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
(2001) Mice lacking the ERK1 isoform of MAP kinase are unim-
paired in emotional learning. Learn Mem 8, 11–19.
Sheehan, T.P., Neve, R.L., Duman, R.S. & Russell, D.S. (2003)
Antidepressant effect of the calcium-activated tyrosine kinase
Pyk2 in the lateral septum. Biol Psychiatry 54, 540–551.
Sklar, P., Gabriel, S.B., McInnis, M.G., Bennett, P., Lim, Y.-L.,
Tsan, G., Schaffner, S., Kirov, G., Jones, I., Owen, M.,
Craddock, N., DePaulo, J.R. & Lander, E.S. (2002) Family-
based association study of 76 candidate genes in bipolar dis-
order: BDNF is a potential risk locus. Mol Psychiatry 7, 579–593.
Souery, D., Van Gestel, S., Massat, I. et al. (2001) Tryptophan
hydroxylase polymorphism and suicidality in unipolar and bipo-
lar affective disorders: a multicenter association study. Biol
Psychiatry 49, 405–409.
Stine, O.C., McMahon, F.J., Chen, L., Xu, J., Meyers, D.A.,
MacKinnon, D.F., Simpson, S., McInnis, M.G., Rice, J.P.,
Goate, A., Reich, T., Edenberg, H.J., Foroud, T., Nurnberger,
J.I. Jr, Detera-Wadleigh, S.D., Goldin, L.R., Guroff, J.,
Gershon, E.S., Blehar, M.C. & DePaulo, J.R. (1997) Initial
genome screen for bipolar disorder in the NIMH Genetics
Initiative pedigrees: chromosomes 2, 11, 13, 14, and X. Am
J Med Genet (Neuropsychiatr Genet) 74, 263–269.
Straub, R.E., Lehner, T., Luo, Y., Loth, J.L., Shao, W., Sharpe, L.,
Alexander, J.R., Das, K., Simon, R., Fieve, R.R., Lerer, B.,
Endicott, J., Ott, J., Gilliam, C. & Baron, M. (1994) A possible
vulnerability locus for bipolar affective disorder on chromo-
some 21q22.3. Nat Genet 8, 291–296.
Toyota, T., Hattori, E., Meerabux, J., Yamada, K., Saito, K.,
Shibuya, H., Nankai, M. & Yoshikawa, T. (2002a) Molecular
analysis, mutation screening, and association study of adeny-
late cyclase type 9 gene (ADCY9) in mood disorders. Am J
Med Genet 114, 84–92.
Toyota, T., Yamada, K., Saito, K., Detera-Wadleigh, S.D. &
Yoshikawa, T. (2002b) Association analysis of adenylate
cyclase type 9 gene using pedigree disequilibrium test in bipo-
lar disorder. Mol Psychiatry 7, 450–452.
Turecki, G., Alda, M., Grof, P., Martin, R., Cavazzoni, P.A., Duffy, A.,
Maciel, P. & Rouleau, G.A. (1996) No association between
chromosome-18 markers and lithium-responsive affective dis-
orders. Psychiatry Res 63, 17–23.
Turecki, G., Grof, P., Grof, E., D’Souza, V., Lebuis, L., Marineau, C.,
Cavazzoni, P., Duffy, A., Betard, C., Zvolsky, P., Robertson, C.,
Brewer, C., Hudson, T.J., Rouleau, G.A. & Alda, M. (2001)
Mapping susceptibility genes for bipolar disorder: a pharmaco-
genetic approach based on excellent response to lithium. Mol
Psychiatry 6, 570–578.
Turecki, G., Rouleau, G.A., Mari, J., Joober, R. & Morgan, K. (1997)
Lack of association between bipolar disorder and tyrosine hydro-
xylase: a meta-analysis. Am J Med Genet 74, 348–352.
Willour, V.L., Zandi, P.P., Huo, Y., Diggs, T.L., Chellis, J.L.,
MacKinnon, D.F., Simpson, S.G., McMahon, F.J., Potash,
J.B., Gershon, E.S., Reich, T., Foroud, T., Nurnberger, J.I. Jr,
DePaulo, J.R. & McIinnis, M.G. (2003) Genome scan of the
fifty-six bipolar pedigrees from the NIMH Genetics Initiative
replication sample: Chromosomes 4, 7, 9, 18, 20, and 21. Am
J Med Genet B Neuropsychiatr Genet 121, 21–27.
Zandi, P.P., Willour, V.L., Huo, Y., Chellis, J., Potash, J.B.,
MacKinnon, D.F., Simpson, S.G., McMahon, F.J., Gershon, E.S.,
Reich, T., Foroud, T., Nurnberger, J.I. Jr, DePaulo, J.R. &
McIinnis, M.G. (2003) Genome scan of a second wave of NIMH
Genetics Initiative bipolar pedigrees: chromosomes 2, 11, 13,
14, and X. Am J Med Genet Part B (Neuropsychiatr Genet)
Zill, P., Malitas, P.N., Bondy, B., Engel, R., Boufidou, F., Behrens,
S., Alevizos, B.E., Nikolaou, C.K. & Christodoulou, G.N. (2003)
Analysis of polymorphisms in the alpha-subunit of the olfactory
G-protein Golf inlithium-treated bipolar patients. Psychiatr Genet
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