Susceptibility Locus For Bipolar Disorder Research Articles

Linkage analysis in bipolar pedigrees adds support for a susceptibility locus on 21q22.

Several studies provide suggestive evidence of a susceptibility locus for bipolar disorder at chromosome 21q22-23. In an attempt to replicate these findings, we have analyzed linkage to 11 polymorphic markers from this region in 18 Bulgarian pedigrees with affective disorder. Two-point linkage analysis under assumption of homogeneity and a dominant model with reduced penetrance produced modest positive values for some of the markers tested under a 'narrow' phenotype definition, including bipolar I and II, and schizoaffective disorder. The maximum two-point score (lod=1.76, theta=0.00) was at marker D21S1919. Non-parametric linkage analysis under the same phenotype model, yielded positive NPLall values (P<0.05) over the region between markers D21S211 and D21S416, with a peak at D21S1252 (NPL Zall=2.32, P=0.0003). The multipoint lod score (GENEHUNTER) reached a suggestive value for linkage (lod=2.10) also at marker D21S1252. The results under a recessive model were completely negative. These data add to the evidence for the existence of a susceptibility locus for bipolar affective disorder on chromosome 21q22.

Polymorphisms in the 13q33.2 gene G72/G30 are associated with childhood-onset schizophrenia and psychosis not otherwise specified

Background Childhood-onset schizophrenia (COS), defined as onset of psychotic symptoms by age 12 years, is a rare and severe form of the disorder that seems to be clinically and neurobiologically continuous with the adult disorder. Methods We studied a rare cohort consisting of 98 probands; 71 of these probands received a DSM-defined diagnosis of schizophrenia, and the remaining 27 were diagnosed as psychosis not otherwise specified (NOS) (upon 2–6 year follow-up, 13 have subsequently developed bipolar disorder). Two overlapping genes, G72 and G30 on 13q33.2, were identified through linkage-disequilibrium-based positional cloning. Single nucleotide polymorphisms (SNPs) at the G72/G30 locus were independently associated with both bipolar illness and schizophrenia. We analyzed SNPs at this locus with a family-based transmission disequilibrium test (TDT) and haplotype analyses for the discrete trait, as well as quantitative TDT for intermediate phenotypes, using the 88 probands (including COS and psychosis-NOS) with parental participation. Results We observed significant pairwise and haplotype associations between SNPs at the G72/G30 locus and psychotic illness. Furthermore, these markers showed associations with scores on a premorbid phenotype measured by the Autism Screening Questionnaire, and with age of onset. Conclusions These findings, although limited by potential referral bias, confirm and strengthen previous reports that G72/G30 is a susceptibility locus both for schizophrenia and bipolar disorder.

Genome-wide scan in Portuguese Island families implicates multiple loci in bipolar disorder: fine mapping adds support on chromosomes 6 and 11.

As part of an extensive study in the Portuguese Island population of families with multiple patients suffering from bipolar disorder and schizophrenia, we performed an initial genome-wide scan of 16 extended families with bipolar disorder that identified three regions on chromosomes 2, 11, and 19 with genome-wide suggestive linkage and several other regions, including chromosome 6q, also approached suggestive levels of significance. Dick et al. [2003: Am J Hum Genet 73:107-114] recently reported in a study of 250 families with bipolar disorder a maxLOD score of 3.61 near marker D6S1021 on chromosome 6q. This study replicates this finding having detected a peak NPL = 2.02 (P = 0.025) with the same marker D6S1021(104.7 Mb). Higher-density mapping provided additional support for loci on chromosome 6 including marker D6S1021 with an NPL = 2.59 (P = 0.0068) and peaking at marker D6S1639 (125 Mb) with an NPL = 3.06 (P = 0.0019). A similar pattern was detected with higher-density mapping of chromosome 11 with an NPL = 3.15 (P = 0.0014) at marker D11S1883 (63.1 Mb). Simulations at the density of our fine mapping data indicate that less than 1 scan out of 10 would find two such scores genome-wide in the same scan by chance. Our findings provide additional support for a susceptibility locus for bipolar disorder on 6q, as well as, suggesting the importance of denser scans. Published 2004 Wiley-Liss, Inc.

Genetic linkage in bipolar disorder.

Bipolar disorder is an etiologically complex syndrome that is clearly heritable. Multiple genes, working singly or in concert, are likely to cause susceptibility to bipolar disorder. Bipolar disorder genetics has progressed rapidly in the last few decades. However, specific causal genetic mutations for bipolar disorder have not been identified. Both candidate gene studies and complete genome screens have been conducted. They have provided compelling evidence for several potential bipolar disorder susceptibility loci in several regions of the genome. The strongest evidence suggests that bipolar disorder susceptibility loci may lie in one or more genomic regions on chromosomes 18, 4, and 21. Other regions of interest, including those on chromosomes 5 and 8, are also under investigation. New approaches, such as the use of genetically isolated populations and the use of endophenotypes for bipolar disorder, hold promise for continued advancement in the search to identify specific bipolar disorder genes.

Familial bipolar disorder and multiple sclerosis: a three-generation HLA family study

The coexistence of bipolar disorder (BD) and multiple sclerosis (MS) is well known. Manic symptoms may represent initial symptoms of MS, at least in some cases, and follow the MS-HLA phenotype frequencies. The purpose of this study was to examine the possible relation of BD and MS based on an HLA family study of a woman with BD and comorbid MS, with family history of BD. Five members of the family from three generations (the patient, her mother, her brother, and her two daughters) were examined regarding the two disorders and the HLA class I and II specificities, performed by serology and molecular techniques. Her deceased father, her brother, and her older daughter suffered from BD. Moreover, in her brother, BD and MS comorbidity was diagnosed. The three affected members and the nonaffected grandmother share the same class I and II, HLA-A2, B18, CW8, DR2, DQ1 haplotype. The shared class II, HLA-DR2, DQ1 haplotype among affected individuals, which is well known to be associated with MS in Caucasians, suggests a possible susceptibility locus for BD, mapped on chromosome 6, very close to the HLA region, underlying the clinical comorbidity of the two disorders.

Evidence that a single nucleotide polymorphism in the promoter of the G protein receptor kinase 3 gene is associated with bipolar disorder.

In a genome-wide linkage survey, we have previously shown evidence suggesting that the chromosome 22q12 region contains a susceptibility locus for bipolar disorder (BPD). Two independent family sets yielded lod scores suggestive of linkage at markers in this region near the gene G protein receptor kinase 3 (GRK3). GRK3 is an excellent candidate risk gene for BPD since GRK3 is expressed widely in the brain, and since GRKs play key roles in the homologous desensitization of G protein-coupled receptor signaling. We have also previously shown GRK3 expression to be induced by amphetamine in an animal model of mania using microarray-based expression profiling. To identify possible functional mutations in GRK3, we sequenced the putative promoter region, all 21 exons, and intronic sequence flanking each exon, in 14-22 individuals with BPD. We found six sequence variants in the 5'-UTR/promoter region, but no coding or obvious splice variants. Transmission disequilibrium analyses of one set of 153 families indicated that two of the 5'-UTR/promoter variants are associated with BPD in families of northern European Caucasian ancestry. A supportive trend towards association to one of these two variants (P-5) was then subsequently obtained in an independent sample of 237 families. In the combined sample, the P-5 variant had an estimated allele frequency of 3% in bipolar subjects, and displayed a transmission to non-transmission ratio of 26 : 7.7 (chi(2)=9.6, one-sided P value=0.0019). Altogether, these data support the hypothesis that a dysregulation in GRK3 expression alters signaling desensitization, and thereby predisposes to the development of BPD.

Linkage of a bipolar disorder susceptibility locus to human chromosome 13q32 in a new pedigree series.

Bipolar (BP) disorder or manic depressive illness is a major psychiatric disorder for which numerous family, twin and adoption studies support a substantial genetic contribution. Recently, we reported the results of a genome-wide search for BP disorder susceptibility loci in 20 pedigrees. Suggestive evidence for linkage was found in this study at three markers on 13q, representing possibly two peaks separated by 18 cM. We have now collected a second set of 32 pedigrees segregating BP disorder and have tested for evidence of linkage to markers on human chromosome 13q. In this sample, we have replicated the linkage result in 13q32 at D13S154 (lod=2.29), the more proximal of the two original peaks. When all 52 pedigrees were combined, the multipoint maximum lod score peaked approximately 7 cM proximal to D13S154 (lod=3.40), with a second peak occurring between D13S225 and D13S796 (lod=2.58). There have been several other reports of significant linkage to both BP disorder and schizophrenia in this region of chromosome 13. These pedigrees provide additional evidence for at least one locus for BP disorder in 13q32, and are consistent with other reports of a possible genetic overlap between these disorders.

Genetic refinement and physical mapping of a 2.3 Mb probable disease region associated with a bipolar affective disorder susceptibility locus on chromosome 4q35.

A susceptibility locus for bipolar affective disorder has been mapped to chromosome 4q35 in a large multigenerational pedigree. We have expanded this analysis to include 55 pedigrees (674 individuals, 214 affecteds). The evidence for linkage to 4q35 was strengthened in this larger cohort, with a maximum two-point LOD score of 3.2 for marker D4S1652. Several other markers in the region gave LOD scores greater than 1.5. Non-parametric analysis provided additional support for linkage to the 4q35 region. To further refine this region, haplotype analysis was carried out in 16 of the 55 pedigrees that showed evidence of linkage. As there is no evidence for an ancestral haplotype, nor a one-to-one correspondence between the disease and putative disease haplotype, we undertook an analysis based on pedigree-specific, identical-by-descent allele-sharing in order to define a probable disease region. This analysis indicated that the percentage sharing of alleles, identical-by-descent, in affecteds of all linked pedigrees increases from 60% at the centromeric markers to 75% for markers at the telomere. Maximal allele sharing occurred between markers D4S3051 and 4qTEL13 with this 24 cM region defining a probable disease region. We have constructed a physical map of the 4q35 interval consisting of a YAC contig and BAC clones. Based on this map the probable disease region between D4S3051 and 4qTEL13 corresponds to only 2.3 Mb. This region is very gene poor with only three known genes indicated from the YAC/BAC map. The small number of genes will facilitate systematic screening for variations associated with bipolar disorder.

A transcript map encompassing a susceptibility locus for bipolar affective disorder on chromosome 4q35.

Bipolar affective disorder is one of the most common mental illnesses with a population prevalence of approximately 1%. The disorder is genetically complex, with an increasing number of loci being implicated through genetic linkage studies. However, the specific genetic variations and molecules involved in bipolar susceptibility and pathogenesis are yet to be identified. Genetic linkage analysis has identified a bipolar disorder susceptibility locus on chromosome 4q35, and the interval harbouring this susceptibility gene has been narrowed to a size that is amenable to positional cloning. We have used the resources of the Human Genome Project (HGP) and Celera Genomics to identify overlapping sequenced BAC clones and sequence contigs that represent the region implicated by linkage analysis. A combination of bioinformatic tools and laboratory techniques have been applied to annotate this DNA sequence data and establish a comprehensive transcript map that spans approximately 5.5 Mb. This map encompasses the chromosome 4q35 bipolar susceptibility locus, which localises to a "most probable" candidate interval of approximately 2.3 Mb, within a more conservative candidate interval of approximately 5 Mb. Localised within this map are 11 characterised genes and eight novel genes of unknown function, which together provide a collection of candidate transcripts that may be investigated for association with bipolar disorder. Overall, this region was shown to be very gene-poor, with a high incidence of pseudogenes, and redundant and novel repetitive elements. Our analysis of the interval has demonstrated a significant difference in the extent to which the current HGP and Celera sequence data sets represent this region.

Support for the presence of bipolar disorder susceptibility loci on chromosome 5: Heterogeneity in a homogeneous population in Quebec

A very large pedigree derived from the Saguenay-Lac-St-Jean region of Quebec contains a branch where a distal chromosome 5q haplotype seems to cosegregate with bipolar affective disorder. The authors used a diagnosis model where Bipolar Types I and II and schizoaffective disorder bipolar type were considered as affected, while single or recurrent episode major depression was classified as unknown and all the others diagnoses as unaffected. Model-free two-point LOD score values of 3.41 and 2.21 were observed at D5S432 in the 5p region with sib_ibd and sib_phase from the ASPEX package, but simulation studies did not permit the conclusion of a significant linkage because associated empirical P values were equal to .0026 and .0037. A parametric LOD score value of 2.15 was obtained at locus D5S412 in the distal chromosome 5q area. In order to investigate heterogeneity in the single multigenerational family, the pedigree was divided into five branches. Our simulation study suggested that the five branches of the Saguenay-Lac-St-Jean bipolar pedigree had low power to detect linkage under intrapedigree heterogeneity in this region.

Genome scan for susceptibility loci for schizophrenia and bipolar disorder

Background: Despite the widely accepted view that schizophrenia and bipolar disorder represent independent illnesses and modes of inheritance, some data in the literature suggest that the diseases may share some genetic susceptibility. The objective of our analyses was to search for vulnerability loci for the two disorders. Methods: A genomewide map of 388 microsatellite DNA markers was genotyped in five schizophrenia and three bipolar disorder Austrian families. Linkage analyses was used to compute the usual parametric logarithm of the likelihood of linkage (LOD) scores and nonparametric linkage analysis (NPL scores Z all) was used to assess the pattern of allele sharing at each marker locus relative to the presence of the disease (GENEHUNTER). Affected status was defined as severe affective disorder or schizophrenia. Results: Across the genome, p values associated with NPL scores resulted in evidence (i.e., p < .0007) for linkage at marker D3S1265 on chromosome 3q (NPL score Z all = 3.74, p = .0003). Two other markers (on 3q and 6q) showed p values of < .01. Conclusions: We detected a potential susceptibility locus for bipolar disorder and schizophrenia on chromosome 3q, which has not been reported previously. The possibility of a false positive result has to be taken into account. Our data suggest shared loci for schizophrenia and bipolar affective disorders and are consistent with the continuum model of psychosis.

Linkage analysis in psychiatric disorders: the emerging picture.

Gene finding in genetically complex diseases has been difficult as a result of many factors that have diagnostic and methodologic considerations. For bipolar disorder and schizophrenia, numerous family, twin, and adoption studies have identified a strong genetic component to these behavioral psychiatric disorders. Despite difficulties that include diagnostic differences between sample populations and the lack of statistical significance in many individual studies, several promising patterns have emerged, suggesting that true susceptibility loci for schizophrenia and bipolar disorder may have been identified. In this review, the genetic epidemiology of these disorders is covered as well as linkage findings on chromosomes 4, 12, 13, 18, 21, and 22 in bipolar disorder and on chromosomes 1, 6, 8, 10, 13, 15, and 22 in schizophrenia. The sequencing of the human genome and identification of numerous single nucleotide polymorphisms (SNP) should substantially enhance the ability of investigators to identify disease-causing genes in these areas of the genome.

A search for specific and common susceptibility loci for schizophrenia and bipolar disorder: a linkage study in 13 target chromosomes.

We report the first stage of a genome scan of schizophrenia (SZ) and bipolar disorder (BP) covering 18 candidate chromosomal areas. In addition to testing susceptibility loci that are specific to each disorder, we tested the hypothesis that some susceptibility loci might be common to both disorders. A total of 480 individuals from 21 multigenerational pedigrees of Eastern Québec were evaluated by means of a consensus best-estimate diagnosis made blind to diagnoses in relatives and were genotyped with 220 microsatellite markers. Two-point and multipoint model-based linkage analyses were performed and mod scores (Z, for max Z(max)) are reported. The strongest linkage signals were detected at D18S1145 (in 18q12; Z = 4.03) for BP, and at D6S334 (in 6p 22-24; Z(het) = 3.47; alpha = 0.66) for SZ. Three other chromosomal areas (3q, 10p, and 21q) yielded linkage signals. Chromosomes 3p, 4p, 5p, 5q, 6q, 8p, 9q, 11q, 11p, 12q, 13q, 18p and 22q showed no evidence of linkage. The 18q12 results met the Lander and Kruglyak (1995) criterion for a genome-wide significant linkage and suggested that this susceptibility region may be shared by SZ and BP. The 6p finding provided confirmatory evidence of linkage for SZ. Our results suggest that both specific and common susceptibility loci must be searched for SZ and BP.

Further evidence for a bipolar risk gene on chromosome 12q24 suggested by investigation of haplotype sharing and allelic association in patients from the Faroe Islands.

A number of studies have strongly suggested a susceptibility locus for bipolar affective disorder on chromosome 12q24. The present study investigates for a shared chromosomal segment among distantly related patients with bipolar affective disorder from the Faroe Islands, using 17 microsatellite markers covering 24 cM in the previously suggested region on chromosome 12q24. D12S342 showed possible allelic association to bipolar affective disorder (P-value using CLUMP below 0.01). Increased sharing among cases of two-marker haplotypes were suggested at D12S1614--D12S342 (P-values using CLUMP below 0.01), and D12S2075--D12S1675 (P-values using CLUMP around 0.001). The region of most interest is around 6 cM and bounded by markers D12S1614 and D12S1675 as suggested by the interesting two-marker haplotypes. This area contains the minimum interesting region between D12S342 and D12S1658 suggested by the previously reported haplotypes in the two Danish families with bipolar affective disorder.

The human genome: susceptibility loci.

Back to table of contents Previous article Next article Images in NeuroscienceFull AccessThe Human Genome: Susceptibility LociWade H. Berrettini, M.D., Ph.D., Wade H. BerrettiniSearch for more papers by this author, M.D., Ph.D., Philadelphia, Pa.Published Online:1 Jun 2001https://doi.org/10.1176/appi.ajp.158.6.865AboutSectionsView articleView PDFView EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail View articleMany psychiatric illnesses, such as bipolar disorder and schizophrenia, are complex genetic disorders, in which genetic heterogeneity is assumed. However, identifying chromosomal regions linked to these syndromes (susceptibility loci) has its challenges. In family linkage analysis, failure of subsequent studies to confirm previously nominated susceptibility loci is commonplace. Several methodological issues are at play in this failure to confirm, including the power of the individual studies, the inherent limitations of linkage analysis, and variation among population samples. Despite this, multiple susceptibility loci have been identified for several psychiatric diagnoses, including schizophrenia and bipolar disorder. Most probably, these susceptibility loci interact with each other and the environment to produce the clinical syndromes. Susceptibility loci are identifiable regions of a chromosome that are inherited with the illness in families, and they are assumed to include the illness vulnerability allele that partially explains illness risk in these families.Geneticists now see that some of these susceptibility loci for schizophrenia overlap with loci for bipolar disorder. The figure identifies the loci for bipolar disease alone (B), for schizophrenia alone (S), and for bipolar and schizophrenia (*). While bipolar disorder and schizophrenia are two distinct psychiatric diagnostic categories, each with its own characteristic symptoms, course of illness, and pharmacology, they have several similarities: age at onset, lifetime risk, suicide risk, gender distribution, and heritability estimates. Family studies indicate that the first-degree relatives of bipolar probands and the first-degree relatives of schizophrenia probands are at higher than normal risk for schizoaffective and recurrent unipolar disorders, suggesting some shared familial risk. The molecular data represented here support the idea of shared genetic risk. The family study and molecular data suggest that these two groups of disorders may be more closely related than previously considered. Novel genes corresponding to the loci will be identified over the next decade. Characterization of these susceptibility alleles will allow for correlation between the genetic data and clinical phenotype. Because environmental factors drive gene expression, knowledge of the environmental risk factors will certainly inform data from the molecular level.Address reprint requests to Dr. Tamminga, Maryland Psychiatric Research Center, University of Maryland, P.O. Box 21247, Baltimore, MD 21228. Image is an updated version of one published in Biological Psychiatry (W.H. Berrettini, 48:531–538; copyright 2000 by the Society of Biological Psychiatry); reprinted by permission of Elsevier Science. Figure. Ideograms of human chromosomes showing susceptibility loci for bipolar disorder, schizophrenia, and both disorders. The identifying symbols are placed to the right of the structures to which they refer. FiguresReferencesCited byDetailsCited ByCurrent Opinion in Psychiatry, Vol. 16 Volume 158Issue 6 June 2001Pages 865-865 Metrics History Published online 1 June 2001 Published in print 1 June 2001

Fine mapping supports previous linkage evidence for a bipolar disorder susceptibility locus on 13q32.

A region between D13S71 and D13S274 on 13q32 showed linkage to bipolar disorder (BP) based on a genome scan using markers with an average spacing of approximately 6 cM and an average heterozygosity of approximately 60% [Detera-Wadleigh et al., 1999: Proc Natl Acad Sci USA 96:5604-5609]. In an attempt to confirm this finding and achieve fine mapping of the susceptibility region, nine additional microsatellite markers with average heterozygosity of approximately 86%, located between D13S71 and D13S274, were typed in the same sample. The strongest linkage evidence was detected by multipoint linkage analysis (ASPEX program) around D13S779-D13S225 with maximum LOD score of 3.25 under Affection Status Model II (ASM II; P = 0.0000546). Data from additional nine markers resulted in a decrease of the 95% confidence interval of the linkage region. Association analyses with GASSOC TDT and ASPEX/sib_tdt detect potential linkage disequilibrium with several markers, including D13S280 (ASPEX TDT P = 0.0033, ASM I). These data generated using a higher marker density within the proposed susceptibility region strengthen the validity of our previous findings and suggest a finer localization of the susceptibility gene(s) on 13q32.

A possible susceptibility locus for bipolar affective disorder in chromosomal region 10q25--q26.

In an attempt to identify susceptibility loci for bipolar affective disorder, we are currently conducting a systematic genome screen with highly polymorphic microsatellite markers at an average marker spacing of 10 cM in a series of 75 families, comprising 66 families from Germany, eight families from Israel, and one family from Italy. The families were ascertained through index cases with bipolar affective disorder. The distribution of diagnoses is as follows: 126 individuals with bipolar I disorder, 40 with bipolar II disorder, 14 with schizoaffective disorder of the bipolar type, 40 individuals with recurrent unipolar depression, 51 with a minor psychiatric diagnosis, and two individuals with a diagnosis of schizophrenia. One hundred and seventy-one individuals are unaffected. Here, we present results from chromosome 10. Linkage analyses using a total of 33 microsatellite markers with parametric and non-parametric methods provided evidence for linkage at chromosomal region 10q25--q26. The highest two-point LOD score (2.86, theta = 0.05) was obtained for D10S217 using a dominant genetic model and a broad definition of affection status. The GENEHUNTER program localized the putative susceptibility locus within a ca 15-cM interval between markers D10S1483 and D10S217 with a maximum NPL(all) score of 3.12 (P = 0.0013). Positive linkage findings that have been reported by two independent studies further support the hypothesis of a susceptibility gene for bipolar affective disorder on 10q25-q26.

Association study between cannabinoid receptor gene (CNR1) and pathogenesis and psychotic symptoms of mood disorders.

Cannabis can induce mood change and sometimes psychotic symptoms in normal persons. In brain, the main active ingredient of cannabis acts via the cannabinoid CB1 receptor (CNR1) which is located on chromosome 6q14-15. Linkage studies have suggested the presence of a bipolar disorder susceptibility locus on chromosome 6q. In this population based association study, we tested the hypothesis that a microsatellite polymorphism in the promoter region of the CNR1 gene confers susceptibility to mood disorders and psychotic features. We genotyped the CNR1 gene is 154 mood disorder patients and 165 normal controls. The results showed that the triplet repeat polymorphism in the promoter region of the CNR1 gene was not likely to be involved in the pathogenesis or in the psychotic symptoms of mood disorders.

Association study on the DUSP6 gene, an affective disorder candidate gene on 12q23, performed by using fluorescence resonance energy transfer-based melting curve analysis on the LightCycler.

We introduced a new genotyping method, fluorescence resonance energy transfer-based melting curve analysis on the LightCycler, for the analysis of the gene, DUSP6 (dual specificity MAP kinase phosphatase 6), in affective disorder patients. The DUSP6 gene is located on chromosome 12q22-23, which overlaps one of the reported bipolar disorder susceptibility loci. Because of its role in intracellular signalling pathways, the gene may be involved in the pathogenesis of affective disorders not only on the basis of its position but also of its function. We performed association analysis using a T>G polymorphism that gives rise to a missense mutation (Leu114Val). No evidence for a significant disease-causing effect was found in Japanese unipolars (n = 132) and bipolars (n = 122), when compared with controls (n = 299). More importantly, this study demonstrates that melting curve analysis on the LightCycler is an accurate, rapid and robust method for discriminating genotypes from biallelic markers. This strategy has the potential for use in high throughput scanning for and genotyping of single nucleotide polymorphisms (SNPs). Molecular Psychiatry (2000) 5, 489-494.

A human myo-inositol monophosphatase gene (IMPA2) localized in a putative susceptibility region for bipolar disorder on chromosome 18p11.2: genomic structure and polymorphism screening in manic-depressive patients.

For several decades, lithium has been the drug of choice in the long-term treatment of manic-depressive illness, but the molecular mechanism(s) mediating its therapeutic effects remain to be determined. The enzyme myo-inositol monophosphatase (IMPase) in the phospholipase C signaling system is inhibited by lithium at therapeutically relevant concentrations, and is a candidate target of lithium's mood-stabilizing action. Two genes encoding human IMPases have so far been isolated, namely IMPA1 on chromosome 8q21. 13-21.3 and IMPA2 on chromosome 18p11.2. Interestingly, several studies have indicated the presence of a susceptibility locus for bipolar disorder on chromosome 18p11.2. IMPA2 is therefore a candidate for genetic studies on both etiology and lithium treatment of manic-depressive illness. Here we report that the genomic structure of IMPA2 is composed of eight exons, ranging in size from 46 bp to 535 bp. The promoter region contains several Sp1 elements and lacks a TATA-box, features typical for housekeeping genes. By a preliminary polymorphism screening of exons 2-8 in a sample of 23 Norwegian bipolar patients, we have identified nine single nucleotide polymorphisms (SNPs). Seven of the polymorphisms were located in the introns, one was a silent transition in exon 2 (159T>C) and one was a transition in exon 5 (443G>A) resulting in a predicted amino acid substitution (R148Q). Our data show that even in a small sample of bipolar patients, several variants of the IMPA2 gene can be identified. IMPA2 is therefore an intriguing candidate gene for future association studies of manic-depressive illness.