Genetic linkage studies have been ongoing in the mapping of susceptibility loci for bipolar disorder for more than a decade. In that time, numerous chromosomal regions reportedly have been linked to bipolar or to the broader affective disorder phenotype. However, due to the various analytic methods employed, the different pedigree structures, and the variety of markers used in these studies, replication of linkage results has been ambiguous. In addition, consistent replication of linkage to oligogenic traits is highly unlikely due to the segregation of different subsets of susceptibility genes in various samples.1
Despite these limitations, replicated evidence of linkage has been reported for several chromosomal areas.
Linkage Studies of Bipolar Illness With Support from More Than One Study
GENETIC LINKAGE FINDINGS
The most widely studied findings have been on chromosome 1 8. Berrettini and colleagues2 initially reported linkage to the pericentromeric region. Subsequent studies in another pedigree sample appeared to confirm this initial linkage report and suggested that the bulk of the linkage evidence came from families with paternally inherited disease.3 Two families have been identified with a chromosomal inversion involving this region of chromosome 18 in which some of the carriers of the chromosomal inversion have bipolar disorder or schizophrenia.
Studies of large pedigrees from an isolated region in Costa Rica supported linkage to the tip of 18p, as well as 18q22-23. Subsequent analyses of one of these pedigrees suggest two potential clusters of markers, separated by 13 cM on chromosome 18q, with evidence of linkage to bipolar disorder.4
It is important to note that the evidence favoring linkage to chromosome 18 has not been uniform, with several studies, using a variety of analytic strategies, failing to consistently replicate linkage to this region.
Linkage to chromosome 12 has been confirmed following the initial report by Craddock5 of a family in which major affective disorder was co-segregating with Darier' s disease. The Darier's disease gene was recently identified and termed the ATP2A2 gene. Screening for mutations in this gene in a sample of bipolar probands without Darier's disease did not identify any gene mutations, suggesting that the bipolar-susceptibility gene in this region is distinct from the Darier's disease gene.
Morissette and colleagues6 completed a genome screen in a large French Canadian pedigree with more than 100 individuals. From this screening, evidence for linkage to chromosome 12q23-q24 was reported in some but not all branches of the pedigree. The maximum Z-score in this pedigree was 3.92, near the marker D12S86. These results suggest that more than one locus may be segregating in this isolated population, as not all portions of the pedigree linked to the same chromosomal region.
Analysis of a second, smaller pedigree from the same geographic region appeared to support evidence of a locus on chromosome 12. Other investigators of independent samples have found evidence of linkage to 12q22-24. These studies have identified a broad region of approximately 30 cM with positive lod scores.
Linkage to chromosome 21q22, with the marker PFKL, was initially reported by Straub et al.7 Further evidence of linkage to this region was observed by Detera-Wadleigh et al.8 in two independent samples. Several other investigators have also found evidence of linkage to 21q22. Liu et al.9 found evidence of linkage in 56 families to chromosome 21 with a two-point lod score of 3.56 at D21S1260. Other groups have also found evidence in their samples supporting this chromosomal region.
Linkage to chromosome 4p was initially reported by Visscher and colleagues.10 A reanalysis using variance component methods suggests gene variation on 4p may account for 25% of the variation in affective disorder diagnosis in a large Scottish pedigree.
Detera-Wadleigh et al.3 provided evidence of linkage to 4pl6-pl4 with increased allele sharing in 22 pedigrees analyzed using affected sibling-pair linkage methods and a broad definition of the disease phenotype. Escamilla and colleagues" reported possible linkage disequilibrium in this area in a Costa Rican population-based sample.
Possible linkage has been recendy reported to chromosome 4q35 by Adams et al.12 They screened the genome using a portion of a large Australian pedigree (n = 35). In those regions identified with promising linkage results, the remaining portion of the family was genotyped (n = 52). Analyses included a dotninant disease model (lod = 2.2), as well as nonparametric extended pedigree methods (Z-score = 2.62).
Conflicting linkage results have been reported on the X chromosome. Fine mapping has been undertaken in a sample of Finnish pedigrees supporting linkage to Xq24-27.1. Genotyping of eight markers in a 10 cM region provided evidence of association for some of the markers; however, there did not appear to be a particular haplotype in this region associated with disease.13
Analyses of the National Institutes of Mental Health (NIMH) Genetics Initiative pedigrees also support linkage to the X chromosome.14 Increased allele sharing among brother pairs was observed at Xp22 and increased sharing among sister pairs at Xq26. Further analyses have supported identified increased allele sharing on Xq22.1 at DXS6789, as well as on Xp21.1 near the marker DXS6810.15 Not all studies have confirmed evidence of linkage to this region.
Linkage to chromosome IO was reported in the NIMH Genetics Initiative pedigrees. Interestingly, this region has also been linked to schizophrenia. This linkage finding suggests a locus with pleiotropic effects might be located in this chromosomal region of chromosome 1Op. Notably, linkage to this region has been reported for numerous disorders in addition to bipolar and schizophrenia, including type Í diabetes, Crohn's disease, obesity, and blood pressure problems.
Linkage to 1Oq has also been reported by several groups. Ewald et al.16 reported linkage to 1Oq in a sample from the Faroe Islands in Finland. Cichon et al.17 found evidence of linkage to this region using 75 German, Israeli, and Italian pedigrees. The highest parametric two-point lod score was 2.86 at the marker D10S217; an NPL score of 3.12 was also found in the same region.
Possible linkage of psychiatric illness to chromosome 22 has been pursued for several years, due to me association of velo-cardio-facial syndrome (VCFS) and its related microdeletion and psychoses. Linkage of this region to schizophrenia has been reported previously.18,19 Several groups have reported linkage to this region in samples with bipolar, including the NIMH Genetics Initiative samples as well as the NIMH Neurogenetics pedigrees.
Further support for a bipolar susceptibility locus in this region was recently reported by Kelsoe et al.20 in a series of 20 pedigrees. Thirteen markers spanning 32 cM had lod scores greater than 1, with the highest lod score (lod = 3.8) obtained with the marker D22S278.
Stine and colleagues14 reported some evidence of linkage to chromosome 13q32 in the 97 NIMH Genetics Initiative pedigrees. Increased allele sharing was observed at the markers D13S800 and D13S793. In the NIMH Neurogenetics pedigrees, further support for this linkage finding was reported following a high density genome screen with an average 6 cM intermarker distance.3 Sibiing pair analyses using narrower and broader disease definitions yielded lod scores of 3.4 and 3.3, respectively, near the markers D 13Sl 271 and D13S779.
More recently, nine additional markers were genotyped between the markers D13S71 and D13S274 in the same sample, creating a map with an average spacing of 0.9 cM in this chromosomal region of interest.21 The highest lod scores were obtained with model II, the broader disease definition, with a maximum lod score of 3.25 (P = 0.00005) around D13S779 and D13S225 when sibling pairs were analyzed. This region of chromosome 13q also produced lod scores greater than 2 for three markers (D 13Sl 54, D13S225, D13S796) in the 20 pedigrees studied by Kelsoe et al.20 They found six additional markers in this 20 cM region had lod scores greater than 1.
Previous analyses in various dataseis have detected linkage to various regions of chromosome 1 . Most recently, Blackwood et al.22 reported a family with a (I;ll)(q42;ql4.3) translocation that cosegregates with schizophrenia and affective disorders. Analyses performed with the schizophrenia phenotype generated a lod score of 3.6; a score of 4.5 was found for those with the affective disorder phenotype. The joint analyses of both phenotypes and recurrent major depression produced a maximum lod score of 7. 1 , Interestingly, family members with the translocation who lacked psychiatric symptoms had reduced P300 amplitude and latency prolongation.
Recently, evidence of linkage to chromosome 8q has been reported by several groups. Ln a series of 57 extended pedigrees, linkage to 8q was reported using a dominant model of disease, with a lod score of 2.47.23 Dense fine mapping to an intermarker interval of 5 cM as well as genotyping of 500 additional individuals continues to support linkage to this region. More recently, 75 families, primarily from Germany but also from Israel and Italy, were genotyped and the highest two-point LOD score was obtained on chromosome 8q24 at the marker D8S1514 (lod = 3.62).21
APPROACHES FOR GENE IDENTIFICATION
While several promising linkage results appear to replicate across at least some studies, the identified chromosomal regions are relatively broad. Numerous groups have begun fine mapping using a variety of approaches.
The study of patients with cytogenetic abnormalities has been particularly useful in the physical mapping of several genes. Several groups have identified patients with affective disorder or psychoses who also have a translocation in chromosomal region previously linked to bipolar disorder. This literature has been summarized by Craddock and Owen.25 By further delineating the breakpoints in these patients, it may be possible to narrow the critical chromosomal interval and identify a smaller number of candidate genes for further testing.
Linkage disequilibrium studies may be particularly useful in genetically isolated populations. Researchers are developing single nucleotide polymorphism maps within linked regions as a means to test for linkage disequilibrium in more genetically heterogeneous samples. Such studies are currently underway in the chromosome 18q2 1.3-22.1 region.
Another approach being used in the fine mapping of the chromosome 18q21Hnked region has been to identify novel genes Ltirough exon trapping. Chen et al.26 has identified 285 unique sequences (exons), of which 32 have homology to known genes or expressed sequence tagged sites (ESTs), 29 have significant homology to known genes, and 19 are homologous to the short DNA sequence of ALU or other repeats. Interestingly, 205, or 72%, of the sequences do not have homology with any published sequence. Further characterization of these sequences will result in the identification of candidate genes to be tested for association with bipolar disorder.
With the report of anticipation in pedigrees with bipolar, several groups have focused their efforts to identify expanded trinucleotide repeat sequences that might then represent candidate sequence for a bipolar-susceptibility gene. Del-Favero et al.27 proposed a novel method resulting in region-specific isolation of such repeated sequences. This will significantly improve the efficiency in detecting such repeats; typically, most methods have resulted in the identification of many such sequences that do not map to regions previously linked to the disorder.
A powerful method for candidate gene identification is differential display polymerase chain reaction (PCR). Such mRNA methods are often hampered by the availability of appropriate tissue. When such materials are available, however, the identification of transcripts with altered expression can prove a powerful means to identify candidate genes with possible functional significance. This method has been applied by Karkera and colleagues28 using mRNA isolated from cortex and caudate of a subject with bipolar and a control. Of the more than 100 differentially expressed transcripts that were identified, six map to regions previously linked to bipolar disorder.
CANDIDATE GENES IN BIPOLAR AFFECTIVE DISORDER
Serotonin Transporter and Serotonin Receptor Genes
The human gene for the serotonin transporter (5HTT) has been mapped to 17ql 1.1-12. In 1996, Collier et al.29 reported an association of the short promoter allele with bipolar and unipolar illness considered together. In separate work, the short allele was associated with reduced promoter activity.
Subsequent studies have provided mixed results. Recently, the short allele was found to be associated with antidepressant-induced mania or hypomania in one study30 and violent suicide attempts in a meta-analysis.31 Evidence has also been presented for the association of bipolar with allele 12 of a variable number of tandem repeats in intron 2, although conflicting studies exist.32
At this point, data are not compelling for a bipolar-susceptibility gene at the 5HTT locus. The possibility that this gene might have a small effect (less than or equal to 1.5 relative risk) cannot be eliminated. Suggestive data has also recently been reported for 5HT6, 5HT2C,33 and 5HT3a.
Expanded Trinucleotide Repeats
A number of central nervous system diseases have been demonstrated to be associated with genes that contain trinucleotide repeats, usually CAG or CTG, where the repeated element expands as the gene is transmitted through the family.34 Lindblad et al.35 used a general method for detecting repeated sequences at any location in the genome. They reported an elevated number of such sequences in patients with bipolar disorder. It was subsequently learned that the great majority of repeats detected with this method, known as repeat expansion detection (RED), resulted from expansions at two loci, CTG 18.1 on 18q21.1, and ERDAl on 17q21.3. In a subsequent report, the authors concluded that CTG 18.1 conferred substantial increased risk for bipolar. Other groups have not generally replicated these findings, although increased numbers of expanded repeats were recently reported in Portuguese families. It seems likely that repeats at this locus do not account for a major portion of the vulnerability to bipolar.
Other expanded sequences have been studied with negative results, including a series on chromosome 12 and one on chromosome 19. A CAG repeat in the interleukin receptor gene (1L9R), located in the pseudoautosomal region on Xq28, was studied by Hawi et al.36 Only this last appeared potentially encouraging. However, the underlying hypothesis is sufficiently interesting, and the confirmed expansions in 1 5 or more conditions sufficiently convincing as a viable mechanism of illness in the central nervous system, to indicate further investigations.
Linkage studies have supported linkage to one or more loci for both schizophrenia and bipolar on chromosome 22q. One area implicated is near the location of deletions causing VCFS, a multisystem condition that has been associated with both schizophreniform and affective syndromes, in particular rapid-cycling bipolar disorder.37 The group at Einstein Medical Center37 also identified an allele for a variant of the catecholamine metabolic enzyme catechol-O-methyltransferase (COMT) in this same genomic area as being related to rapid-cycling in bipolar patients. However a multicenter study of bipolar did not find an association.38 Egan et al.39 recently reported an association between COMT alleles and cognitive function in schizophrenia.
Tyrosine Hydroxylase and Tryptophan Hydroxylase
Interest in tyrosine hydroxylase (TH), the synthetic enzyme for norepinephrine, has dated to the original report of linkage to the 1 lpl 5 area in Amish pedigrees. A gene for TH and a gene for the serotonin synthetic enzyme tryptophan hydroxylase (TPH) have been localized to this area. Though initial assessments of linkage and association to TH were inconsistent, positive reports have continued. A recent multicenter European study including 527 patients with bipolar and matched controls did not show differences in TPH-allele frequency related to diagnosis or to suicide attempts.40
Dopamine Transporter and Dopamine Receptor Genes
Greenwood et al.41 reported differential transmission of a haplotyped marker consisting of five single nucleotide polymorphisms within the dopamine transporter on 5pl5.3 (P = 0.0004) in 50 proband-parent triads from families linked to this area. Massatt et al.42 reported association of alleles at the D2 receptor gene locus with bipolar, using 358 patients and 358 controls matched for geographic origin.
The gene for the alpha subunit of the olfactory G-protein (G-olf or GNAL) has been of interest because of its location in the centromeric region of chromosome 18, reported to be linked by Berrettini et al.2 and others. However, positive association data in patients with bipolar has yet to be reported. The gene for myo-inositol monophosphate 2 (IMPA2) has been cloned and localized to 18pl 1.2. Initial results from two laboratories indicate that this gene, which codes for a lithium-sensitive protein, is subject to variation in bipolar patients.
Kelsoe and colleagues43 have developed a method they refer to as "convergent functional genomics" and have used this to establish a candidate gene on chromosome 22. Gene chip methods were used to study gene expression following an amphetamine challenge in rats. Those genes with the greatest changes in brain expression were screened to identify those located in a region homologous to the linked region on chromosome 22q. The most promising candidate was Greceptor kinase 3, which was then demonstrated to be down-regulated in cell culture specimens from patients with bipolar. This group has since identified polymorphisms in the promoter region of this gene that appear to be associated with bipolar disorder.
A positive association in 12q23-24 has been reported for the pancreatic phospholipase A2 gene.44 A gene associated with synaptic vesicle function on chromosome 21q22 (SNYJl) was studied by Saito et al.45 Several rare alleles with possible functional significance were found in patients with bipolar.
Turecki et al.46 reported an association of one allele for an isozyme of phospholipase in a case-control series including 136 lithium-responsive patients with bipolar and 163 controls. Modest evidence of linkage in the subgroup of subjects with unilineal families was also presented.
Mynett-Johnson et al.47 reported an allelic association for a dinucleotide polymorphism within the gene for an alpha subunit of Na+, K+ adenosine triphosphatase (ATPl A3 on chromosome 1 9q 1 2- 1 3.3). This is of interest in view of pathophysiologic hypotheses implicating ATPase in bipolar. However, no evidence was found for linkage to ATPl A3 and ATP 1B3 subunits in sibling pairs from Old Order Amish families.
Papadimitriou et al.48 found a possible association with alleles of the GABA-A receptor alpha5 subunit gene (GABRA5) in 48 bipolar patients and 50 controls, all of Greek ancestry. The gene is on chromosome 15ql l-ql3, and the relationship to pathophysiology is suggested in many reviews by Petty. Massat et al.49 present evidence for association of GABRA3 alleles (a positional candidate on Xq28) with bipolar in both men and women.
Preisig et al.50 reported a variance in monoamine oxidase A alleles between female patients with bipolar and controls in their series of 155 female patients, and in pooled data consisting of 319 female patients. However, others have not found such an association.
Kato et al.51 reported an increased frequency of the mitochondrial 5178C genotype in 125 patients with bipolar, excluding patients with illness on the paternal side. Another group did not find mitochondrial DNA associations with bipolar, however.
Results from recent genetic studies of bipolar disorder have identified several chromosomal regions with promising results (Table 1, see page 22). While few, if any, genes or regions have replicated in all genetic studies, this is to expected, because there are likely numerous susceptibility genes influencing the risk of bipolar disorder.
For a candidate gene to be convincingly shown to be a susceptibility gene, the following elements should probably be present: some evidence of linkage in the location of the candidate; association in case-control series of more than 200 subjects; association in family-based triad series; evidence of a potential pathophysiologic role for the candidate; and independent replication of results. Importantly, it may be necessary to consider other factors, such as gene-environment and gene-gene interactions, to demonstrate definitely the role of a candidate gene in disease susceptibility.
While no genes have been shown to play a definite role in the risk for bipolar disorder, recent progress suggests that the identification of some of these genes is possible within the next few years.
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20. Kelsoe JR, Spence MA, Loetscher E, et al. A genome survey indicates a possible susceptibility locus for bipolar disorder on chromosome 22. Proc Natl Acad Sci USA. 2001 ;98(2):585-590.
21. Liu J, Aita VM, Knowles JA, et al. Search for susceptibility loci in extended pedigrees with bipolar affective disorder. Mol Psychiatry. 1999:4(1):S21.
22. Blackwood DH, Fordyce A, Walker MT, et al. Schizophrenia and affective disorders-cosegregation with a translocation at chromosome Iq42 that directly disrupts brain expressed genes: clinical and P300 findings in a family. Am J Hum Genet. 2001;69(2):428-433.
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30.Mynett-Johnson L, Kealey C, Claffey E, et al. Multimarker haplotypes within the serotonin transporter gene suggest evidence of an association with bipolar disorder. Am J Med Genet. 2000;96(6):845-849.
31. Lerer B, Macciardi F. Segman RH, et al. Variability of 5-GT2C receptor cys23ser polymorphism among European populations and vulnerability to affective disorder. Moi Psychiatry. 2001:6(5):579-585.
32. Margolis RL, Mclnnis MG, Rosenblatt A, Ross C. Trinucleotide repeal expansion and neuropsychiatrie disease. Arch Gen Psychiat. 1999:56(11):1019-1031.
33. Lindblad K, Nylander PO, De Bryun A. et al. Detection of expanded CAG repeats in bipolar affective disorder using me repeat expansion detection (RED) method. Neurobiol Dis. 1995:2(1):S5-62.
34. Hawi Z, Mynett-Johnson L, Gill M, et al. Pseudoautosomal gene: possible association with bipolar males but not with schizophrenia. Psychiatr Genet. 1999:9(3): 129-134.
35. Lachman HM, Morrow B, Shprintzen R, et al. Association of codon 108/158 catechol-O-methyltransferase gene polymorphism with the psychiatric manifestations of velo-cardio-facial syndrome. Am J Med Genet. 1996;67(5):468472.
36. Biomed European Bipolar Collaborative Group. No association between bipolar disorder and alleles at a functional polymorphism in the COMT gene. Br J Psychiatry. 1997:170:526-528.
37. Egan MF, Goldberg TE, Kolachana BS, et al. Effect of COMT Val 108/ 158 Met genotype on grontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA. 2001:98(12):6917-6922.
38. Souery D, Van Geste! S, Massat I, et al. Tryptophan hydroxylase polymorphism and suicidality in unipolar and bipolar affective disorders: a multicenter association study. Biol Psychiatry. 2001;49(5):405-409.
39. Greenwood TA. Alexander M, Keck PE. et al. Evidence for linkage disequilibrium between the dopamine transporter and bipolar disorder. Am J Med Genet. 2001;105(2): 145-151.
40. Massat I, Souery D, Lipp O, et al. A European multicenter association study of HTR2A receiptor polymorphism in bipolar affective disorder. Am J Med Genet. 2000;96(2):136-140.
41. Niculescu AB 3rd, Segal DS, Kuczenski R, et al. Identifying a series of candidate genes for mania and psychosis: a convergent functional genomics approach. Physiol Genomics. 2000: 4(1):83-91.
42. Dawson E. Gill M. Curtis D. et al. Genetic association between alleles of pancreatic phospholipase A2 gene and bipolar affective disorder. Psychiatr Genet. 1995 ;5(4):177-180.
43. Saito T, Guan F, Papólos DF, et al. Mutation analysis of SYNJ 1 : a possible candidate gene for chromosome 21 q22-linked bipolar disorder. Mol Psychiatry. 2001;6(4):387-395.
44. Turecki G, Grof P, Cavazzoni P. et al. Evidence for a role of phospholipase C-P1 in the pathogenesis of bipolar disorder. Mol Psychiatry. 1998;3(6):534-538.
45. Mynett-Johnson L, Murphy V. McCormack J, et al. Evidence for an allelic association between bipolar disorder and Na+, K+ adenosine triphosphatase alpha subunit gene (ATP1A3). Biol Psychiatry. 1998;44(1):47-51.
46. Papadimitriou GN, Dikeos DG, Karadima G, et al. Association between the GABA-A receptor a5 subunit gene locus (GABRA5) and bipolar affective disorder. Am J Med Genet. 1998;81(l):73-80.
47. Massat I, Souery D, DetFavero J, et al. Excess of allele 1 for a3 subunit GABA receptor gene (GABRA3) in bipolar patients: a multicentric association study. Mol Psychiatry. 2002;7(2):201-207.
48. Preisig M, Bellivier F, Fenton BT, et al. Association between bipolar disorder and monoamine oxidase A gene polymorphisms: results of a multicenter study. Am J Psychiatry. 2000;157(6):948-955.
49. Kato T, Kunugi H, Nanko S, Kato N. Association of bipolar disorder with the 5178 polymorphism in mitochondrial DNA. Am J Med Genet. 2000:96(2): 182- 186.
Linkage Studies of Bipolar Illness With Support from More Than One Study