Cytogenetic Studies May Help To Localise Genes Contributing To Bipolar Disorder

Cloning genes disrupted by chromosome rearrangements has been a very fruitful approach for a wide variety of inherited neurological conditions. In contrast to linkage and association studies, where the results, even if positive, define broad areas at the molecular level, abnormalities of chromosomes can precisely pinpoint the position of disrupted genes (Evans etal., 2001).

One of the earliest areas of interest was chromosome 21, stemming from the longheld idea that Down's syndrome (trisomy 21) as a condition is mutually exclusive with bipolar disorder. This is not the case, and there are good descriptions of both mania and depression in Down's syndrome, although the risk of bipolar disorder may be decreased, and unipolar disorder is held by some to be increased in frequency. Trisomies involving the sex chromosomes have also been implicated, but the initial studies were not well controlled, and more recent work has not provided good evidence that they are a substantial risk factor for bipolar disorder (Mors et al., 2001).

Carriers of a reciprocal translocation t(1;11)(q42.2;q21), which was stably inherited in a large Scottish pedigree, were shown to have very high rates of major psychiatric illness when compared to non-carriers. The strongest evidence for linkage (Lod score of 7.1) was found with a phenotype that included both schizophrenia and affective psychosis—with cases of bipolar and recurrent unipolar disorder in translocation carriers (Blackwood et al., 2001; St Clair et al., 1990).

Candidate genes for schizophrenia and bipolar disorder isolated by a direct molecular genetic analysis of the breakpoint, DISC1 and DISC2, were detected by cloning of a translocation breakpoint that disrupted their exonic structure (Millar et al., 2000).

A small pedigree has been described with a t(9;11)(p24;q23.1) translocation where five carriers had bipolar disorder and one had early-onset recurrent major depression that co-segregated with affective disorder. There are four unaffected carriers, but the pedigree is probably too small to yield to linkage analysis (Baysal et al., 1998). However, recently, a mannosyltransferase gene has been shown to be disrupted by the chromosome 11q23 breakpoint (Baysal et al., 2002). This has been labelled DIBD1 (disrupted in bipolar disorder 1), a 15-exon brain-expressed gene that is possibly involved in protein n-glycosylation. Linkage analyses in two separate sets of NIMH bipolar pedigrees did not yield conclusive results, but one polymorphic marker pair did show evidence of increased allele sharing in the first series of multiplex pedigrees. Further studies on this gene will be interesting, and, as the region is also a "hot spot" for schizophrenia, it may also be one that transcends the usual diagnostic boundaries.

A recent and striking observation has been made of a high rate of affective psychosis in patients with Prader-Willi syndrome, especially where this has originated through uniparental disomy of chromosome 15 (Boer et al., 2002). This region contains several imprinted genes that could be candidates. A similar situation where a contiguous gene syndrome may be associated with bipolar disorder is the Velocardiofacial syndrome, involving an interstitial deletion on chromosome 22 (Papolos et al., 1996; Pulver et al., 1994). This deletion includes several genes, and the completion of the full sequence of chromosome 22 should rapidly yield candidate genes for further testing in the general population.

A cross-referencing search of two large cytogenetic registers, one in Scotland and the other in Denmark, revealed two unrelated individuals with the rare pericentric inversion inv(18) (p11.3q21.1), in which one subject had schizophrenia and the other bipolar disorder (Mors et al., 1997). Linkage has been reported at both breakpoint regions for schizophrenia and bipolar disorder. A breakpoint at 18q22.1 was also reported in a patient with schizoaffective disorder by Overhauser et al. (1998), and two related individuals with a translocation at 18q22.3 were diagnosed as having schizoaffective disorder and bipolar disorder (Calzolari et al., 1996).


Despite promising positive linkage findings, no genes have been identified as being unequivocally involved in bipolar disorder. However, powerful new approaches are becoming available to elucidate the neurobiological basis of the disorder. These include microarrays in genomics and proteomics, permitting the rapid, simultaneous screening of many genes and proteins in large patient samples. Another development is the combination of structural brain imaging with a candidate-gene approach that has shown, in a recent study, an association between a variant of the serotonin transporter gene and increased neuronal activity in the amygdala, as assessed by functional magnetic resonance imaging (Hariri et al., 2002).


Avissar, S. & Schreiber, G. (2002). Toward molecular diagnostics of mood disorders in psychiatry. Trends Mol Med, 8, 294-300.

Baron, M. (2002). Manic-depression genes and the new millennium: poised for discovery. Mol Psychiatry, 7, 342-358.

Baysal, B.E., Potkin, S.G., Farr, J.E., et al. (1998). Bipolar affective disorder partially cosegregates with a balanced t(9;11)(p24;q23.1) chromosomal translocation in a small pedigree. Am J Med Genet, 81, 81-91.

Baysal, B.E., Willett-Brozick, J.E., Badner, J.A., et al. (2002). A mannosyltransrerase gene at 11q23 is disrupted by a translocation breakpoint that co-segregates with bipolar affective disorder in a small family. Neurogenetics, 4, 43-53.

Bearden, C.E., Hoffman, K.M. & Cannon, T.D. (2001). The neuropsychology and neuroanatomy of bipolar affective disorder: a critical review. Bipolar Disord, 3, 106-150; discussion 151-153.

Berridge, M.J., Downes, C.P. & Hanley M.R. (1989). Neural and developmental actions of lithium: a unifying hypothesis. Cell, 59, 411-419.

Blackwood, D.H., He, L., Morris, S.W., et al. (1996). A locus for bipolar affective disorder on chromosome 4p. Nat Genet, 12, 427-430.

Blackwood, D.H., Fordyce, A., Walker, M.T., St Clair, D.M., Porteous, D.J. & Muir, W.J. (2001). Schizophrenia and affective disorders—cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet, 69, 428-433.

Blackwood, D.H., Visscher, P.M. & Muir, W.J. (2001). Genetic studies of bipolar affective disorder in large families. Br J Psychiatry Suppl, 41, s134-136.

Blangero, J. & Elston, R.C. (1989). Familial analysis of bipolar affective disorder using logistic models. Genet Epidemiol, 6, 221-227.

Boer, H., Holland, A., Whittington, J., Butler, J., Webb, T. & Clarke, D. (2002). Psychotic illness in people with Prader Willi syndrome due to chromosome 15 maternal uniparental disomy. Lancet, 359(9301), 135-136.

Borkowska, A. &Rybakowski, J.K. (2001). Neuropsychological frontal lobe tests indicate that bipolar depressed patients are more impaired than unipolar. Bipolar Disord, 3, 88-94.

Calzolari, E., Aiello, V., Palazzi, P., et al. (1996). Psychiatric disorder in a familial 15;18 translocation and sublocalization of myelin basic protein of 18q22.3. Am J Med Genet, 67, 154-161.

Cardon, L.R. & Bell, J.I. (2001). Association study designs for complex diseases. Nat Rev Genet, 2, 91-99.

Cavanagh, J.T., Van Beck, M., Muir, W. & Blackwood, D.H. (2002). Case-control study of neuro-cognitive function in euthymic patients with bipolar disorder: an association with mania. Br J Psychiatry, 180, 320-326.

Clark, L., Iversen, S.D. & Goodwin G.M. (2001). A neuropsychological investigation of prefrontal cortex involvement in acute mania. Am J Psychiatry, 158, 1605-1611.

Craddock, N., Dave, S. & Greening, J. (2001). Association studies of bipolar disorder. Bipolar Disorders, 3, 284-298.

Drevets, W.C., Price, J.L. & Simpson, J.R., Jr., etal. (1997). Subgenual prefrontal cortex abnormalities in mood disorders. Nature, 386(6627), 824-827.

Egeland, J.A., Gerhard, D.S., Pauls, D.L., et al. (1987). Bipolar affective disorders linked to DNA markers on chromosome 11. Nature, 325(6107), 783-787.

Evans, K.L., Muir, W.J., Blackwood, D.H. & Porteous, D.J. (2001). Nuts and bolts of psychiatric genetics: building on the Human Genome Project. Trends Genet, 17, 35-40.

Ferrier, I.N., Stanton, B.R., Kelly, T.P. & Scott, J. (1999). Neuropsychological function in euthymic patients with bipolar disorder. Br J Psychiatry, 175, 246-251.

Furlong, R.A., Rubinsztein, J.S., Ho, L., et al. (1999). Analysis and metaanalysis of two polymorphisms within the tyrosine hydroxylase gene in bipolar and unipolar affective disorders. Am J Med Genet, 88, 88-94.

Furlong, R.A., Ho, L., Rubinsztein, J.S., Walsh, C., Paykel, E.S. & Rubinsztein, D.C. (1999). Analysis of the monoamine oxidase A (MAOA) gene in bipolar affective disorder by association studies, meta-analyses, and sequencing of the promoter. Am J Med Genet, 88, 398-406.

Hariri, A.R., Mattay, V.S., Tessitore, A., et al. (2002). Serotonin transporter genetic variation and the response of the human amygdala. Science, 297(5580), 400-403.

Kato, T. (2001). Molecular genetics of bipolar disorder. Neurosci Res, 40, 105-113.

Kato, T. & Kato N. (2000). Mitochondrial dysfunction in bipolar disorder. Bipolar Disord, 2(3 Pt 1), 180-190.

Kirov, G., Murphy, K.C., Arranz, M.J., et al. (1998). Low activity allele of catechol-O-methyltransferase gene associated with rapid cycling bipolar disorder. Mol Psychiatry, 3, 342-345.

Leboyer, M., Malafosse, A., Boularand, S., et al. (1990). Tyrosine hydroxylase polymorphisms associated with manic-depressive illness. Lancet, 335(8699), 1219.

Manji, H.K. & Lenox, R.H. (2000). Signaling: cellular insights into the pathophysiology of bipolar disorder. Biol Psychiatry, 48, 518-530.

Manji, H.K., Drevets, W.C. & Charney, D.S. (2001). The cellular neurobiology of depression. Nat Med, 7, 541-547.

Margolis, R.L., McInnis, M.G., Rosenblatt, A. & Ross, C.A. (1999). Trinucleotide repeat expansion and neuropsychiatric disease. Arch Gen Psychiatry, 56, 1019-1031.

McMahon, F.J., Stine, O.C., Meyers, D.A., Simpson, S.G. & DePaulo, J.R. (1995). Patterns of maternal transmission in bipolar affective disorder. Am J Hum Genet, 56, 1277-1286.

McMahon, F.J., Chen, Y.S., Patel, S., et al. (2000). Mitochondrial DNA sequence diversity in bipolar affective disorder. Am J Psychiatry, 157, 1058-1064.

Millar, J.K., Wilson-Annan, J.C., Anderson, S. et al. (2000). Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet, 9, 1415-1423.

Mors, O., Ewald, H., Blackwood, D. & Muir, W. (1997). Cytogenetic abnormalities on chromosome 18 associated with bipolar affective disorder or schizophrenia. Br J Psychiatry, 170, 278-280.

Mors, O., Mortensen, P.B. & Ewald, H. (2001). No evidence of increased risk for schizophrenia or bipolar affective disorder in persons with aneuploidies of the sex chromosomes. Psychol Med, 31, 425-430.

Muir, W.J., Thomson, M.L., McKeon, P., et al. (2001). Markers close to the dopamine D5 receptor gene (DRD5) show significant association with schizophrenia but not bipolar disorder. Am J Med Genet, 105, 152-158.

Niculescu, A.B., III, Segal, D.S., Kuczenski, R., Barrett, T., Hauger, R.L. & Kelsoe, J.R. (2000). Identifying a series of candidate genes for mania and psychosis: a convergent functional genomics approach. Physiol Genomics, 4, 83-91.

Ongur, D., Drevets, W.C. & Price, J.L. (1998). Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci USA, 95, 13290-13295.

Overhauser, J., Berrettini, W.H. & Rojas, K. (1998). Affective disorder associated with a balanced translocation involving chromosome 14 and 18. Psychiatr Genet, 8, 53-56.

Papolos, D.F., Faedda, G.L., Veit, S., et al. (1996). Bipolar spectrum disorders in patients diagnosed with velo-cardio- facial syndrome: does a hemizygous deletion of chromosome 22q11 result in bipolar affective disorder? Am J Psychiatry, 153, 1541-1547.

Potash, J.B. & DePaulo, J.R., Jr. (2000). Searching high and low: a review of the genetics of bipolar disorder. Bipolar Disord, 2, 8-26.

Preisig, M., Bellivier, F., Fenton, B.T., et al. (2000). Association between bipolar disorder and monoamine oxidase A gene polymorphisms: results of a multicenter study. Am J Psychiatry, 157, 948-955.

Pulver, A.E., Nestadt, G., Goldberg, R., et al. (1994). Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives. J Nerv Ment Dis, 182, 476-478.

Rice, J., Reich, T., Andreasen, N.C., et al. (1987). The familial transmission of bipolar illness. Arch Gen Psychiatry, 44, 441-447.

Shimron-Abarbanell, D., Harms, H., Erdmann, J., et al. (1996). Systematic screening for mutations in the human serotonin 1F receptor gene in patients with bipolar affective disorder and schizophrenia. Am J Med Genet, 67, 225-228.

Spence, M.A., Flodman, P.L., Sadovnick, A.D., Bailey-Wilson, J.E., Ameli, H. & Remick, R.A. (1995). Bipolar disorder: evidence for a major locus. Am J Med Genet, 60, 370-376.

St Clair, D., Blackwood, D., Muir, W., et al. (1990). Association within a family of a balanced autosomal translocation with major mental illness. Lancet, 336, 13-16.

Stahl, S. (2000). Essential Psychopharmacology of Depression and Bipolar Disorder, Cambridge University Press.

Stine, O.C., Xu, J., Koskela, R., et al. (1995). Evidence for linkage of bipolar disorder to chromosome 18 with a parent-of-origin effect. Am J Hum Genet, 57, 1384-1394.

Strakowski, S.M., DelBello, M.P., Adler, C., Cecll, D.M. & Sax K.W. (2000). Neuroimaging in bipolar disorder. Bipolar Disord, 2(3 Pt 1), 148-164.

Taylor, J.G., Choi, E.H., Foster, C.B. & Chanock, S.J. (2001). Using genetic variation to study human disease. Trends Mol Med, 7, 507-512.

Turecki, G., Rouleau, G.A., Mari, J., Joober, R. & Morgan, K. (1997). Lack of association between bipolar disorder and tyrosine hydroxylase: a meta-analysis. Am J Med Genet, 74, 348-352.

Vaidya, V.A. & Duman, R.S. (2001). Depresssion—emerging insights from neurobiology. BMJ, 57, 61-79.

Visscher, P.M., Yazdi, M.H., Jackson, A.D., et al. (2001). Genetic survival analysis of age-at-onset of bipolar disorder: evidence for anticipation or cohort effect in families. Psychiatr Genet, 11, 129-137.

Williams, R.S., Cheng, L., Mudge, A.W. & Harwood, A.J. (2002). A common mechanism of action for three mood-stabilizing drugs. Nature, 417(6886), 292-295.

Defeat Depression

Defeat Depression

Learning About How To Defeat Depression Can Have Amazing Benefits For Your Life And Success! Discover ways to cope with depression and melancholic tendencies! Depression and anxiety particularly have become so prevalent that it’s exceedingly common for individuals to be taking medication for one or even both of these mood disorders.

Get My Free Ebook

Post a comment