Molecular genetics of bipolar disorder
E. P. Hayden* and J. I. Nurnberger Jr
Institute of Psychiatric Research, Indiana University School of
Medicine, Indianapolis, IN, USA
*Corresponding author: E. P. Hayden, Institute of Psychiatric
Research, Indiana University School of Medicine, 791 Union
Drive, Indianapolis, IN 46202-4887, USA. E-mail: elhayden@
Bipolar disorder (BPD) is an often devastating illness
characterized by extreme mood dysregulation. Although
family, twin and adoption studies consistently indicate a
strong genetic component, specific genes that contrib-
ute to the illness remain unclear. This study gives an
overview of linkage studies of BPD, concluding that the
regions with the best evidence for linkage include areas
on chromosomes 2p, 4p, 4q, 6q, 8q, 11p, 12q, 13q, 16p,
16q, 18p, 18q, 21q, 22q and Xq. Association studies are
summarized, which support a possible role for numer-
ous candidate genes in BPD including COMT, DAT,
HTR4, DRD4, DRD2, HTR2A, 5-HTT, the G72/G30 com-
plex, DISC1, P2RX7, MAOA and BDNF. Animal models
related to bipolar illness are also reviewed, with special
attention paid to those with clear genetic implications.
We conclude with suggestions for strategies that may
help clarify the genetic bases of this complex illness.
Keywords: Association studies, bipolar disorder, linkage
analysis, molecular genetics
Received 4 January 2005, revised 22 February 2005,
accepted for publication 23 February 2005
Current systems of classifying mental illness (American Psy-
chiatric Association 1994) describe the bipolar disorders
(BPDs) asa group ofaffective illnesses characterized byexces-
sive shifts in mood. Patients with BPD experience episodes of
either mania (bipolar I disorder) or hypomania (bipolar II dis-
order). Manic episodes are persistent periods of abnormally
elevated or irritable mood accompanied by several associated
symptoms such as grandiosity, decreased sleep, excessive
talkativeness, racing thoughts, distractibility, and increases in
goal-directed and pleasurable activities. Hypomanic states are
similar in terms of symptomatology but may be of shorter
duration and have less associated impairment. Most patients
with BPD also experience major depressive episodes, which
are periods of either sad mood or loss of interest accompanied
by symptoms such as changes in weight, appetite, sleep and
activity, along with fatigue, guilt, impaired concentration and
thoughts of death. Bipolar disorder is relatively common, with
bipolar I illness affecting 0.5–1% of the population.
Twin studies show a markedly elevated concordance rate
of BPD in monozygotic twins compared to dizygotic twins
(Bertelsen et al. 1977; Cardno et al. 1999), and BPD is more
common among the biological parents than the adoptive
parents of BP adoptees (Mendelwicz & Rainer 1977). Family
studies have established that severe forms of affective ill-
ness, including BPD, run in families and appear to be highly
heritable (Nurnberger et al. 1994). Thus, although twin,
family and adoption studies do not identify specific vulner-
ability genes, such designs consistently indicate a strong
genetic component to BPD susceptibility.
Strategies for elucidating specific genetic bases for BPD
include linkage and association methods. Linkage methods
test the location of vulnerability genes by studying chromo-
somal fragments that are inherited together with an illness.
Such analyses often test LOD scores (the logarithm of the
odds that loci are linked), with higher LODs reflecting greater
probability of linkage. Although recommended cutoffs for
LODs vary slightly depending upon the type of analysis, a
LOD of 1.9 is the minimum score suggestive of linkage,
while LODs of 3.3–3.6 reflect significant linkage in genome-
wide surveys of complex disorders (Lander & Kruglyak
1995). Parametric linkage analyses specify a mode of gene
inheritance (e.g. dominant and recessive), while non-
parametric methods simply measure sharing of gene variants
or alleles without indicating a mode of inheritance. Association
methods examine whether a given gene variant is associated
with illness. Because it is unclear which phenotype best
captures the underlying genetic mechanisms of the disorder,
affected status is often defined in multiple ways in studies.
For example, studies may use narrow, intermediate and
broad disease models in analyses, meaning that disease
status can refer to narrowly defined BPD only or can include
a relatively broad spectrum of affective illnesses.
The present paper reviews current research from linkage,
association and animal studies on the molecular bases for
BPD, with an emphasis on papers published since 1999. In
determining which linkage studies to include, we generally
follow Lander and Kruglyak’s (1995) cutoffs for LOD scores,
except in instances where multiple studies implicate the
Genes, Brain and Behavior (2006) 5: 85–95
Copyright # Blackwell Munksgaard 2005
same region. In such cases, we may also include studies
reporting LOD scores that approach these cutoffs. While
some studies report P-values for significance of LOD scores,
we did not use this information in determining which linkage
studies to include as these values can be misleading. While
LOD scores give odds of probability of linkage, these values
for probability are often misinterpreted as P-values. As
genome-wide studies include multiple tests, a LOD score of
3 (indicating an odds of 1000:1 for linkage) corresponds to a
P-value of 0.05, not 0.001. With respect to association stud-
ies, we included those studies which we felt had the strong-
est designs, based on factors such as sample size and
statistical methods. In the rare instance where a finding can
be considered confirmed, we have noted this. We reviewed
animal models related to bipolar illness that we felt had the
clearest implications for genetic research.
Linkage and association studies
Detera-Wadleigh and colleagues (1999) reported a suggest-
ive linkage to 1q31-32 in a genome-wide scan of 22 pedi-
grees. Linkage of multiple psychiatric diagnoses, including
BPD, to 1q42 was found in a family with a translocation
(Millar et al. 2004). Millar et al. also report an association
between the disrupted-in-schizophrenia 1 gene (DISC1; a
gene at 1q42 coding for a neuronal structural protein) and
BPD in the Scottish population.
Liu and colleagues (2003) examined an Israeli and American
sample of 57 extended families (1508 Caucasian individuals)
with BPD, reporting a two-point parametric LOD score of
3.20 for the region 2p13-16 using an intermediate disease
phenotype and a dominant model of transmission.
Significant linkage to chromosome 4p was initially reported
by Blackwood et al. (1996) in a Scottish pedigree, and
Detera-Wadleigh et al. (1999) also reported linkage to 4p16-
p14. Suggestive linkage was reported to chromosome 4q35
by Adams et al. (1998). Badenhop et al. (2003) examined a
55-pedigree sample comprised of 674 individuals, conducting
two-point parametric LOD score analyses on chromosome
4q35. Several markers in this region showed evidence
for linkage,including D4S3051
(LOD¼2.49) and D4S1652 (LOD¼3.19), all under a broad
disease model. Liu et al. (2003) report a suggestive two-point
LOD score of 3.16 at D4S1625 (on 4q31) under a dominant
model and broad disease phenotype.
Using non-parametric multipoint linkage analysis, Dick et al.
(2002) analyzed chromosomes 5, 15, 16, 17 and 22 in a
replication sample of 56 multiplex families from the National
Institute of Mental Health (NIMH) Genetics Initiative for BPD.
Sibling-pair analysis revealed a suggestive LOD score of 2.8
for a broad disease model at marker D5S207. However, the
LOD score for this marker decreased to 2.0 when the repli-
cation and original sample were combined for an analysis
restricted to sibling pairs with genotyped parents.
Greenwood et al. (2001) reported differential transmission
of a haplotype (a group of closely linked alleles inherited
together) of five single-nucleotide polymorphisms (SNPs;
common variants in the genome sequence) within the dopa-
mine (DA) transporter (DAT) gene. DAT, which has been
mapped to 5p15.3, mediates reuptake of DA. Ohtsuki and
colleagues (2002) examined polymorphisms of the serotonin
4 receptor (HTR4) gene on 5q32 in a case–control sample of
48 patients with mood disorder, finding that four polymorph-
isms at or in close proximity to exon d showed an association
with BPD with odds ratios of 1.5–2. HTR4 encodes the
serotonin 4 receptor gene and influences DA secretion.
Ginns et al. (1996) reported suggestive linkage at marker
D6S7 (on proximal 6p) in an Amish pedigree. Dick et al.
(2003) conducted genome-wide linkage analyses on 1152
individuals from 250 families in the NIMH Genetics Initiative
Bipolar Survey, reporting that chromosome 6 yielded a sug-
gestive multipoint maximum LOD score of 2.2 (near marker
D6S1021), under a broad disease model. Combined analysis
of 399 NIMH pedigrees (including those in Dick et al. 2003)
yielded a significant LOD of 3.8 at 113cM on 6q (A. Hinrichs
et al. unpublished data).
Using affected sib-pair (ASP) analyses, Liu et al. (2003) report
a suggestive multipoint LOD score of 2.78 at 7q34 using an
intermediate disease phenotype. Additional suggestive evi-
dence for linkage to 7q has been reported by Detera-Wadleigh
and colleagues (1997, 1999).
Segurado et al. (2003) applied meta-analytic techniques to 18
BP genome scans (see Levinson et al. 2003 for a review of
the methods). Chromosome 8q (8q24.21-qter) appeared
linked to BPD under narrow and broad disease models, sug-
gesting that loci with small effects on BPD may be located in
this region. Dick et al. (2003) also report evidence for linkage
to 8q in this same region, finding a suggestive LOD score of
2.46 under a narrowly defined disease phenotype, near the
marker D8S256. Also near this marker, McInnis and col-
leagues (2003a) report a suggestive non-parametric LOD of
2.1 on 8q24 using an intermediate model of disease.
The Segurado et al.‘s (2003) study described above produced
modest evidence that a region near the centromere on
Hayden and Nurnberger
Genes, Brain and Behavior (2006) 5: 85–95
chromosome 9 contains loci that influence BPD. Additionally,
a number of candidate genes for BPD are located on chromo-
some 9. As lithium and valproate may produce some of their
(NMDAR), genes that code for the subunits of NMDAR are
candidates for BPD. GRIN1, on chromosome 9q34.3, codes
for the zeta-1 subunit of NMDA receptors. Mundo et al.
(2003) examined three polymorphisms of this gene for link-
age disequilibrium in BPD in 288 probands with narrowly
defined BPD and related disorders and their parents. A pre-
ferential transmission of the G allele was found for the
1001G/C and 6608G/C variants of the GRIN1 in affected
McInnis et al. (2003b) conducted a genome-wide scan of 153
pedigrees as part of the NIMH Genetics Initiative, finding a
suggestive non-parametric LOD of 2.2 for the marker
D10S1423 on chromosome 10p12 under an intermediate
disease model. This linkage was also reported by Foroud
et al. (2000) in a subset of the aforementioned sample, and
the region has been implicated in linkage studies of schizophre-
nia as well (Faraone et al. 1998; Schwab et al. 1998). Older
reports from Ewald et al. (1999) and Cichon et al. (2001)
reported linkage to 10q. More recently, Liu et al. (2003)
obtained a suggestive LOD of 2.33 at 10q24 under a domin-
ant, narrowly defined phenotype. Under a narrowly defined
model, Segurado et al. (2003) found evidence that the region
10q11.21-q22.1 may influence BPD.
Since the first indication of linkage in Old Order Amish
kindred (Egeland et al. 1987), chromosome 11 has been of
interest to investigators. Zandi et al. (2003) scanned chromo-
somes 2, 11, 13, 14 and X in 56 families of 354 individuals
who were part of the NIMH Genetics Initiative on BPD.
Parametric analysis revealed a heterogeneity LOD score of
2.0 near the marker D11S1923 under a dominant, intermedi-
ate disease model.
The DA D4 receptor (DRD4) and tyrosine hydroxylase (TH)
genes were examined in 145 Canadian patients and their
biological parents (Muglia et al. 2002). Both DRD4, which
encodes the D4 subtype of the DA receptor, and TH, a
rate-limiting enzyme in the synthesis of catecholamines, are
located on 11p. Biases in TH allele transmission were not
found, consistent with several older studies finding no asso-
ciation with BPD and TH (Turecki et al. 1997; Souery et al.
2001; although see also Meloni et al. 1995). However,
excess transmission of the DRD4 four-repeat alleles was
detected (associated with an increased odds of BPD of 1.7)
while the two-repeat allele was transmitted at reduced rates
(non-transmission associated with an increased odds of BPD
of 6.88), leading the authors to propose that this allele may
provide protection from risk for BPD.
Sklar et al. (2002) genotyped SNPs in 136 patient–parent
triads from the same sample as McInnis et al. (2003a), find-
ing an association between BPD and SNPs in the brain-
derived neurotrophic factor (BDNF) gene on chromosome
11p13-15. Sklar et al. confirmed this association in two inde-
pendent samples of BP patients (although multiple family
members seem to have been treated as independent
cases). Further evidence for the role of BDNF in BPD was
reported by Neves-Pereira et al. (2002), although negative
results have also been reported (Nakata et al. 2003). BDNF,
which has also been implicated in unipolar depression,
encodes a nerve growth factor protein and its transcription
is highly susceptible to modulation by antidepressants (Ivy
et al. 2003).
In 469 BP patients and 524 matched controls, Massat
et al. (2002a) investigated the DA D2 receptor (DRD2).
Mapped to 11q22.2-22.3, DRD2 encodes the D2 subtype of
the DA receptor. An increased odds ratio for BPD of 1.9 was
found for allele 5 (especially the 5-5 genotype). Nearby on
11q23.1, polymorphisms of the neural cell-adhesion mol-
ecule 1 (NCAM1) gene were found to be nominally asso-
ciated with BPD in a Japanese sample of 151 patients
compared to 357 controls (Arai et al. 2004). NCAM1 is
involved in neuronal growth and pathway formation.
Craddock et al. (1999) reported linkage to chromosome 12 in
a family in which major affective disorder cosegregated with
Darier’s disease. Other studies suggest that while regions
near the Darier’s disease gene may confer vulnerability to
BP, it may not be the Darier’s disease gene itself that does
so (Jacobsen et al. 2001; Jones et al. 2002). Morissette et al.
(1999) have shown evidence for linkage to 12q24 in large
French Canadian families. Also in this region, Barden et al.
(2004) recently reported evidence from linkage and associ-
ation studies indicating that the purinergic receptor P2X,
ligand-gated ion channel, 7 (P2RX7) gene is a susceptibility
gene for BPD and major depression. P2RX7 influences neuro-
transmitter release and neurogenesis.
Stine and colleagues (1997) reported modest evidence of
linkage to chromosome 13q32 in the NIMH Genetics Initi-
ative pedigrees, and further support for this finding was
reported by Detera-Wadleigh et al. (1999) in the neuro-
genetics sample. Liu et al. (1999) and Kelsoe et al. (2001)
have also reported suggestive findings of linkage on chromo-
some 13q. More recently, Potash et al. (2003) examined four
chromosomal regions thought to confer susceptibility to both
schizophrenia and BPD in a sample of 65 BP probands and
237 relatives affected with a major mood disorder. Subsets
of families were created based upon the number of mem-
bers with psychotic mood disorder (mood disturbances
accompanied by hallucinations and/or delusions). Families
with multiple cases of psychotic mood disorders showed
Genes, Brain and Behavior (2006) 5: 85–95
evidence of non-parametric linkage to 13q31, with a LOD
score of 2.52; these regions showed little evidence of link-
age when the sample was examined in its entirety. Badner
and Gershon (2002) conducted a meta-analysis of published
whole-genome scans of BPD and schizophrenia, reporting
that 13q shows significant evidence for linkage to both dis-
orders. Finally, Liu et al. (2003) report a suggestive multipoint
ASP LOD score of 2.2 under an intermediate diagnostic
model for the D13S779 marker on 13q32.
With respect to association studies, Hattori et al. (2003)
examined the relationship between the G72/G30 gene locus
on 13q33 and BPD in two pedigrees, one from the Clinical
Neurogenetics branch of NIMH (Berrettini et al. 1991) and
another from the NIMH Genetics Initiative. The investigators
performed transmission/disequilibrium testing and haplotype
analysis. A similar haplotype was overtransmitted in both
samples, which suggests that a susceptibility variant for
BPD exists in this region. DePaulo (2004) recently suggested
that the G72/G30 complex be considered the first confirmed
gene related to BPD, as several independent groups have
reported findings consistent with Hattori et al. (Chen et al.
2004; Schumacher et al. 2004). The G72 gene appears to
influence activity of NMDA receptors, while the function of
the G30 gene is unclear.
Ranade et al. (2003) examined linkage and association
between BPD and serotonin 2A receptor (HTR2A) gene poly-
morphisms in a sample of 93 patients and their parents.
Comparing the BP patients to 92 controls revealed an asso-
ciation of BPD with SNPs on exons 2 and 3, consistent with
haplotype differences. Examining patients and their parents
suggested significant linkage and association with 1354C/T
and haplotypes containing this SNP. HTR2A, located on
13q14-q21, may mediate the effects of some types of anti-
After finding suggestive linkage signals at marker D16S2619
in both the original and the replication samples from the
NIMH Genetics Initiative, Dick et al. (2002) examined the
combined samples for additional evidence of linkage. Using
non-parametric affected relative pair analysis, they identified
a region containing four markers that all yielded LOD scores
greater than 2.0, with the highest LOD occurring at D16S749
Within the NIMH Genetics Initiative sample, Itokawa et al.
(2003) examined a functional polymorphism in the promoter
region of the GRIN2A gene (which codes for an NMDA
receptor subunit), located on 16p13.3. In this sample, asso-
ciation analysis of a panel of 96 multiplex BP pedigrees
indicated a statistically significant bias in the transmission
of longer alleles. Results suggested that longer than average
alleles resulted in decreased glutamatergic neurotransmis-
sion, which in turn contributes to BP susceptibility. Also on
16p13, the adenylate cyclase type 9 (ADCY9) gene is a
candidate gene for BPD. Adenylate cyclases influence
neuronal signaling and may be targets of antidepressants.
However, findings from association studies have been incon-
sistent (Toyota et al. 2002a, 2002b).
Examining affected relative pairs, Dick et al. (2003) found
suggestive evidence for linkage on chromosome 17q where
they obtained a multipoint, non-parametric LOD score of 2.4
under an intermediate disease model. Liu et al. (2003)
reported a suggestive two-point parametric LOD score of
2.68 at D17S921 under a dominant model of narrowly
Collier et al. (1996) found an association of the short
allele of the serotonin transporter (5-HTT) gene, which
maps to 17q11.1-12, with BPD and major depression.
Rotondo et al. (2002) examined the 5-HTT gene in a sample
of Italian BP patients with (n¼49) and without (n¼62) a
co-occurring diagnosis of panic disorder (an anxiety disorder)
and 127 healthy subjects. Relative to the healthy subjects,
BP patients who did not also have panic disorder had sig-
nificantly higher frequencies of the short allele of the 5-HTT
gene-linked polymorphic region; 58% of the non-comorbid
patients had a short allele compared to 43% of the controls.
In addition, a recent meta-analysis of 5-HTT indicated a posi-
tive association with BPD (Anguelova et al. 2003). A repeat
length polymorphism in the promoter of this gene affects the
rate of serotonin uptake.
Berrettini and colleagues (1994) and Detera-Wadleigh et al.
(1999) reported suggestive and significant linkage to the
pericentromeric region of chromosome 18. Additionally,
Costa Rican pedigrees supported linkage to the tip of 18p
and 18q22-23 (Garner et al. 2001). Segurado et al. (2003)
identified several regions on chromosome 18 as potentially
encompassing susceptibility loci for BPD, including 18pter-
p11 and 18p11-q12.3. Genes in this region potentially asso-
ciated with BPD include CHMP1.5 (or C18-ORF2, unknown
function) (Berrettini 2003) and G-olfa (or GNAL; guanine
nucleotide-binding protein, alpha-stimulating, olfactory type),
although negative findings have been published regarding
the role of G-olfain BPD (Turecki et al. 1996; Zill et al. 2003).
Willour et al. (2003) analyzed 56 multiplex bipolar pedigrees
from the wave 2 sample of the NIMH Genetics Initiative for
BPD, examining chromosomes 4, 7, 9, 18, 19, 20 and 21.
While evidence for linkage was modest in the wave 2 sample
alone, analysis of the combined samples from waves 1 and 2
detected a suggestive non-parametric LOD score of 2.38 at
D20S162, under a broad disease model.
Straub et al. (1994) reported significant linkage to chromo-
some 21q22, and additional evidence for linkage to this
Hayden and Nurnberger
Genes, Brain and Behavior (2006) 5: 85–95
region was observed by Detera-Wadleigh et al. (1996) in two
independent samples. In a recent extension of the Straub
et al.‘s study, Liu et al. (2001) reported additional evidence of
linkage in 56 families to chromosome 21.
Several groups have reported linkage to chromosome 22 in
bipolar samples, including the NIMH Genetics Initiative sam-
ples, the NIMH Neurogenetics pedigrees and Kelsoe et al.
(2001). Badner and Gershon’s (2002) meta-analysis provided
strong evidence that 22q harbors a common susceptibility
locus for both BPD and schizophrenia. Potash et al. (2003)
found evidence of linkage in families with psychotic mood
disorders to 22q12, reporting a non-parametric LOD score of
Lachman et al. (1996) found a relationship between an
allele for a variant of the catechol O-methyltransferase
(COMT) gene and rapid cycling in BPD. Rotondo et al.
(2002) examined the frequency of the polymorphisms for
the COMT gene in affected and unaffected groups. Relative
to the healthy subjects, BP patients without an additional
diagnosis of panic disorder had significantly higher frequen-
cies of the COMT Met158 allele (56% vs. 39%). COMT
catalyzes the neurotransmitters DA, epinephrine and norepin-
ephrine. Recently, Barrett et al. (2003) examined the role of
the G-protein receptor kinase 3 (GRK3) gene in two independ-
ent sets of families with BP probands. An SNP was found to
be associated with disease in the families of Northern
European descent in this sample. GRK3 appears to regulate
the brain’s response to DA.
McInnis et al. (1999) reported linkage to the X chromosome
on Xp22.1 with a heterogeneity LOD of 2.3 in their analyses
of the NIMH Genetics Initiative pedigrees (waves 1 and 2,
153 families). Ekholm et al. (2002) examined the relationship
between the X chromosome and BPD in a sample of 341 BP
Finnish individuals from 41 families. Using a dominant model
of inheritance, a suggestive maximum two-point LOD score
of 2.78 was found at marker DXS1047 under a narrow dis-
ease model. Previous research from this group has also
supported linkage between BPD and markers on Xq24-
q27.1 (Pekkarinen et al. 1995). Zandi et al. (2003) report a
suggestive parametric heterogeneity LOD of 2.25 at marker
GATA144D04 at Xp11.3 under a narrow, recessive model.
A dysfunction in gamma amino butyric acid (GABA) sys-
tem activity has been hypothesized to play a role in BP
vulnerability. Massat et al. (2002b) examined the GABA
maps to Xq28, in a matched European sample of 185 BP
patients and 370 controls, and found that BP patients were
much more likely to have the 1-1 genotype than control
subjects, with increased odds of 2.5 of having BPD with
this genotype. In addition, a meta-analysis of MAOA, which
breaks down an array of monoamines, indicated a significant
association (Preisig et al. 2000). MAOA is located on the
short arm of chromosome X.
Animal models of BPD
One line of research in animal models of mood disorders
examines the relationship between genetic characteristics
of animals and behavior during laboratory situations that
replicate environments thought to cause depression in
humans (e.g. early maternal separation and chronic stress).
In the frequently used learned helplessness paradigm,
animals are administered an inescapable aversive stimulus,
often an electric shock. Following the inescapable portion of
the paradigm, animals are again administered the aversive
stimulus, but are capable of acting to escape or terminate the
stimulus. Longer latencies to escape in this portion of the
task are seen as indicative of a ‘learned helpless’, depresso-
typic response to the task. That escape latencies are
shortened in response to antidepressant dosing is taken as
evidence for the validity of this task as a depression model
(Nestler et al. 2002). The Porsolt swim test (Porsolt et al.
1977), another animal model of depression, entails placing an
animal in water in an enclosed space. The period of time
spent floating motionlessly, as opposed to the amount of
time spent actively seeking escape, is seen as an index of
depressive behavior. Although this model has somewhat
limited face validity, behavior tapped during the task does
show strong responsivity to antidepressants (Porsolt et al.
Lira et al. (2003) examined serotonin transporter-deficient
mice in this task, finding that such mice had increased
latency to escape and also showed depressive-like behavior
in a variety of other laboratory tasks. Additionally, Kohen et
al. (2003) found that congenitally helpless rats had abnorm-
alities in signal transduction and regulation of apoptosis.
These rats had reduced expression of cAMP-response
element-binding protein (CREB) messenger ribonucleic acid
in the hippocampus and increased levels of the antiapoptotic
protein bcl-2 mRNA in prefrontal cortex, among other
changes. Effects of the non-receptor tyrosine kinase Pyk2
on behavior during a learned helplessness task have also
been investigated by Sheehan et al. (2003), who reported
that enhancing levels of Pyk2 in the lateral septum increased
escape behavior. Enhancing expression of CREB in the rat
hippocampus appears to produce similar effects on behavior
during a learned helplessness task (Chen et al. 2001).
Synaptotagmin IV knockout mice were examined during a
modified version of the Porsolt swim test and were found to
be highly sensitive to the effects of the antidepressant imi-
pramine (Ferguson et al. 2004). Synaptotagmin IV is one of
the families of proteins that regulate vesicle trafficking in
neurons and appears to be downregulated in some forms
of psychiatric illnesses. Male DRD5 null mutant mice were
found to show less immobility during the Porsolt swim test
(Holmes et al. 2001), although these mice did not appear
Genes, Brain and Behavior (2006) 5: 85–95
different on other behavioral tasks tapping depressive-like
Currently, more animal models of depressive illness exist
than of mania or of the cyclical nature of BPD (Nestler et al.
2002). Lithium response is viewed as a validating character-
istic for such models (Nestler et al. 2002). Based on this
criterion, probably the most valid of these models is animal
activity level (Nestler et al. 2002). BDNF heterozygous mice
have abnormalities in general activity level (Kernie et al.
2000), and extracellular signal-related kinases also appear to
influence motor behavior in mice (Selcher et al. 2001). The
genetic bases for other animal behaviors potentially relevant
to BPD have been also studied, including eating (Kernie et al.
2000) and aggression (Lyons et al. 1999).
As can be seen, multiple regions are putative susceptibility
loci in BPD, with 2p, 4p, 4q, 6q, 8q, 11p, 12q, 13q, 16p, 16q,
18p, 18q, 21q, 22q and Xq arguably showing the most sup-
port. Studies have produced positive findings for a number of
candidate genes, including COMT, DAT, HTR4, DRD4,
DRD2, HTR2A, 5-HTT, the G72/G30 complex, DISC1,
P2RX7, MAOA and BDNF, among others (Table1). To date,
the G72/G30 complex is the single finding we would con-
sider fully replicated.
A combinationof linkage,
approaches will probably be necessary to clarify the genetic
mechanisms of BPD. Findings in BP genetics may prove
more robust through increased use of designs that incorpor-
ate the complex nature of BPD. For example, while genetic
risk for BPD likely results from the effects of multiple genes
that interact with one another, few studies have examined
interaction effects. Methods that treat individual genetic
effects as independent of one another are likely to be incom-
plete. Future association studies may be able to study mul-
tiple candidate genes known to play a role in mood regulation
and their interactive effects.
Although the influence of genes in BPD is clearly critical,
evidencesuggeststhatenvironmental factors playa significant
Table1: Overview of recent evidence for candidate genes for bipolar disorder (BPD)
GeneLocation Functional significance Supportive evidence
DISC11q42 Neuronal structural proteinMillar et al. (2004)
DRD54p16.1 DA system regulates emotion and motivationHolmes et al. (2001)*
DAT5p Mediates reuptake of DAGreenwood et al. (2001)
HTR45q Encodes the 5-HT4 receptor, which influences DA secretionOhtsuki et al. (2002)
GRIN19q Codes for a critical NMDA receptor subunit; lithium may act
Mundo et al. (2003)
DRD411p DA system regulates emotion and motivationMuglia et al. (2002)
BDNF11p Neuronal growth factor involved in stress and antidepressant
Sklar et al. (2002), Neves-Pereira et al. (2002),
Kernie et al. (2000)*, Dluzen et al. (2001)*,
Lyons et al. (1999)*
DRD2 11q DA system regulates emotion and motivationMassat et al. (2002a)
NCAM1 11q Involved in neuronal growth and pathway formationArai et al. (2004)
P2RX712q Calcium-stimulated ATPase; influences neurotransmitter
release and neurogenesis
Barden et al. (2004)
G72/G30 13q G72 interacts with D-amino acid oxidase; G30 unknown Hattori et al. (2003), Chen et al. (2004),
Schumacher et al. (2004)
HTR2A13qMay mediate effects of serotonin reuptake inhibitors Ranade et al. (2003)
GRIN2A 16p Glutamate receptor subunitItokawa et al. (2003)
ADCY916p Second messenger in neuronal signaling; may be
Toyota et al. (2002b)
5-HTT 17qPromoter alleles affect transcriptional efficiency of 5-HTTCollier et al. (1996), Rotondo et al. (2002)
CHMP1.518pAffects G-protein signaling Berrettini (2003)
COMT22qCOMT alleles affect enzymatic activity Lachman et al. (1996), Rotondo et al. (2002)
GRK322qRegulates homeostatic brain response to DABarrett et al. (2003), Niculescu et al. (2000)*
GABRA3Xq BPD may stem in part from GABA deficitMassat et al. (2002b)
MAOAXpDegrades DA, serotonin, norepinephrinePreisig et al. (2000)
DISC1, disrupted-in-schizophrenia 1; DA, dopamine; DRD, dopamine D; DAT, dopamine transporter; NMDAR, N-methyl-D-aspartate receptors;
BDNF, brain-derived neurotrophic factor; NCAM1, neural cell-adhesion molecule 1; P2RX7, purinergic receptor P2X, ligand-gated ion channel, 7;
ADCY9, adenylate cyclase type 9; COMT, catechol O-methyltransferase; GRK3, G-protein receptor kinase 3; GABRA3, gamma amino butyric
acid receptor 3; GABA, gamma amino butyric acid.
Hayden and Nurnberger
Genes, Brain and Behavior (2006) 5: 85–95
role in the course of the illness. For example, several studies
have provided evidence that life events may precipitate episo
des (Amberlas 1979; Johnson et al. 2000; Mortensen et al.
2003). Gene-environment models haverecently beensuccess-
fully applied to major depression (Caspi et al. 2003), and suffi-
cient research on psychosocial influences on BPD (e.g.
stressful or goal-attaining life events) currently exists to sug-
gest some useful starting points for multivariate studies.
Future studies of the genetics of BPD may benefit from the
investigation of phenotypes of increased specificity and
increased breadth. For example, several studies have used the
strategy of examining subgroups of BP patients based on
factors such as early age of onset (Faraone et al. 2004), psycho-
tic symptomatology (Potash et al. 2003), treatment response
(Turecki et al. 2001) and comorbid anxiety disorders (Rotondo et
al. 2002). Other investigations have yielded intriguing results by
examining whether BPD and schizophrenia have a common
underlying genetic diathesis (Badner & Gershon 2002). Further
exploration is needed to clarify whether such phenotypes yield
greater consistency of linkage and association findings.
Genetic research on BPD may also benefit from the
increased use of endophenotypes (i.e. traits associated
with the disease that are heritable and possibly precede
disease onset and are present in unaffected relatives). As
such traits are often quantitative, they may more accurately
reflect the underlying genetic phenomena and may lend
greater power to statistical analyses (Baron 2002). In schizo-
phrenia research, endophenotypes have received much
attention but are less widely used in BPD research. Candi-
date endophenotypes include circadian rhythm disruption,
response to sleep deprivation, psychostimulants, tryptophan
depletion and white matter hyperintensities (see Lenox et al.
2002 for a review of these), as well as temperament (e.g. high
behavioral activation, hyperthymic temperament; Johnson
et al. 2000; Kwapil et al. 2000; Lozano & Johnson 2001), and
melatonin levels (Nurnberger et al. 2000). Further research is
needed to establish whether these markers validly reflect
underlying genetic vulnerability.
Animal studies of endophenotypes may also provide clues
about the genetics of BPD. For example, studies have exam-
ined the genetic bases of circadian rhythms in animals
(Hofstetter et al. 2003). As disruption of circadian processes
may contribute to BPD, and as animal data suggest suscept-
ibility to circadian rhythm disruption is heritable (Mayeda &
Nurnberger 1998), such approaches may prove fruitful. In
addition, research into the genetic loci regulating prepulse
inhibition in rats (Palmer et al. 2003) may be informative as
prepulse inhibition appears to be abnormal in manic BP
patients (Perry et al. 2001; although studies of prepulse
inhibition in euthymic patients have yet to be carried out).
Studies have also examined activity level in response to
stimulants, finding that BDNF heterozygous mice show
significant increases in locomotor behavior when administered
an amphetamine challenge (Dluzen et al. 2001); Niculescu
et al. (2000) found that a variety of candidate genes for BPD,
including GRK3, were upregulated in the prefrontal cortex of
rats following a methylamphetamine injection. Future animal
studies of endophenotypes may wish to emphasize under-
explored areas such as response to sleep deprivation. Rats
demonstrate a variety of manic-like behaviors in response to
sleep deprivation, including hyperactivity and irritability
(Gessa et al. 1995); this may provide a substrate for genetic
studies targeting inbred strains or examining genetically
modified animals. Examination of the genetic underpinnings
of reward sensitivity and motivation (Depue et al. 1987), is
also probably warranted. Convergent functional genomics,
which integrates such animal models with human linkage
data to identify high-probability candidate genes (Niculescu
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Portions of this work were supported by AA07462, MH059545,
and a grant to the clinical laboratories at the Institute of Psychia-
tric Research from the Indiana Division of Mental Health and
Genes, Brain and Behavior (2006) 5: 85–95