function and health. Trends Mol Med 2007;13:269–277.
113. Domschke K, Deckert J, O’Donovan MC, Glatt SJ. Metaanalysis of COMT val158met in panic disorder: ethnic
heterogeneity and gender specificity. Am J Med Genet B
Neuropsychiatr Genet 2007;144:667–673.
114. Pooley EC, Fineberg N, Harrison PJ. The met(158) allele of
catechol-O-methyltransferase (COMT) is associated with obsessive-compulsive disorder in men: case-control study and
meta-analysis. Mol Psychiatry 2007;12:556–561.
Depression and Anxiety