Genetic overlap between polycystic ovary syndrome and bipolar disorder:
The endophenotype hypothesis
Bowen Jiang*, Heather A. Kenna, Natalie L. Rasgon
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Center for Neuroscience in Women’s Health, 401 Quarry Road,
Stanford, CA 94305, United States
a r t i c l e i n f o
Received 3 December 2008
Accepted 7 December 2008
s u m m a r y
Polycystic Ovary Syndrome (PCOS) is a polygenic disorder caused by the interaction of susceptible geno-
mic polymorphisms with environmental factors. PCOS, characterized by hyperandrogenism and men-
strual abnormalities, has a higher prevalence in women with Bipolar Disorder (BD). Theories
explaining this high prevalence have included the effect of PCOS itself or the effect of drugs such as Val-
proate, which may cause PCOS either directly or indirectly. Incidentally, metabolic abnormalities are
observed in both bipolar and PCOS patients. Endophenotypes such as insulin resistance, obesity, and
hyperglycemia are common among BD and PCOS patients, suggesting some degree of pathophysiological
overlap. Since both BD and PCOS are complex polygenetic diseases, the endophenotype overlap may be
the result of common genetic markers. This paper postulates that shared clinical endophenotypes
between PCOS and BD indicate common pathophysiological platforms and will review these for the
potential of genetic overlap between the two disorders.
Published by Elsevier Ltd.
and a leading cause of female infertility. PCOS affects approximately
and menstrual abnormalities, hyperandrogenism, and insulin resis-
tance . Several authors have suggested that PCOS is caused by a
combination of genetic, neuroendocrine, and metabolic factors.
A connection between PCOS and Bipolar Disorder (BD) was sug-
gested by Matsunaga and Sarai and further clarified by one of us
(Rasgon) [2,3]. In these studies, the authors suggested that a rela-
tionship might exist between abnormal menstrual cycles and bipo-
lar symptoms, resulting in a higher prevalence of PCOS in women
with bipolar disorder. Theories have been formulated to explain
the high prevalence of PCOS in these populations, which include
the effects of anti-bipolar agents, such as valproic acid, a com-
monly prescribed mood stabilizer. This connection was first pre-
sented in a paper by Isojarvi et al. , which found ultrasound
evidence of polycystic ovaries in 43% of epileptic outpatients taking
Valproate . Along with a later publication by Isojarvi et al. in
1998, the conclusion was that PCOS may be positively associated
with Valproate use . Similarly, a study by O’Donovan et al. 
found that 47% of female bipolar patients taking Valproate had
menstrual abnormalities compared with 13% of female bipolar pa-
tients not taking Valproate .
Similar metabolic disorders are associated with both PCOS and
BD, such as insulin resistance, obesity, hyperleptinemia, and hy-
per-activation of the Hypothalamus–Pituitary–Adrenal (HPA) axis.
These common morbidities may represent an indirect link between
PCOS and bipolar disorder. For instance, a paper by Lewy et al. sup-
ports the hypothesis that PCOS is stimulated by decreased periph-
eral insulin sensitivity and hyperinsulinemia while a review by
Rossum et al. suggests that glucocorticoid resistance results in im-
paired negative feedback mechanisms, HPA hyperactivity, and
overproduction of mineralcorticoids and androgens in PCOS pa-
tients [7,8]. Likewise, insulin resistance, disturbances in HPA, and
hypersecretion of cortisol have been documented in both depres-
sive and manic phases of BD [9,10]. The commonalities between
the diseases and the predisposition for common symptoms suggest
possible pathophysiological overlap. Moreover, since both disor-
ders are genetic in origin, the endophenotype similarities seem
to suggest molecular overlap on the genetic level. This paper pro-
poses that genetic vulnerabilities common to overlapping endo-
phenotypes of both PCOS and BD may account for the link
between the two disorders and reviews the evidence herein.
The widely used diagnostic criteria for PCOS set forth by the
National Institute of Child Health and Human Development
(NICHD/NIH) include clinical or biochemical hyperandrogenism,
0306-9877/$ - see front matter Published by Elsevier Ltd.
* Corresponding author. Address: 401 Quarry Rd. MC 5723 Stanford, CA 94305,
United States. Mobile: +1 301 768 7528; fax: +1 650 724 3144.
E-mail address: firstname.lastname@example.org (B. Jiang).
Medical Hypotheses 73 (2009) 996–1004
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oligo-ovulation, and polycystic ovaries. A more recent meeting of
the European Society of Human Reproductive Medicine (ESHRE)/
American Society of Reproductive Medicine (ASRM) characterized
PCOS to include two of the following three criteria: (1) oligomen-
orrhea or anovulation, (2) clinical or biochemical hyperandroge-
nism, and (3) polycystic ovaries on ultrasonography with the
exclusion of related endocrinopathies (adrenal hyperplasia or
Cushings etc.) . PCOS is interrelated with several metabolic
and endocrine disorders, including insulin resistance, cardiovascu-
lar disease, hyperlipidemia, and obesity .
A 5–10% prevalence of PCOS is a reasonable estimate, with med-
ian estimates of 6% [13,14]. PCOS has been documented to occur
frequently among premenopausal women with type-2 diabetes
. Most reports show a higher prevalence (up to 26%) of PCOS
in women with epilepsy taking Valproate than in the general pop-
ulation . In one study by Rasgon et al., 65% of women reported
menstrual abnormalities concurrent with bipolar disorder and 38%
reported developing menstrual abnormalities after treatment of
bipolar disorder .
According to the definitions aforementioned, PCOS patients can
be defined by ovulatory dysfunction, hyperandrogenism, and
exclusion of related disorders . Ovulatory dysfunction may be
observed clinically in the form of oligomenorrhea or amenorrhea.
Hyperandrogenism refers to hirsutism, acne, or alopecia. Infertility
was included in the original description of PCOS by Stein and
Leventhal, but recent studies have shown that not all women with
PCOS are infertile.
PCOS is a complex disorder with several possible contributing
causes. Endocrine, metabolic, neurologic, or genetic factors have
all been implicated. On the endocrine level, increased steroidgenic
activity has been hypothesized to be a potential cause for hyperan-
drogenism and impaired ovarian function. In a study by Gilling-
Smith et al., it was observed that isolated thecal cells from polycys-
tic ovaries had hypersecretion of androstenedione and 17-hydrox-
glucocorticoid biosynthesis pathways . Several hormonal
abnormalities contribute to reproductive disorders in PCOS pa-
tients. Elevated serum LH, increased LH/FSH ratio, and elevated
androgens (gonadotropin hormonal imbalance) lead to an increase
in LH-stimulated steroidgenesis of the ovaries along with a de-
crease in follicle maturation . Abnormal endocrine function
and increased steroidgenic activity may be caused by genetic
There has also been evidence supporting the insulin hypothesis,
that decreased peripheral insulin sensitivity and hyperinsulinemia
may lead to PCOS . Insulin inhibits the production of insulin-
like growth factor 1 binding protein, which in turn causes an in-
crease in free insulin-like growth factor 1 [21,22]. Both insulin
and free insulin-like growth factor 1 stimulate the production of
thecal androgen and increase free testosterone [23,24]. A possible
cause of insulin resistance may be due to defects in insulin receptor
autophosphorylation, which has been reported in approximately
50% of women with PCOS . Another possible cause is dysfunc-
tion of the pancreatic beta-cells, which can lead to the develop-
ment of type-2 diabetes . Interestingly, PCOS is also more
common among women with epilepsy, occurring in 10.5–26% of
that patient population [27,28]. Epileptic discharge may affect
in the androgenand
the secretion of gonadotropin releasing hormone (GnRH). In-
creased GnRH promotes LH secretion and an elevated LH/FSH ratio
. Finally, as previously mentioned, bipolar disorder is observed
more frequently in PCOS patients and vice a versa [2,3]. A plausible
explanation is the role of pharmacology, in which BD patients on
Valproate are more likely to develop PCOS; Valproate potentiates
androgen biosynthesis in human ovarian theca cells, which could
explain hyperandrogenism and menstrual abnormalities .
However, controversy exists as to whether PCOS is caused by bipo-
lar disorder, its treatment, or both [31,32]. Recently, the hypothesis
that bipolar disorder itself leads to the development of PCOS inde-
pendent of pharmacology has gained evidence [33–35]. The mech-
anism for the connection is still poorly understood.
Genetics basis for PCOS
Familial aggregation of PCOS phenotypes and associated meta-
bolic abnormalities has long been established, suggesting that ge-
netic factors may also play a role . PCOS appears to be a
complex, polygenetic disorder, with possible genetic defects rang-
ing from ovarian androgen biosynthesis to insulin receptors. Coo-
per et al. first reported that a history of oligomenorrhea and
polycystic ovaries was more common in the mothers and sisters
of PCOS patients compared with controls . Male relatives were
reported to have increased pilosity while the proposed mechanism
Givens et al. has conducted multiple kindred studies on meta-
bolic function [37,38]. They discovered familial aggregation of
hyperandrogenism, hyperlipidemia, and diabetes mellitus. These
studies were also the first to reveal cardiovascular abnormalities
such as hypertension and arteriosclerosis in family aggregates. Ele-
vated LH/FSH ratios were found in some males and 89% of their
daughters had PCOS [37,38]. Although this evidence, along with
oligospermia and elevated LH secretions in males, suggested an
X-linked pattern of inheritance, the method of inheritance for PCOS
is still controversial.
Ferriman and Purdie studied a large cohort of 700 hirsute wo-
men with enlarged ovaries . The frequency of oligomenorrhea
and menstrual abnormalities in relatives were determined. Forty-
six percentage of female first-degree relatives were similarly af-
fected while some male first-degree relatives reported increased
baldness. Similar results were observed by Lunde et al., on a pop-
ulation of 132 Norwegian women exhibiting two or more of the
following symptoms: menstrual irregularities, obesity, hirsutism,
and/or infertility . First-degree female relatives of these wo-
men were found to have a significantly increased frequency of
PCOS symptoms. Among first-degree male relatives, balding and
increased pilosity were observed at a higher percentage compared
with the controls.
Various other studies have phenotyped women based on de-
tected polycystic ovary morphology on an ovarian ultrasound. In
a study by Hague et al., high resolution ultrasound identified poly-
cystic ovary phenotypes in 61 women with hyperandrogenism,
obesity, and infertility. 67% of the mothers and 87% of the sisters
of the probands were affected . A study by Carey et al. esti-
mated the segregation ratio among family members to be 51.4%,
consistent with an autosomal dominant mode of inheritance
. However, monozygotic twin studies argued against this mode
of inheritance. Although no clear pattern of inheritance has
emerged, family studies have been helpful in suggesting a genetic
component does exist.
Recent studies have shown that hyperandrogenism, insulin
resistance, and other aspects of metabolic homeostasis may be
inheritable as well. Goodarzi et al. reported significant correlation
B. Jiang et al./Medical Hypotheses 73 (2009) 996–1004
of adrenocorticotropic hormone-stimulated steroid hormone levels
between 27 women with PCOS and their 28 sisters  Norman
et al. has reported that elevated insulin levels were found among
first-degree relatives of PCOS patients . Colilla et al. reported
heritable beta cell dysfunctions in families of women with PCOS
. Similarly, familial correlations have been documented in glu-
cose intolerance and insulin resistance [46,47].
Most studies of genomic variation in PCOS populations have ap-
plied the candidate gene approach, focusing on polymorphisms of
genes involved in androgen and insulin pathways. Recently, genes
involved in the regulation of inflammatory response have also been
targeted, due to the growing evidence of chronic inflammation on
Genes relating to steroidgenesis
The most important biochemical phenotype in PCOS is in-
creased LH secretion and corresponding acyclic FSH production.
From the stimulation of elevated LH, the ovaries and the adrenal
glands secrete excess androgens, resulting in decreased conversion
of androgens to estrogen. Through feedback with the HPA axis, cir-
culating androgens further increases LH levels relative to FSH lev-
els. The precise mechanism by which this process occurs it not yet
clearly known, but factors regulating gonadotropin secretion or ac-
tion and steroidgenesis could be targeted for candidate gene
The most relevant genes involved in steroidgenesis and the
androgen biosynthetic pathway are CYP11a, CYP21, CYP17, and
CYP19. CYP11a is located at 15q24 and encodes for the P450 cyto-
chrome side chain cleavage enzyme that catalyzes the conversion
of cholesterol into progesterone, the rate limiting step of steroid-
genesis . Case studies from Greece and China have found evi-
polymorphism (untranslated region consisting of a variable num-
ber tandem repeat) and PCOS [49,50]. This positive finding, how-
ever, has since been questioned by large scale studies from the
United Kingdom and Finland . CYP21 encodes for an enzyme
which catalyzes the conversion of 17-hydroxyprogesterone into
11-deoxycortisol. The deficiency of this enzyme, inherited through
an autosomal recessive trait, is responsible for congenital adrenal
hyperplasia. Patients with heterozygous CYP21 mutations also ex-
hibit a PCOS-like phenotype . However, several studies have
indicated no significant correlation between CYP21 mutations and
the development of PCOS [53–56]. CYP17 encodes for an enzyme
(P450c17a) that catalyzes the conversion of 17-hydroxypregneno-
lone and 17-hydroxyprogesterone into dehydroepiandrosterone
and androstenedione, respectively. Increased P450c17a activity
has been reported to be responsible for enhanced androgen levels
in patients with PCOS [57,58]. Carey et al. has identified a rare T/C
single nucleotide polymorphism (SNP) in the promoter region of
CYP17 as a susceptibility locus for PCOS . Although this finding
was initially supported, more comprehensive studies have since re-
vealed no significant association between CYP17 and PCOS [60–62].
Finally, CYP19 encodes for an enzyme complex called aromatase
that catalyzes the conversion of C19 androgens to C18 estrogens.
Aromatase deficiency has been reported in several immunohisto-
chemical studies of PCOS patients [63,64]. However, linkage and
mutation studies have not revealed any etiological correlation be-
tween CYP19 and PCOS [65,66].
Genes involved in hyperandrogenism
Genes involved in steroid hormone effects may also be signifi-
cant. For instance, the androgen receptor gene (ARG) encodes for
a nuclear transcription factor that all androgens must operate
through. The androgen receptor gene is located at Xq11-12 .
The transactivation domain of the androgen receptor gene contains
a trinucleotide repeat in the form of polyglutamines (CAG). The
transcriptional activity of the androgen receptor gene is inversely
related to the length of the polyglutamine repeat . Thus, de-
creased number of CAG repeats results in increased androgen
receptor activity, and subsequently results in hyperandrogenism
. Even though such a relationship exists between androgen
receptor gene and hyperandrogenism, the association does not ex-
ist with PCOS. Several studies have shown that the CAG repeats are
not major determinants of PCOS pathogenesis and that no correla-
tion exists between CAG repeats and body mass index or serum tes-
tosterone levels [70,71]. Another gene that regulates the access of
androgens to target tissues is the sex hormone-binding globulin gene
(SHBG). Serum SHBG levels are commonly low in PCOS patients,
contributing to increased tissue androgen availability . A pen-
tanucleotide repeat polymorphism in the promoter region of the
SHBG gene has been identified to be associated with PCOS in a Greek
population . In another study by Cousins et al., it was demon-
strated that hirsute, PCOS women with longer pentanucleotide re-
peats had decreased SHBG levels . Based on current evidence,
the SHBG gene is a potential candidate gene for PCOS pathogenesis.
Genes relating to gonadotropin regulation and action
Genes involved in gonadotropin mechanisms are interesting be-
cause increased LH levels are clinical markers for PCOS. The gene
encoding the b-subunit of LH has been researched extensively. In
particular, a single missense mutation, Gly102Ser, and two-point
mutations, Trp8Arg and Ilg15Thr, have failed to be associated with
PCOS [75,76]. Studies with the LH receptor gene have yielded sim-
ilar negative results [70,77]. However, Takahashi et al. has recently
demonstrated that certain SNP’s in the promoter region of the LH
b-subunit gene are more common among PCOS patients than nor-
mal ovulatory women. The functional effects of LH and its receptor
genes do not appear to play significant roles in PCOS pathogenesis
as of yet, but further studies on the Takahashi SNP’s may be mean-
ingful. Follistatin, a glycoprotein that binds activin, is intimately in-
volved in FSH and insulin secretion. As the activin binding protein,
follistatin can modulate activin induced responses in FSH and insu-
lin. Increased activin binding through overexpression of follistatin
may reduce FSH, arrest follicular maturation, increase androgen
production, and impair insulin release, all of which are features
of PCOS. The follistatin gene has been explored as a candidate gene
for PCOS but no mutations or polymorphisms have been estab-
lished as significant [78–80].
Genes involving insulin
In a review by Dunaif, 50% of PCOS women studied had abnor-
malities in an enzyme regulating insulin receptor tyrosine kinase
activity . Dunaif also reported an increase in insulin resistance
and compensatory hyperinsulinemia in both obese and non-obese
PCOS women . Insulin resistance appears to be due to defects
in insulin receptor signaling or abnormalities in insulin secretion
and action. The commonly explored candidate genes have included
the insulin gene (INS), the insulin receptor gene (INSR), the insulin
receptor substrate genes (IRS’s), and calpain-10 (CAPN10).
The insulin gene (INS) includes a variable tandem repeat region
(VNTR) ranging from 26 to 200 repeats and is located between the
genes for tyrosine hydroxylase and IGF-II at 11p15.5. The VNTR is
responsible for transcription regulation of the INS gene and poly-
morphisms in this region can be classified into three size classes
. Class I alleles are the shorter polymorphic region, consisting
of an average of 40 repeats. Class II alleles have an average of 80
repeats and Class III alleles contain an average of 160 repeats.
Longer polymorphic VNTR corresponds to greater transcriptional
B. Jiang et al./Medical Hypotheses 73 (2009) 996–1004
activity. Waterworth et al. discovered an association between PCOS
and allelic variations in the VNTR of the insulin gene in three inde-
pendent populations, and that Class III allele genotypes were asso-
ciated with anovulatory PCOS . In support, Michelmore et al.
demonstrated that class III alleles and paternal class III allele trans-
missions were related to increased PCOS features and insulin resis-
tance among PCOS patients . However, several studies have
failed to show any association between INS VNTR and PCOS
[84,85]. Sample size, variable ethnic and geographical regions,
and selection bias may explain the conflicting results.
The insulin receptor gene (INSR) is located on the long arm of
Chromosome 19 (19p13.2) and encodes for a heterotetrameric gly-
coprotein that functions as a receptor for insulin. A number of
studies have investigated INSR in an attempt to explain insulin
resistance in PCOS patients, resulting in conflicting conclusions.
Conway analyzed the sequence of the tyrosine kinase domain of
INSR in hyperinsulinemic PCOS patients but discovered no signifi-
cant mutations relevant to insulin resistance in PCOS . Simi-
larly, Talbot et al. used molecular scanning to examine the
coding region of INSR in 24 hyperinsulinemic PCOS patients to
yield the same results . However, using a dinucleotide marker
D19S884, Tucci et al. showed a significant association with INSR in
causing insulin resistance in PCOS patients . Recently, a com-
prehensive study by Urbanek et al. scanned 19p13.2 and found
strong evidence for the association of D19S883 with PCOS .
The tyrosine kinase domain of INSR has also been further investi-
gated by Siegel et al., who found that a SNP at the domain was
associated with PCOS . It appears that further studies on INSR
and the tyrosine kinase domain are necessary in order to clarify
current experimental results.
The insulin receptor substrates (IRS) are activated by insulin
receptor phosphorylation and function to signal downstream effec-
tors to promote the metabolic functions of insulin. The Gly972Arg
polymorphism in IRS1 gene (IRS1) and the Gly1057Asp polymor-
phism in the IRS2 gene (IRS2) have been implicated in insulin resis-
tance and shown to increase susceptibility to type-2 diabetes
mellitus [91,92]. Due to this correlation, IRS polymorphisms have
been studied in PCOS, again resulting in conflicting results. Sir-Pet-
ermann et al. observed higher frequency of the Gly972Arg IRS1
polymorphism in PCOS patients in Chilean population while Dilek
et al. reported a similar finding in Turkish women with PCOS
[93,94]. To the contrary, El Mkadem et al. could not find a signifi-
cant association in either IRS1 or IRS2 polymorphism with PCOS
. Recent conclusions indicated that the IRS polymorphisms ap-
pear to be associated with insulin resistance independent of PCOS,
suggesting more comprehensive investigations are necessary.
Variations in the CAPN10 gene encoding calpain-10 have been
associated with type-2 diabetes . Since PCOS and type-2 diabe-
tes share many etiological factors, Ehrmann et al. investigated vari-
ations in CAPN10 for association to pathogenesis of PCOS. The study
discovered an association between the 112/121 haplotype of this
gene and increased peripheral insulin levels and an increased risk
for PCOS . Similar results were obtained by Gonzales et al. who
found that SNP-44 was associated with PCOS in Spanish women
[98,99]. However, Haddad and Escobar-Morreale found no associa-
tion between any SNP and PCOS [100,101].
Genes involved in satiety and inflammation
The adipose tissue is an active endocrine organ that secretes
many adipocytokines. Because a significant number of PCOS pa-
tients are obese, the level of adipose tissue is quite significant. Can-
didate gene studies have focused on the leptin gene and leptin
receptor genes, which play important roles in satiety. However, no
association was found between polymorphisms in the leptin family
genes and PCOS, although changes in leptin expression may be the
result of HPA abnormalities having systematic effects rather than
mutations in the gene itself . Chronic inflammation appears
to be important to insulin resistance and may be involved in the
pathogenesis of PCOS. The polymorphisms of TNF-a do not appear
tobe a keyrole,despitebeinga cytokinesecreted bythe adiposetis-
sue [103,104]. Positive associations were found in the TNF receptor
type two (TNFR2) gene between a Met196Arg variant and PCOS
. In interleukin-6 (IL-6), an association was significant between
the -174 G/C locus and PCOS . Similarly, the Gly148Arg variant
in the IL-6 signal transducer gp 130 and CA repeats in the IL-6 recep-
tor-a were positively associated with PCOS [107,108].
A more thorough review of PCOS genetics, including those
genes reviewed in this article, can be found in a review by Unluturk
et al. .
Bipolar disorder background
Bipolar disorder is a mood disorder characterized by two ex-
tremes. At one extreme is a manic phase, which is a week or longer
period of elevated and irritable mood accompanied by at least three
of the following: distractibility, decreased need for sleep, inflated
grandiosity, flight of ideas, increased psychomotor agitation, and/or
excessive involvement in self-indulging . At the other extreme
is the depressive phase, a two weeks or longer period characterized
by depressed mood and diminished interests or lost of pleasure in
most activities. The depressive phase may be further accomplished
by feelings of worthlessness, sleep disturbances, fatigue, indecisive-
ness, psychomotor retardation, and suicidal tendencies.
The prevalence of bipolar disorder is approximately 1% of adults
in the United States, affecting roughly 2.3 million Americans .
Several studies have shown that 20–40% of adolescents with major
depression will develop mania within five years . The inci-
dence of bipolar disorder among relatives of affected patients is
higher than in the general population . As previously men-
tioned, the prevalence of menstrual and metabolic abnormalities
is higher in women with bipolar disorder [3,17].
A number of comorbidities have been observed in patients with
bipolar disorder, including neurologic, metabolic, and menstrual
disorders. Bipolar disorder often coexists with other psychiatric
disorders such as anxiety disorder, obsessive compulsive disorder,
social phobia, and PTSD . Epidemiological and clinical studies
have also identified an association between bipolar disorder and
obesity. For instance, 377 participants in a Systematic Treatment
Enhancement Program for Bipolar Disorder were evaluated for
height and weight and found to have average body mass indices
of 27.7 ± 6.2 kg/m2. Fifty-five percentage of patients were either
overweight or obese [114,115]. Increased prevalence of diabetes
mellitus and metabolic syndrome have also been observed com-
pared to the general population. Finally, numerous reports have
shown high prevalence of PCOS in bipolar populations [3,17].
Genetics of bipolar disorder
Bipolar disorder is a complex disorder involving several genetic
components, none of which singularly cause the disease. Early ap-
B. Jiang et al./Medical Hypotheses 73 (2009) 996–1004
proaches to genetic studies include family and twin studies. These
studies showed family aggregation of the disorder: for instance,
first-degree relatives of bipolar probands are at increased risk for
the disorder when compared with first-degree relatives of controls
. Similarly, twin studies have shown increased concordance
rate in monozygotic versus dizygotic twins. These earlier family
and twin studies have been thoroughly reviewed elsewhere by
Tsuang and Faraone . In two adoption studies, Mendlewicz
and Rainer investigated the biological and adoptive parents of 29
bipolar and 22 normal adoptees and found significant greater risk
of bipolar disorder and unipolar disorder in the biological parents
than the adoptive parents . Taken together, family, twin,
and adoption studies provided consistent evidence that genes
determine predisposition to bipolar disorder.
Molecular genetic studies can be divided into position and can-
didate gene approaches. In the positional approach, chromosomal
locations of susceptible genes are determined through linkage
studies. The observation that trisomy 21 patients had less suscep-
tibility to mania led to other studies which intensively focused on
chromosomal abnormalities . This observation, along with
new advances in genetic markers and positional linkage studies,
has helped to identify several loci of interest. Early studies have at-
tempted to identify a single, autosomal gene in causing bipolar dis-
order. This approach has been fruitless, and several other modes of
inheritance have been proposed, including locus heterogeneity,
allelic heterogeneity, epistasis, dynamic mutation, imprinting,
and X-linked [118–121]. Recent studies showed that mood disor-
ders are observed more frequently in maternal relatives of children
with mitochondrial disease as opposed to paternal relatives, sug-
gesting a mitochondrial inheritance . The mtDNA 3644 muta-
tion, which reduce mitochondrial membrane potential, has been
associated with bipolar disorder . The positional candidate
approach has shown linkage of bipolar disorder with several other
loci, of which the most significant are 2p, 4p and 4q, 9p, 10q, 11p
and 11q, 12q, 18p and 18q, 21q, 22q, and Xq . While this ap-
proach has identified many regions to be in association with bipo-
lar disorder, the range of possible loci is very broad, with the
corresponding number of genes even more amassing.
Gene expression and genetic analysis studies have identified
candidate genes from post-mortem brains of bipolar patients.
Among the genes differentially expressed in the post-mortem
brains of bipolar patients, PDLIM5 had significant changes in lym-
phoblastoid cells [124,125]. Promoter SNP that may alter the bind-
ing to transcription factors in PDLIM5, which encodes for an
adaptor protein linking calcium channels, have been associated
with bipolar disorder [126,127]. In another study, Nakatani et al.
found that the NDUFV2 and SST genes were altered in post-mortem
brains. After analyzing 43 SNP’s, Nakatani et al. discovered an asso-
ciation between bipolar disorder and a haplotype of the SST
(somatostatin) gene. Promoter SNP of the NDUFV2 gene was found
to be associated with bipolar disorder in Japanese and parents-pro-
band trios from NIMH Genetics Initiative but was not found to be
significant in an extended trio sample from NIMH [128,129].
In the DNA microarray data focused on mitochondria-related
genes, LARS2 was upregulated in postmortem tissues of bipolar pa-
tients . LARS2 encodes for an enzyme that catalyzes the
aminoacylation of mitochondrial tRNA. In a study by Kato et al.,
they applied highly sensitive PCR and detected small amounts of
mtDNA 3243 mutations in three bipolar patients . In another
study, two endoplasmic reticulum stress-related genes, XBP1 and
HSPA5, were downregulated in patients . An initial associated
promoter polymorphism in XBP1 was not replicated in a large Cau-
casian and a smaller Chinese population [132,133]. Nominal asso-
ciation was found with SNP’s of HSPA5 in a Japanese populations
and no association was found in the NIMH trios [134,129].
Replication studies of previously reported candidate genes are
most active in the molecular genetic research of bipolar disorder
today. Candidate genes such as DRD1 [135,136], DRD4 , MAOA
, HTT , HTR2A , and IMPA2 [141,142] have recently
been examined. Some previous associations have been con-
tradicted by further replication studies. For instance, there has
been a failure to confirm the association of candidate genes such
as the Val66Met polymorphism of BDNF [143,144]. Several new
candidate genes have recently been identified, involving signal
transduction cascades, intracellular signaling, or neuronal net-
works. These genes include TPH2, HTR3B , ADRA2C ,
PIK3C3 , GABAABeta2, GABAAGamma2 , PCDH11Y ,
and GSK3Beta [150,151]. Most of these genes have shown negative
results, but positive associations were reported in HTR3B and
Recent advances in candidate gene studies have focused on the
association between comorbidities of bipolar disorder as well as
phenotypes of bipolar disorder that are similar with other neuro-
logical diseases. For instance, comorbidities with panic disorders
and psychotic symptoms have led to a strong link has been ob-
served between schizophrenia and bipolar disorder. Although the
two are dissimilar disorders, many mood-based psychotic features
are difficult to distinguish. These similar features led to many
molecular genetic linkage studies. One of the more robust findings
is the association with G72, found at a common locus of 13q34 in
bipolar disorder and schizophrenia. G72 encodes for a D-amino acid
oxidase activator (DAOA). While the role of G72 in schizophrenia is
pinpointed to the D-serine metabolism pathway, its role in bipolar
disorder is not well studied. The association between G72 and
bipolar disorder was first reported by Hattori et al. when they dis-
covered over-transmission of common haplotypes in two pedi-
grees . This association was supported by evidence from
another study with a sample size of 139 patients . However,
the robustness of the G72 association has recently come into ques-
tion. Several reports disagreed with the suggested SNP’s and hap-
lotypes in theHattori paper
association between G72 with delusions  or psychosis 
rather than bipolar disorder. G72 is a promising candidate gene
for bipolar disorder, but conflicting evidence makes it too early
to deem it a risk factor for bipolar disorder.
Another genetic linkage between the two disorders is DISC1
(disrupted in schizophrenia 1), the only gene that has been estab-
lished as a causative gene for mental disorder. DISC1 was first
cloned from a translocation break point at 1q42.1 in a schizophre-
nia pedigree. Multiple sources state that DISC1 is intimately in-
volved in neural development, neurite extension,
migration, and neurotransmitter signaling . Single nucleotide
polymorphism studies have shown association between DISC1 and
bipolar disorder .
Phenotype overlap studies have also discovered a genotypic link
between BD and depression. Most studies have focused on well-
studied functional polymorphisms such as HTTLPR and BDNF
Val66Met. Another area of interest has been the serotonin hypoth-
esis, which states that serotonin regulation and secretion may be
the link between BD and depression. Recently, a rare mutation of
tryptophan hydroxylase 2 (TPH2) was found to be significant in a
population of patients with major depression. However, no associ-
ation between TPH2 and bipolar disorder was reported [160,161].
B. Jiang et al./Medical Hypotheses 73 (2009) 996–1004
Although these associations are still inconclusive and require addi-
tional studies, the phenotypic overlap approach has been promis-
ing in determining potential genotypic candidates.
The main problem with the most previous candidate gene ap-
proaches is that efficiency in the choice of candidates is inevitably
a function of the level of previous understanding of disease patho-
physiology. Most candidate gene studies in BD have focused on the
major neurotransmitter systems that are influenced by medication
used in clinical management of the disorder. Even recent develop-
ments with phenotype overlap studies have failed to steer away
from the realm of neuroendocrinology. The associations between
BD, schizophrenia, and depression are based on the observation
of common psychiatric symptoms. Thus, studies of known poly-
morphisms have been conducted for several genes encoding recep-
tors or enzymes involved in metabolism or re-uptake of dopamine,
serotonin (5HT), and noradrenalin. Other genes involved like BDNF,
DAOA, and DISC-1 are within this realm as well. An extension of
this procedure to include endophenotypes may help clarify our
understanding of BD pathogenesis. The analysis should include
systems involved in signal transduction and modulation of gene
expression not restricted to just the brain. For instance, the meta-
bolic abnormalities (i.e. hyperglycemia, hypertension, insulin resis-
tance, elevated triglycerides, decreased HDL cholesterol, HPA
dysregulation, hyperandrogenism, and central obesity) observed
as shared commonality clinical endophenotypes to both BD and
PCOS may be a logical starting point given the robust positive asso-
ciation of increase incidences between the two disorders.
In both the depressive and manic phases of bipolar disorder and
symptomatic PCOS, there is a positive association with chronic
stress and elevated cortisol . Hyperactivity of the HPA axis
is the most prominent neuroendocrine abnormality in major
depression and a possible cause of hyperandrogenism in PCOS
. Abnormalities in HPA function are also found in some BD pa-
tients along with increased levels of basal cortisol and absence of
diurnal cortisol variations , making HPA axis dysfunction
potentially a trait of bipolar disorder.
Abnormal dexamethasone/corticotrophin releasing hormone
(DEX/CRH) is found in patients during mania . In both BD
and PCOS, chronically elevated glucocorticoid from HPA hyperacti-
vation impedes glucose uptake by insulin, which in turn promotes
cardiovascular diseases and obesity . Dysregulation of the
HPA axis is also associated with obesity and elevated levels of lep-
tin, suggesting that the obesity may be due to inefficient leptin sig-
naling and decreased satiety . Another consequence of
elevated cortisol is increased activity of lipoprotein lipase, which
increases the amount of adipose tissue . Elevated cortisol
secretion also causes insulin resistance in muscles and affects the
function of glycogen synthase, which again leads to insulin resis-
tance . Because of these similarities between clinical endo-
phenotypes of BD and PCOS, genes related to HPA and cortisol
function may be important for the link between the two disorders.
For instance, cortisol–glucocorticoid receptor and complex genes,
the leptin gene, glycogen synthase gene, and lipoprotein lipase
gene may be candidate genes for research.
As previously mentioned, inflammation is important to PCOS
and may be a cause of HPA hyperactivity and hypersecretion of
cortisol, leading to development of insulin resistance and cardio-
vascular disease. Recent studies have shown that BD is also associ-
ated with an increase in pro-inflammatory markers [170,171].
Specifically, IL-6 is elevated during depressive and manic phases
of BD . IL-6 is released by adipose tissue and a stimulator of
corticotropin-releasing hormone, which may contribute to higher
cortisol levels and HPA axis hyperactivation. IL-6 also promotes
the production of C-reactive proteins, a strong predictor for myo-
cardial infarctions and diabetes . The proinflammatory cyto-
kine interferon-c has recently been indicated in depression.
Interferon-c induces indolamine 2,3 dioxygenase, an enzyme that
converts tryptophan into kynurenine. Reduced levels of trypto-
phan, the precursor to serotonin, leads to decreased serotonin syn-
thesis and may further support the aforementioned serotonin
hypothesis . From this evidence, it appears that inflammation
is significant in BD and certainly important to PCOS. The observa-
tion of elevated IL-6 in both PCOS and BD make the IL-6 and IL-6
receptor genes candidates for future linkages studies.
Increased glucose tolerance and insulin resistance are more
common in BD patients than the general population . Depres-
sion is also a strong risk factor for the development of type-2 dia-
betes. The increased rates are observed in patients with BD before
the introduction of neuroleptics. Recently, researchers have found
a positive link between tyrosine hyroxylase and pathogenesis of BD
and identified the tyrosine hydroxylase gene as a candidate gene
[174,175]. Of course, as stated in the etiology section, insulin resis-
tance and diabetes are prevalent among PCOS populations. Inter-
estingly, the insulin gene and insulin-like growth factor gene,
both candidate genes for PCOS, are found clustered with the tyro-
sine hydroxylase gene on Chromosome 11q, a susceptibility gene
and locus for type-2 diabetes [176,177]. The gene cluster of tyro-
sine hydroxylase, insulin, and insulin-like growth factor on 11q
should receive more research attention to clarify its role as a can-
didate gene cluster for both PCOS and BD.
PCOS and bipolar disorder are complex, poly-genetic disorders
that share common endophenotypes in insulin resistance, hyper-
lipidemia, and other metabolic abnormalities. The incidences of
PCOS are also higher in bipolar patients and vice a versa. Further
research is necessary to crystallize the common genetic associa-
tions between the two disorders. Linkage studies could focus on
chromosomal loci overlap between the two disorders to identify
candidate genes related to metabolism. In fact, shared commonal-
ity traits as indicated by clinical endophenotypes may provide a
platform to discover new biomarkers for the two diseases. Such
candidate genes may involve those important to the HPA axis,
insulin, metabolism, inflammation, and/or glucocorticoids. Clini-
cally, it is also important for an endocrinologist to recognize that
PCOS patients are prone to bipolar disorder, and that the treatment
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