Bipolar disorder (BPD) is a common disorder characterized by episodes of mania, hypomania and depression. The genetic background of BPD remains undefined, although several putative loci predisposing to BPD have been identified. We have earlier reported significant evidence of linkage for BPD to chromosome Xq24–q27.1 in an extended pedigree from the late settlement region of the genetically isolated population of Finland. Further, we established a distinct chromosomal haplotype covering a 19 cM region on Xq24–q27.1 co-segregating with the disorder. Here, we have further analyzed this X-chromosomal region using a denser marker map and monitored X-chromosomal haplotypes in a study sample of 41 Finnish bipolar families. Only a fraction of the families provided any evidence of linkage to this region, suggesting that a relatively rare gene predisposing to BPD is enriched in this linked pedigree. The genome-wide scan for BPD predisposing loci in this large pedigree indicated that this particular X-chromosomal region provides the best evidence of linkage genome-wide, suggesting an X-chromosomal gene with a major role for the genetic predisposition of BPD in this family.
Bipolar disorder (BPD) is a common mental disorder with a lifetime risk of 0.6–1.2%.1 BPD is thought to be equally frequent in both sexes and no ethnic differences have been observed.1 The clinical phenotype includes episodes of both mania and depression or only mania. Epidemiological studies together with increasing evidence based on genome-wide scans and targeted DNA studies indicate strong genetic predisposition in BPD.2,3,4,5,6,7 Although the genetic background of bipolar disorder is poorly characterized, BPD most likely represents a polygenic disease.
The process of identifying genes underlying mental disorders faces many difficulties due to complex patterns of inheritance, lack of diagnostic biological tests and strong confounding or interacting influence of environmental factors. One possibility to simplify the complexity is to collect study samples from genetic isolates with potentially fewer predisposing alleles and more homogeneous environment.8 The Finnish population originates from a limited number of founders and has remained relatively isolated, resulting in increased genetic homogeneity. In fact, genome-wide scans using family material from internal isolates of Finland have already been successful in the identification of predisposing loci in several complex illnesses such as multiple sclerosis,9 familial combined hyperlipidemia,10 type 2 diabetes11 and schizophrenia.12 Most of the identified loci have also been found in more heterogeneous populations, emphasizing their general significance.
We have earlier reported a linkage between bipolar disorder and markers on Xq24–q27.1.13 In that study, a lod score of 3.54 was obtained with marker DXS994 in a single extended Finnish family (P101).13 Here we report the data of the fine mapping of this 13 cM wide critical region on the X-chromosome in a population-wide Finnish study sample of BPD families. Further, we performed a genome-wide scan for BPD loci in the original multiplex pedigree to address the issue of genome-wide significance of this X-chromosomal finding.
Materials and methods
Collection of study sample
The National Hospital Discharge Register was used to identify all patients born between 1940 and 1969 with a diagnosis of bipolar disorder. The register was established in 1968, and it indexes all admission and discharge dates and primary diagnoses for inpatient stays at public and private hospitals. Before 1987 the International Classification of Diseases, version 8 (ICD-8) criteria were used for the diagnosis. Thereafter psychiatric diagnoses have been coded according to the Finnish version of ICD-9,14 using the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Version III Revised (DSM-III-R). To identify first-degree relatives of probands, we used the National Population Register, containing information on place of birth, residence, marital status and first-degree relatives for each Finnish citizen. While our aim was to select a family sample which included individuals who were more genetically susceptible, we searched for the first-degree relatives of those probands, who had their first bipolar episode under 31 years of age. Information on these relatives was linked to the National Hospital Discharge Register to obtain data on their hospital treatments. An extensive search was made for all available records from hospitals, clinics, general practitioners, reports from medico-legal experts and various other sources that might provide diagnostic information.
Two psychiatrists, being unaware of the family relationships, made independent diagnoses of the subjects based on all available case notes according to DSM-IV diagnostic criteria for bipolar disorder type I. Two Scandinavian studies have reported the validity of a lifetime diagnosis of bipolar disorder in the hospital discharge register to be over 0.90.15,16 When diagnoses, based on case notes, were compared to the diagnoses confirmed by structured interviews in the Finnish twin-study, the accuracy was 0.97 (95% Confidence Interval 0.92–0.99).16 Thus we think that the two-step method of using both register information and information from medical records provides both valid and cost-effective methods to ascertain bipolar cases.
Requests to participate in the study were sent to the probands fulfilling BPD diagnostic criteria through their treating psychiatrist. If permission was obtained from the proband, the family members were contacted. In addition, we have included six families from a population-based study on schizophrenia in Finland. In these families there was at least one member suffering either from bipolar disorder or schizoaffective disorder, bipolar type.
The permit for the register searches was obtained by the ethical committee of the National Public Health Institute, and all blood samples were taken in accordance with the Helsinki Declaration and its amendments.
The family material consisted of 341 individuals from 37 nuclear families (sibpair families) and from four extended families, where the largest family consisted of four generations with 18 affected subjects. In all families, there were a total of 154 affected individuals, including all diagnostic categories, of whom 81 were males and 73 females. The average age in the study sample was 55.14 years. Five hierarchical diagnostic categories were applied prior to statistical analysis: (I) bipolar disorder type I; (II) schizoaffective disorder, bipolar type; (III) bipolar disorder type II, bipolar NOS (not otherwise specified) and cyclothymia; (IV) recurrent major depressive disorder; (V) other mental disorders (Table 1).
Genomic DNA was extracted from venous blood samples using a standard protocol.17 We studied eight microsatellite markers (DXS737, DXS1047, DXS994, HPRT, DXS1062, DXS6854, DXS102 and DXS984) on chromosome Xq24–q27 on a 13 cM or 12.8 Mb (http://genome.ucsc.edu; Aug. 6, 2001 Freeze) interval. The average intermarker distance was 1.6 cM. All microsatellite markers were amplified using PCR. The fluorescently labeled PCR products were electrophoretically separated on an automated laser fluorescence DNA sequencer ABI 377 (Perkin-Elmer, Welleslay, MA, USA), with the GENESCAN (version 2.1) fragment-analysis software. The alleles were identified using the GENOTYPER program (version 2.0) (Perkin-Elmer). Two researchers checked independently the interpretation of alleles. The order of the markers was confirmed using radiation hybrid mapping.18,19 The marker order was also in accordance with the sequence assembly obtained by the human genome browser at UCSC (http://genome.ucsc.edu/), only marker DXS6854 could not be found by sequence.
In the genome-wide scan the 398 microsatellite markers that were genotyped were all di-, tri- and tetranuclotide repeats selected from the Marshfield Medical Research Foundation (Weber set 6 and 9). Map positions were derived primarily from the Marshfield integrated map. The genomic DNA was extracted with the same protocol as earlier mentioned.17 The fluorescently labeled PCR products were electrophoretically separated, either on an automated laser fluorescence DNA sequencer ABI 377 (Perkin-Elmer), with the GENESCAN (version 2.1) fragment-analysis software or by LI-COR DNA 4200 Genetic Analyzer. The alleles were identified using the GENOTYPER program (version 2.0; Perkin-Elmer) or by the genotyping software SAGA version 5.1.
The genotype data were analyzed using five different diagnostic categories as described above using the affected only (AO) model. In the AO model, all unaffected subjects are treated as unknown in order to avoid problems caused by incomplete penetrance and genetic ambiguity of the unaffected phenotype. In parametric linkage analysis, we tested both the dominant and recessive mode of inheritance. The lifetime prevalence of BPD is 0.6–1.2% in various populations,1 and thus the prevalence of BPD is set at 1% in our analysis.
In the statistical analyses we used the ANALYZE package,20 an accessory program to the LINKAGE package, which encloses MLINK, HOMOG program, SIBPAIR program, HRR and TDT. For the parametric analysis a disease-allele frequency of 0.005 was used for the dominant model and 0.100 for the recessive model, allowing a phenocopy rate of 0.1%. MLINK was used for parametric linkage analysis. The genetic heterogeneity between families was tested by the HOMOG program.9,21 The ASP (Affected Sib Pair) analysis was performed by SIBPAIR program.9 For association analysis we performed HRR analysis (Haplotype Relative Risk) in which the number of transmitted alleles is compared with the number of nontransmitted alleles in the parent–child trios.22 The TDT (Transmission Disequilibrium Test) was also used to test for family-based association by looking at the transmission of alleles from heterozygous parents to their affected children.23 All the analyses, including the association analyses were performed using all the sibships in the pedigree structures.
Nonparametric and parametric multipoint analyses were performed using only the diagnostic categories that gave the highest lod score in the two-point analysis. These multipoint analyses were done using the GENEHUNTER program.24
A simulation study of the diagnostic categories I–II was carried out by the SIMULATE25 program to assess the empirical P-value. The SIMULATE program simulates genotypes in family members for a map of linked markers unlinked to a given affection status locus.
We fine mapped the Xq24–q27.1 region by genotyping eight X-chromosomal markers covering a 13 cM (12.8 Mb) region of interest flanking the marker DXS994 that gave the most significant result in the previous study,13 in 41 Finnish bipolar families. Family P101, which in the previous study gave a lod score of 3.54 to marker DXS994 in two-point linkage analysis was also included in this study.13 To test for the general impact of this X-chromosomal region for genetic risk of bipolar disease in the rest of the families, family P101 was analyzed separately.
Analysis of the fine map markers in pedigree P101
The BPD pedigree P101 consists of 61 individuals and displays affective disorder in at least four generations.13 The number of genotyped affected individuals was eight in the diagnostic categories I–II. In fine mapping of eight markers on Xq24–q27, a maximum lod score of 1.89 was obtained (Table 2) in the two-point analyses with marker DXS994 at θ = 0.0 using dominant mode of inheritance for the diagnostic category I–II. In the ASP analysis none of the markers produced a lod score >1.0. Furthermore, a trend of association was found in the TDT analysis with two markers approximately 5 cM apart, DXS737 (P-value = 0.06) and HPRT (P-value = 0.004). The significance of this weak association is further challenged by the fact that HRR analysis did not show any evidence of association for these markers. In multipoint analysis of markers over the 117 cM region, a multipoint lod score of 4.5 was obtained for family P101, peaking over a wide interval of 27 cM (Figure 1). This confirms the X-chromosomal haplotype in the pedigree P101, reported in the earlier study.13 The haplotype analysis revealed that all the genotyped family members affected by bipolar disorder type I (n = 8) carry the same haplotype in one of their chromosomes with no obligatory recombination events within the 13 cM (12.8 Mb) region of interest. Among 44 unaffected family members, this haplotype was observed in six unaffected females and one unaffected male.
Analysis of the fine map markers in the 40 new pedigrees
The other 40 analyzed BPD families produced a maximum lod score of 1.34 (alpha (α) = 0.37) with marker DXS1047 that locates in the immediate vicinity (1.2 cM) of DXS994. Out of 40 families, 15 were provided some linkage information (Zmax > 0.2 when θ = 0.0), 21 were not linked (Zmax < 0.2 when θ = 0.0) and four families were uninformative for marker DXS1047. The linkage result was retrieved using dominant mode of inheritance and diagnostic categories I–II at θ = 0.0. Marker DXS1047 was the only marker which exceeded a lod score >1.0 in two-point analysis (Table 2). Under homogeneity the same marker produced a lod score of 1.12 at θ = 0.2. In the ASP analysis a lod score of 1.25 was obtained with marker DXS1047 when using diagnostic category I–II. In the TDT analysis, marker DXS1062, located 9 cM telomeric from marker DXS1047, was the only marker providing any trend of association (P-value = 0.08). However, HRR provided no evidence for association for any of the markers. Multipoint analyses for 40 nuclear families using the GENEHUNTER program,24 resulted in a lod score peak of 1.61 at DXS1047 (Figure 1). When haplotypes were constructed from genotypes of the markers over the 13 cM (12.8 Mb) fine map region (DXS737–DXS984) using the GENEHUNTER24 program, no shared haplotype could be observed among affected of the different families.
Combined analyses of the fine map data
In the combined data analysis of all 41 families (including family P101), we obtained suggestive evidence of linkage with marker DXS1047. The dominant model in linkage analysis gave a maximum two point lod score of 2.78 using diagnostic categories I–II (bipolar disorder type I and schizoaffective disorder, bipolar type) with marker DXS1047 at θ = 0.0, when allowing for locus heterogeneity (α = 0.43). The maximum lod score for the same marker under locus homogeneity was 2.18 at θ = 0.18. In the ASP analysis a maximum lod score was 1.49 for marker DXS1047 under diagnostic category I–II. The results of the dominant model are shown in Figure 2 and Table 3. In multipoint analyses with the GENEHUNTER program with the combined data using diagnostic categories I–II, the peak lod score of 2.66 was obtained at marker DXS1047 (Figure 1). Markers HPRT and DXS1062, 1.6 cM apart produced a trend of association in TDT, producing P-values of 0.03 and 0.08, respectively. Again, the HRR analysis did not provide any evidence for association.
To evaluate statistical significance of the best lod score obtained from the combined data analyses we performed a simulation study in our family material using the SIMULATE program. In the analysis of 1000 replicates, no lod scores above 2.78 were obtained, this producing an empirical P-value <0.001.
To address the issue of the genome-wide significance of the putative linkage finding on X-chromosome, we performed a genome-wide search for potential BPD loci in the P101 pedigree. The most significant result among 386 markers throughout the genome was obtained with marker DXS1047 on Xq25, with a two-point lod score of 1.76 (Figure 3), the next best region was found on 4q32 that provided a lod score of 1.6. Six additional regions produced two-point lod score >1 on 12q15 (Zmax = 1.03), 19q13.43 (Zmax = 1.04), 18p11.31 (Zmax = 1.04), 7q31.31 (Zmax = 1.06), 5q31.1 (Zmax = 1.06) and 10q22 (Zmax = 1.28) (Figure 4).
We have earlier reported linkage to bipolar disorder on chromosome Xq24–q27.1 in one extended Finnish pedigree with numerous affected individuals from a subisolate of the late settlement region in Finland.13 A haplotype covering a 19 cM region on Xq24–27.1 was found to segregate with the disorder in this family.13 To test the significance of this X-chromosomal region in other Finnish bipolar families and to monitor for potential haplotype sharing between families on Xq24–q27.1, we fine mapped the core region around the marker DXS994 in a study sample of 341 individuals from 41 bipolar families. The maximum lod score of 2.78 was obtained with DXS1047 in the whole study sample, including the large pedigree P101. When only 40 new families were included in the analyses, a lod score of 1.34 was obtained. According to statistical guidelines for judging significance of linkage reports in complex disorders, a threshold for a significant lod score in genome-wide scans has been suggested to be ∼3.6 and for confirmation a lod score of 1.2.26 Our previous and the current study meet these criteria, with the initial maximum lod score finding being 3.54 and the highest lod score for the 40 new families in this study being 1.34. The fact that the most significant results were obtained with a narrow diagnostic model is also encouraging since fewer phenocopies can be expected with the narrow diagnostic model. Locus heterogeneity in the Finnish study sample is obvious, an alpha value of 43 was obtained in the study sample with marker DXS1047. However family P101 contributed most significantly to the obtained lod score, which was expected due to its size and informativeness.
When only including family P101 in the affected only analysis, a maximum lod score of 1.89 was obtained with marker DXS994. For this marker the family P101 gave a somewhat lower lod score in this study (1.89 vs 3.54) when compared with our previous study. This is mostly due to more robust statistical parameters used here. In the previous study, age-dependent liability classes were applied opposite to the affected only (AO) model applied here. In the previous study the linkage analyses for the same marker under the AO model resulted in a lod score of 2.17 at θ = 0.0. The 0.28 difference in the maximal two-point lod scores between the two studies can be explained by two additional genotyped individuals and two diagnoses changed in reassessment (one from status I to status V and the other one from status II to status I). The multipoint analysis gave a lod score of 4.5 for family P101 when additional markers from the previous study were included (Figure 1) and restricted the linked region for this specific family to Xq24–q27. All individuals in the pedigree affected by bipolar disorder type I shared the same 13 cM (12.8 Mb) haplotype reaching from marker DXS737 to DXS984. This indicates that the bipolar disease in this family P101 is linked to Xq24–q27 and that a gene predisposing this family to bipolar disorder is very likely located in this X-chromosomal region. Also in the genome-wide scan with family P101, this region is the most promising one genome-wide. Another potentially interesting region for this family could exist on 4q32 based on the initial data of the genome scan.
The 40 nuclear families were analyzed in this study in order to examine if the linkage found in family P101 originating from a subisolate in Finland, could be replicated. These smaller pedigrees were collected nationwide, but only weak evidence of linkage could be attained from these families. In closer analysis of the families indicated, only a fraction of Finnish BPD-families show even suggestive evidence of linkage to this region. The interpretation of this finding is complicated by the varying size of the families, since all families were not as extended and informative as the pedigree P101. However, this particular locus does not represent the major locus in this collection of Finnish BPD families.
It is interesting that some of the strongest linkage findings in bipolar disorder have been in single large pedigrees under the assumption of Mendelian inheritance, for example on chromosomes 4,27 12,7,28,29 18,30 212 and X.13 Such linkage findings from large pedigrees have not always been replicated in genome-wide scans of affected sibling pairs or large collections of small families, a finding that is predicted if substantial locus heterogeneity is present.31 Studies of families recruited for linkage analysis provide support for a Mendelian subset of bipolar disorder. Rare genes with high impact are obviously more readily detected in single large pedigrees than in collections of many small pedigrees.31
Several studies have suggested the involvement of a X-chromosomal region in BPD,32,33,34,35,36 however the methology of the earlier studies has been criticized.13,37 Genome-wide scans have provided additional evidence for linkage findings on this X-chromosomal region Xq24–q28. Liu et al have reported preliminary results suggesting linkage to exactly the same region on Xq24–q27.1 as in our family.38 Stine and colleagues found excess sharing of alleles at marker DXS1047 and GATA31E08 among affected BPDI, BPDII and SAM sibpairs, especially in sister-sister pairs.39 These three studies all imply the involvement of the same X-chromosomal region in bipolar disorder. There are several promising candidate genes in this region that have been of interest in the genetic research of bipolar disorder as glutamate receptor subunit 3 (GRIA3)40 and synaptobrevin-like 1 protein (SYBL1),41 but no functional mutation has been found. Our results imply that a susceptibility gene to BPD on Xq24–q27 represents a significant contributor of the genetic background only in some rare Finnish families. Further steps are now being undertaken to test for association between BPD and allelic SNP-haplotypes of regional candidate genes.
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We are very grateful to the participation of the members of the families involved in the study. We also want to thank Mari Sipila for the excellent technical assistance. In addition, the contribution of Drs Jesper Ekelund, Iiris Hovatta, Tero Hiekkalinna, Per-Erik Bredbacka, Lea Muhonen and Jari Seppälä have been invaluable.
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Ekholm, J., Pekkarinen, P., Pajukanta, P. et al. Bipolar disorder susceptibility region on Xq24–q27.1 in Finnish families. Mol Psychiatry 7, 453–459 (2002) doi:10.1038/sj.mp.4001104
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