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Neuroscience Research 40 (2001) 105– 113 www.elsevier.

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Review

Molecular genetics of bipolar disorder
Tadafumi Kato *
Laboratory for Molecular Dynamics of Mental Disorders, Brain Science Institute, RIKEN, 2 -1 Hirosawa, Wako-shi, Saitama 351 -0198, Japan Received 27 December 2000; accepted 23 February 2001

Abstract Alteration of monoaminergic neurotransmission is implicated in the pathophysiology of bipolar disorder (manic-depressive illness). Candidate genes participating in monoaminergic neurotransmission, especially serotonin transporter and monoamine oxidase A, may be associated with bipolar disorder. And the regulating regions of these genes and the molecules participating in intracellular signal transduction are now under investigation. To date, 13 whole genome positional cloning studies have been performed and many candidate loci identified. Using patients from a pedigree in which schizophrenia, depression or bipolar disorder have been linked with a balanced translocation at 1 and 11, candidate pathogenetic genes were cloned as DISC1 (disrupted in schizophrenia-1) and DISC2. Recently, pathogenetic mutations have been identified in two genetic diseases frequently co-morbid with mood disorder; WFS1 for Wolfram syndrome and ATP2A2 (SERCA2) for Darier’s disease. Transmission of bipolar disorder may be characterized by anticipation and parent-of-origin effect, and extended CTG repeat at SEF2-1B gene was identified from a bipolar patient. However, its pathogenetic role was not supported by subsequent studies. Association of bipolar disorder with mitochondrial DNA has also been suggested. The role of genomic imprinting is also possible because linkage to 18p11 is limited to paternally transmitted pedigrees. These results warrant further study of molecular genetics of bipolar disorder. © 2001 Elsevier Science Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
Keywords: Bipolar disorder; Mood disorder; Molecular genetics; Serotonin; Intracellular signal transduction; Calcium; Mitochondrial DNA

1. Introduction Bipolar disorder (manic-depressive illness) is one of two major psychiatric disorders characterized by recurrent depressive and manic episodes (Goodwin and Jamison, 1990) and genetic factors contribute to the etiology of this disorder as evidenced by twin, adoption, and family studies (Gershon and Cloninger, 1994). While the concordance rate in identical twins is 61– 75%, the risk in first-degree relatives is much smaller (1.5 –15.5%) and this suggests that bipolar disorder is not caused by single major genes but by multifactorial inheritance. Pharmacological evidence, such as the antidepressive effects of monoamine reuptake inhibitors

* Tel.: +81-48-467-6949; fax: +81-48-467-6947. E-mail address: kato@brain.riken.go.jp (T. Kato).

and the anti-manic effects of monoamine receptor antagonists, also suggest that monoaminergic pathways are involved in the disorder (Manji and Potter, 1997). Molecular genetic studies of bipolar disorder have proceeded along two major routes: association study of candidate genes and positional cloning. Recently, novel candidate genes unrelated to monoaminergic pathways have also been identified. These include genes for genetic diseases frequently associated with bipolar disorder, and those related to a characteristic mode of inheritance for this disorder. Although bipolar disorder is the first and most promising target for psychiatric genetics, inconsistent results in large-scaled studies have discouraged researchers. However, recent progress is more encouraging and in this article, the current status of bipolar disorder molecular genetics is summarized (Craddock and Jones, 1999; Potash and DePaulo, 2000).

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2000). 5-HT1A. 11p15. encoding a tryptophan transporter has been significantly associated with mood disorders (Nakamura et al. 2000). Monoaminergic pathway Since monoaminergic systems are thought to be involved in the pathophysiology of bipolar disorder (Manji and Potter. 5-HT1Db. and the finding confirmed by Kirov et al.. The human homologue of Drosophila white gene at 21q22.3. 1999)... 2000).. 1986) and platelets were found to have only MAO-B. 1999). is repeatedly reported. and a meta-analysis suggested that the S allele is a weak but significant risk factor for bipolar disorder with an odds ratio of 1. encoding a rate-limiting enzyme of serotonin synthesis (Bellivier et al. association studies for bipolar disorder have been extensive. Mundo et al. however..b. 1998)... (1999a). allele 12 was shown as associated with bipolar disorder by Collier et al. the low activity allele of COMT.5 and catecol-O-methyltransferase (COMT) gene at 22q11. 5-HT6. which regulates its expression. McQuillin et al. A non-sense mutation of this gene causes X-linked borderline mental retardation with behavioral problems characterized by aggressive behavior (Brunner et al. but the work has not been confirmed (Stoeber et al.6. However. However. 1999.. 5-HT1F. metabolic and catabolic enzymes of dopamine. later meta-analysis did not confirm association with TH (Furlong et al..1. Since a 44bp deletion/insertion polymorphism in the promoter region of the serotonin transporter gene at 17q11-12. Kirov et al... 1977). Although COMT was not associated with bipolar disorder itself. because linkage of bipolar disorder with these loci. 2000). Rietschel et al. 1999b. but there is no other confirmation study yet.. is well known to have a cluster of imprinted genes. Oruc et al. Kunugi et al... (1997) and Rees et al. a negative study was also reported (Liu et al. 1998). Hong et al.. 5-HT2C (Gutierrez et al. The polymorphism of a variable number of tandem repeats (VNTR) on the second intron of this gene is also interesting. This is consistent with clinical evidence that con- .23 encoding enzyme metabolizing monoamines on the mitochondrial outer membrane..5–2. Seven of the serotonin receptors. Thereafter. is reported as associated with an anxiety-related personality trait (Lesch and Mossner (1998). However. 1998. Massat et al. 1999).. However. 2000. 1997) and 5-HT6 (Vogt et al. Methylation status causing epigenetic modification of TH gene is now being investigated (Aranyi et al. and 5HT7 receptors. Shimron-Abarbanell et al. 1999) and 5-HT6 (Hong et al. 1999). altered imprinting status rather than mutation may affect the expression of this gene. may not be stand up to scrutiny and at least five studies demonstrate a negative association with the 5-HT2A receptor (Blairy et al. the significance of these genes cannot be totally excluded. 1997).. 1997)...106 T.. There are eight positive and seven negative reports (Potash and DePaulo. Therefore. 1996. was associated with rapid cycling bipolar disorder (Kirov et al. Turecki et al. Significant association of the CA repeat in intron 2 in MAO-A gene with bipolar disorder has been confirmed by meta-analysis (odds ratio 1. This gene is particularly intriguing because it is located in a chromosomal region where linkage has been suggested and decreased activity of MAO in platelet was previously regarded as a biochemical marker of bipolar disorder (Leckman et al. 1999a. 1999. 5-HT2A. however one of a number of promising candidate genes for bipolar disorder. 1999a... 2000). a more robust family-based association study failed to confirm an association (Kirov et al. 2000.5 and 22q11.. Furlong et al. 1998). (1996) showed association of allele 9 with unipolar depression. (1996). 1999b). MAO-A is. the results are not conclusive. 2000). (1999)). Although a positive association was initially reported for the tryptophan hydroxylase (TPH) gene at 11p1415. Papolos et al. many candidate genes in the pathway have been studied. 1999a. 1993). or may be linked nearby functional polymorphisms. This VNTR has recently been reported as possessing enhancer-like properties (Fiskerstrand et al. a polymorphism of VNTR in the promotor region causing different transcriptional activity has not been associated with bipolar disorder (Kunugi et al. Kato / Neuroscience Research 40 (2001) 105–113 2. The CA repeat polymorphism may have some effect on gene expression by itself.. 2000. (1997)... 2000). Such positive studies as exist. 2000).. On the other hand. Candidate genes 2. and most were negative with positive findings reported for 5-HT2A (Vincent et al.. 1999). Preisig et al. have already been examined for bipolar disorder (Potash and DePaulo (2000) for review. and one study each showing no association with 5-HT2C (Vincent et al. 1999a. Tut et al. 1996). Five dopamine receptors as well as the dopamine transporter were reported to have no association with bipolar disorder (Kirov et al. Although a positive association was once reported for tyrosine hydroxylase (TH) gene at 11p15.. 11p15. 5-HT1Da.. (1996). However. causing higher synaptic catecholamine concentration. 5-HT2C.. for review). The chromosomal region. Preisig et al. a brief summary of which follows. subsequent studies have not confirmed the association (Kunugi et al.. this finding has not been supported by later studies (Bagdy et al. (1999b).b. A positive association was initially reported for the monoamine oxidase A (MAO-A) gene at Xp11. having four or more manic or depressive episodes per year. Vincent et al. Ogilvie et al.2 (Furlong et al.. Potash and DePaulo.3. 1997) and COMT (Biomed European Bipolar Collaborative Group.

2000). especially those of the genes located at the chromosomal regions that are linked with bipolar disorder. 1998).1. 1998). And a negative response to serotonin selective reuptake inhibitors has been associated with the absence of the L/L allele of the serotonin transporter gene (Kim et al. DISC1 may participate in a molecular cascade causing them. peripheral blood cells. were identified at 1q42.3-16. especially balanced translocation.3). While symptomatic treatments such as antidepressants and antimanic agents act via monoamines. depletes myo-inositol in neuronal cells. These extensive studies suggest that none of the genes involved in monoaminergic neurotransmission have a major impact on bipolar disorder except for serotonin transporter and MAO-A.. and TPH (Serretti et al. 8p21. Further studies on function of this molecule are needed. MAO-A at Xp11. and finally desensitizes inositol phospholipid (PI) pathway. 1999).. 2000) and a search for other functional polymorphisms nearby is needed.and thrombin-induced calcium mobilization linked with PI pathway is enhanced in platelets of bipolar disorder patients (Ozawa. 5-HT2C receptor at Xq24...1 (Baysal et al. 3. Significant but weak association was found for the Gz protein a subunit at 22q11 (Saito et al.23. where linkage with bipolar disorder has been reported. No association or linkage was found on a2A and a2C adrenergic receptors.. However. which has prophylactic efficacy..3 (Millar et al. Although no mutation has been identified. 15q22-24 (Kunugi et al. Xq28 (Craddock and Owen. 1994). 9p24 and 11q23.5. 1995). then the chromosomal region may be a candidate locus. preliminary analysis suggests that patients showed decreased expression of this gene in a family in which bipolar disorder has been linked to 22q11. and COMT at 22q11.. When chromosomal abnormality. TPH at 11p14-15. both of which were disrupted in the affected individuals. has not yet been excluded. suggest a possible role of intracellular second messenger systems linked to monoamines in the pathophysiology of bipolar disorder. a truncated protein is thought to be expressed in these patients. affects intracellular signal transduction systems.. and in vivo magnetic resonance spectroscopy (Ozawa et al. but possibly regulates expression of DISC1 because it has a complementary sequence to DISC1.. IMPase. These findings together with those from postmortem brains. 15q1113. while no gene was found at 11q14. participating in nonadrenergic systems (Potash and DePaulo. is much more promising because it was mapped to 18p11.2.2. is found in a patient with bipolar disorder. A weak association of a silent polymorphism in IMPA2 with bipolar disorder was reported (Yoshikawa et al. The number of studies on intracellular signal transduction systems is still too small to draw a conclusion. IMPA1 at 8q21 was not associated with bipolar disorder (Steen et al. DISC2 is not thought to encode a protein. 1998).. Another IMPase. 2000). 1999) and phospholipase C-g3 (Turecki et al. Positional cloning 3. 1998). 5-HT7 receptor at 10q2124. 21. Research has identified a Scottish family in which mental disorders including schizophrenia. Because translocation occurred in the intron of DISC1. Although it is not yet known whether or not mutations of these genes are associated with sporadic cases of schizophrenia or bipolar disorder. (2000) have used the GeneChip to identify genes located at loci linked with bipolar disorder.q14. IMPA2.3. This suggests that abnormalities in post receptor intracellular signaling systems may be fundamental to bipolar disorder. One gene named as DISC1 (disrupted in schizophrenia-1) encodes a novel protein expressed in the brain. Serotonin. Cytogenetic method 2.T. Yamawaki et al. DRD5 at 4p15. Lithium accumulates inositol-1-phosphate by inhibiting inositol monophosphatase (IMPase). DISC2 is transcribed in the opposite direction and overlaps with DISC1. Further studies are needed. . possible association of unknown regulatory regions. 1997).. Kato / Neuroscience Research 40 (2001) 105–113 107 tinuous use of antidepressants also causes rapid cycling (Wehr and Goodwin..1.2. Recently. 1998). 1996).1. Among the target enzymes of lithium. which up-regulates after amphetamine treatment in rats. Intracellular signal transduction systems Lithium is used in the prophylaxis and treatment of bipolar disorder. and found that GRK-3 (G protein coupled receptor kinase-3) is located at 22q11 in humans. et al. 1998. Such regions include. 2000). whose function is not known yet. 1979). several candidate genes in this pathway have been examined and no mutation found in Gs protein a subunit at 20q13 (Ram et al.11) (q42. 11q21-25. Association of these genes with treatment response in bipolar disorder has also been examined. These include 5-HT2A receptor at 13q14-21. and Golf protein a subunit at 18p11 (Berrettini et al. And two genes. dopamine D4 receptor. Lithium response has been associated with the S allele of the serotonin transporter gene.1. depression and bipolar disorder have been segregated with a balanced translocation (1.. lithium. DRD4 and TH at 11p15. Niculescu et al..

. Mutations of WFS1 have also been examined for patients with bipolar disorder without Wolfram syndrome. thus causing pessimism. However. it is not true. WFS1 for Wolfram syndrome and calcium(Ca)-ATPase for Darier’s disease. Ohtsuki et al. While two groups could not find any disease-associated mutations (Evans et al. 3.2. again showed positive links (Smyth et al.2. 1996). 1996). such a linkage was subsequently denied by the authors themselves.. especially depression. is also a frequent symptom of this syndrome. 1998). was located at 4p16.3. mutations of patients presenting neuropsychiatric symptoms (10 of 17 probands) were localized only in exon 13–19. the last exon of WFS1. Calcium-ATPase Darier’s disease is an autosomal-dominant inherited dermatological disease characterized by abnormal keratinazation (epidermal differentiation) and acantholysis (loss of cohesion) frequently comorbid with mental disorders. deletions. Kato / Neuroscience Research 40 (2001) 105–113 3. 1995). Middle et al. 1996). interaction with mtDNA is suggested by disease symptoms that resemble mitochondrial disorders and by multiple deletions of mitochondrial DNA (mtDNA) detected in the disorder (Barrientos et al. In 1998. which are frequently accompanied by psychiatric disorders including bipolar disorder. SERCA2. Identification of no6el genes of inherited diseases as a risk factor of bipolar disorder Recently. a third group identified a mutation (Ala559Thr) associated more frequently for affective disorder (Furlong et al. 1998.. This was suggested not by molecular genetics but by using phenotype of color blindness and glucose-6-phosphate dehydrogenase deficiency. all mutations were located on exon 8. genetic association studies are not easy. The first study by Egeland et al. Interestingly. the mutation was thought to have pleiotropic effects in the brain and skin.4. Parametric linkage analysis is based on an assumption that bipolar disorder is caused by a single major gene inherited by a Mendelian mode of inheritance.2.. In addition. Therefore. parametric linkage analysis is not suitable for the study of bipolar disorder.5 is still one of the candidate loci. in which no specific mode of inheritance is assumed. This isolated population has been regarded as a good source of linkage studies. Psychiatric illness. 1998). was began to be used since . (1987) was performed using a large isolated population of old order Amish. A family of bipolar disorder co-segregating with Darier’s disease has been reported. Because many variants have been identified in WFS1. 1998). 1999c).. However. However.. two genes causing inherited diseases.. Jacobsen et al. 2000. and insertion. two groups using positional cloning identified the pathogenic gene for the syndrome (Inoue et al. was considered highly significant. (1987) in Nature suggesting strong linkage with 11p15. none of them was associated with bipolar disorder using a large sample (324 bipolar patients and 327 controls). family members with major depression show variable results even for one pedigree depending upon phenotype definition. Although they found six mutations in the gene.. Linkage analysis – parametric analysis The first region indicated by linkage analysis was Xq28 (Baron et al.1. 11p15. Because altered intracellular calcium response is thought to be involved in bipolar disorder (Yamawaki et al.. for which a link with bipolar disorder has already been suggested (Blackwood et al. Therefore. 3. Linkage analysis: non-parametric analysis Family studies do not indicate that bipolar disorder is caused by a single major gene or genes. a gene encoding endoplasmic reticulum CaATPase. 1999). Non-affected carriers of this gene are thought to have a 26-fold increased risk of psychiatric hospitalization (Swift et al. 3. Strom et al. deletion.108 T.1. Later replication studies in this region. WFS1 /wolframin Wolfram syndrome is an autosomal recessive inherited disease characterized by diabetes mellitus and optic atrophy. and insertions.2..1 region. 2000). The pathogenic gene for this disorder has been identified as ATP2A2 at 12q23-24. intermarriage between close relatives and existence of bilinear transmission makes it difficult to assume that a single autosomal dominant inherited gene is involved in the pedigree.5. 2000. WFS1/wolframin. and at least 40 types of mutation have already been identified. Nineteen probands had 17 different mutations including missense. However. To overcome this problem. (2001) searched for mutations in this gene in 15 probands from multiply affected pedigrees of bipolar disorder showing linkage with markers in the 12q23-24. 3. however. Interestingly. Because the finding was not supported by subsequent molecular genetic studies. The paper by Egeland et al. which can generate false-positive results by multiple testings. have been identified by positional cloning. The gene.... 1987).. non-parametric linkage analysis. There are many kinds of mutations: point mutations. Most probands had different mutations. recent studies suggesting some evidence of linkage at Xq24-26 (Pekkarinen et al. in comparison with patients without mental symptoms having mutations in any region of the gene (Jacobsen et al. Linkage to phenotype markers on Xp was also found in classical studies. Although the function of the transmembrane protein encoded by this gene is unknown. a mistake of phenotype specification was suggested.

were found. In these regions. 18p11 and 22q11-12 (Craddock and Jones.1.1 at 18q21. There is no locus common to all studies. and more often have affected maternal relatives than paternal relatives (Winokur and Reich.1 was at first thought to be significantly expanded for bipolar disorder. the mode of inheritance in bipolar disorder provides other heuristic approaches to the discovery of disease-related genes. a human homolog of transcribing factor identified in drosophila. 2000). SEF2-1B.1 and ERDA1 at 17q21. 1999. Some neuroimaging data suggest mitochondrial dysfunction in bipolar disorder (Kato and Kato. Using the repeat expansion detection method (RED). However. 2000). However.. 7 (22%) seemed to be exclusively maternal. 4. 1997).. Gershon et al. and it can also occur by many kinds of environmental factors. Such phenomenon might be an observation bias. Kirk et al. expanded CAG/CTG alleles were sought in the genomes of bipolar disorder patients and the maximum length of CAG repeat for patients with bipolar disorder was discovered as significantly expanded (O’Donovan et al. eight whole genome linkage studies of bipolar disorder were reported and the total number of linkage studies reported is now 13.6%. Of these. Nothen et al.2. Search for imprinted genes in this region may be a promising strategy to identify bipolar disorder-related genes. 1994).. expanded alleles were identified from the genomes of bipolar disorder patients: these were CTG18. The association of bipolar disorder with MAO-A noted above is also coincides with the mitochondrial dysfunction hypothesis. 1997).. CTG18. As noted above. although such reports have major limitations such as the very small number of patients and lack of robust diagnostic procedure. expanded trinucleotide repeats have been examined for bipolar disorder. parent-of-origin effect. 1996. The results have been confirmed by two studies and questioned by two (Craddock and Jones. Autopsy at age 60 revealed 40% of mtDNA from the frontal cortex and basal ganglia with multiple deletion. the levels of deletion were at most 0. ERDA1 is not located in any gene and is thought to have no function. 1970). 4p16. CTG18.. was detected in the lymphoblastoid cell lines of bipolar disorder patients (Jones et al. but the following were linked with bipolar disorder in two or more independent studies. The proband of this family has shown severe retarded depression since the age of 19 with onset of CPEO at 52. After that. 13q11-32. However. 1995. subsequent studies suggest that expansion of this locus is also seen in . which would not directly impair energy metabolism. (1997) quantified mtDNA 4977bp deletion in brains postmortem and found the deletion significantly increased in bipolar disorder (Kato et al. Kato et al. 1999). In their 31 pedigrees selected for linkage studies. Kato / Neuroscience Research 40 (2001) 105–113 109 middle 1990s.. Parent-of-origin effect Patients with bipolar disorder more often have affected mothers than fathers. 4. (1995) first proposed that this might be caused by mitochondrial inheritance. two loci (18p11. Trinucleotide repeat expansion Some researchers believe that lower generation has lower age at onset in bipolar disorder pedigrees. This non-Mendelian gender-related pattern of inheritance is now referred to as ‘parent-of-origin effect’. healthy individuals and is not associated with bipolar disorder (Guy et al. (1999) sequenced the whole mitochondrial genome in 25 patients with bipolar disorder and determined mitochondrial genetic distances by making all possible pairwise comparisons of mtDNA haplotypes in 4. In 2000. McMahon et al. SEF2-1B is expressed in the brain but its function is unknown. All recent linkage studies have been published both as parametric and non-parametric analysis. 1999). no poly-glutamine tract. which should be translated from CAG repeat expansion. 2000). Analysis using specific mode of transmission Association and linkage studies seem to be straightforward solutions to identify pathogenetic genes for bipolar disorder... It has also been reported that linkage to 18p11 is limited to paternally transmitted pedigrees thus suggesting involvement of genomic imprinting (Stine et al. 1998). association of Wolfram syndrome with mood disorder is also coincide with a possible pathophysiological role for mtDNA deletion in mood disorder. And there are several case reports of depressive patients with comorbid mitochondrial encephalomyopathy or known pathogenetic mtDNA mutations (Kato and Kato.. Genomic imprinting mediated by DNA methylation may also play a role. 1995).T. 10q21-26. (1992) report a family with autosomal dominant chronic progressive external opthalmoplegia (CPEO) and depression caused by multiple deletion of mtDNA. Using this method. in which increased allele sharing only in paternally transmitted alleles.1 located at the intron of a gene. 12q23-24. 18q22-23) on chromosome 18 were identified at first (Berrettini et al. DeLisi et al. However.. Suomalainen et al.3 (Lindblad et al. 1999). These are 1q21-42. Since this phenomenon called anticipation can also occur by trinucleotide repeat expansion. 1999). because metabolism of monoamines by MAO damages mitochondria by generating H2O2 (Cohen and Kesler.

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B. ray technique to the study of gene expression in the prefrontal cortex in schizophrenic patients. Acknowledgements The authors thank for Dr. B.. the next step is to find disease-related genes around the loci in these pedigrees in which linkage is possible. 465.W. X.. Ferraro. James. Richard.. J. Z. Berrettini. Such a technique would be useful as a laboratory test for differential diagnosis and prediction of treatment response. Hamburger. A. Korcz. (2001) searched for mtDNA polymorphisms associated with bipolar disorder using heteroduplex analysis and the single strand conformation polymorphism and found the 10 398 polymorphism was significantly associated with bipolar disorder. (2000) sequenced the whole mitochondrial genome in nine unrelated probands selected from large pedigrees with exclusive maternal transmission of bipolar disorder. representing susceptibility to bipolar disorder. Newman. Gen. 1998. Med. M.. 81 – 91. T.. Cardellach. V. Beaufils.A. However. D. 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