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Human Molecular Genetics, 2003, Vol. 12, No. 15 1907-1915
DOI: 10.1093/hmg/ddg199
© 2003 Oxford University Press

Evidence of susceptibility loci on 4q32 and 16p12 for bipolar disorder

Jenny M. Ekholm1,3, Tuula Kieseppä2, Tero Hiekkalinna1,3, Timo Partonen2, Tiina Paunio1,4, Markus Perola1,3, Jesper Ekelund1,2, Jouko Lönnqvist2, Petra Pekkarinen-Ijäs1,2,5 and Leena Peltonen1,3,*

1Department of Molecular Medicine and 2Department of Mental Health and Alcohol Research, National Public Health Institute, 00251 Helsinki, Finland, 3Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA, 4Department of Psychiatry, University of Helsinki, Helsinki, Finland and 5Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland

Received March 26, 2003; Accepted June 3, 2003


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
We performed a genome-wide scan for susceptibility loci in bipolar disorder in a study sample colleted from the isolated Finnish population, consisting of 41 families with at least two affected siblings. We identified one distinct locus on 16p12 providing significant evidence for linkage in two-point analysis (Zmax=3.4). Furthermore, three loci with a two-point LOD score >2.0 were observed with markers on 4q32, 12q23 and Xq25, the latter locus having been earlier identified in one extended Finnish pedigree. In the second stage we fine mapped these chromosomal regions and also genotyped additional family members. In the fine mapping stage, 4q32 provided significant evidence of linkage for the three-point analyses (Zmax=3.6) and 16p12 produced a three-point LOD score of 2.7. Since the identified chromosomal regions replicate earlier linkage findings in either bipolar disorder or other mental disorders, they should be considered good targets for further genetic analyses.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
Bipolar disorder (BPD) is a common psychiatric disorder characterized by mood swings of elation and depression and with a substantial lifetime risk of suicide. It affects about 1% of the worldwide adult population. Twin, family and adoption studies have shown strong genetic etiology in bipolar disorder (1). Twin studies have provided heritability estimates of 60 and 79% (2,3). However, the pattern of inheritance is complex, suggesting the involvement of both multiple genes and environmental factors. No gene has yet been identified for BPD, but several chromosomal regions have repeatedly emerged in linkage studies of families from different populations. Linked regions include 4p16 (4,5), 4q32–35 (6–8), 12q23–q24 (9–12), 16p13–q12 (13,14), 18p11 (15–18), 18q21–q23 (16,17,19–22), 21q21–q22.3 (23–25), 22q11–q13 (26) and Xq24–q26 (27,28).

Identification of genes underlying mental disorders is complicated by numerous factors typical of most common traits: unknown number of loci and pattern of inheritance, difficulties in measuring any environmental influence and perhaps most importantly for psychiatric disorders, the lack of biological diagnostic tests. Given the genetic heterogeneity of BPD, utilization of a study sample from isolated populations should reduce the genetic complexity and potentially also reduce environmental noise (29). In the isolated population of Finland potentially fewer susceptibility alleles could be expected for any complex disorder, and even environmental factors are probably less heterogeneous than in more mixed populations. Hence, the identification of predisposing loci may be simplified. In fact, genome-wide scans using family material from Finland have already been successful in identifying predisposing loci in several complex diseases such as multiple sclerosis (30), familial combined hyperlipidemia (31), type 2 diabetes (32), schizophrenia (33,34), distal interphalangeal arthritis (35) and migraine with aura (36).

In the present study we conducted a genome-wide scan in a Finnish bipolar family set consisting of 37 nuclear families and four extended pedigrees. In the first stage of the scan all 153 affected subjects from the 41 families were genotyped with 389 microsatellite markers across the whole genome. The regions that exceeded a maximum logarithm of odds (LOD) score of 2.0 were subsequently fine mapped with additional markers and by genotyping all available unaffected family members.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
The genome-wide scan with 389 highly informative microsatellite markers provided an average marker density of 7.7 cM. Two hierarchical diagnostic categories were applied in statistical analysis: BPD-I and schizoaffective disorder, bipolar type (SA-BP) (category I) and BPD-I, SA-BP, BPD-II, BPD-NOS (bipolar disorder, not otherwise specified), cyclothymic disorder and recurrent major depression (rMDD) (category II). All families included at least two siblings from diagnostic category I (Table 1).


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  		Table 1. The number of affected individuals under the two diagnostic categories
 
In the statistical analyses we separated one extended pedigree (family P101) from the remaining 40 families due to its significantly larger size, hence its considerable effect on the linkage results. This pedigree alone (family P101) has previously revealed significant evidence of linkage to chromosomal region Xq24–q27 (27,28), and was included in the genome-wide scan in search for other possible linked loci. The detailed genome-wide scan results for family P101 have been described previously (28).

The primary linkage analyses of the genome-wide scan
In the initial two-point analyses of the genome scan markers, three loci on chromosomes 4, 12 and 16 exceeded the threshold set for fine mapping (maximum LOD score Zmax>=2.0) whether or not the large pedigree P101 was included in the analyses. The strongest evidence for linkage was obtained on 16p12 with marker D16S769 (Zmax=3.4), when the large family P101 was excluded from the analyses. This significant LOD score was obtained under a dominant mode of inheritance and using the narrow diagnostic category. Altogether, 18 marker loci exceeded a maximum LOD score of 1.0, when all 41 families were included in the analyses, and 22 marker loci when the family P101 was excluded (40 families). These results are summarized in Tables 2 and 3, and schematically presented in Figure 1A and B.


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  		Table 2. The markers in the genome-wide scan resulting in pair-wise Zmax>1.0 when all 41 families were included in the analyses. Markers shown in bold were also analyzed in the fine mapping stage
 

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  		Table 3. The markers in the genome-wide scan resulting in pairwise Zmax>1.0 when family P101 was excluded from the analyses. Markers shown in bold were also analyzed in the fine mapping stage
 


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  		Figure 1. (A) Maximum two-point LOD score results of the genome-wide scan when all 41 pedigrees were included in the analyses. Bars indicate the results for individual markers. (B) Maximum two-point LOD score results of the genome-wide scan when pedigree P101 is excluded from analyses (40 families). Bars indicate the results for individual markers.

 
Analyses of denser marker maps on chromosomes 4q, 12q and 16p
The chromosomal regions that exceeded the maximum LOD score of 2.0 were further analyzed by genotyping additional markers and including all available unaffected family members (Table 4). When all 41 families were included in linkage analyses, four chromosomal regions on 4q32, 12q23, 16p12 and Xq25 produced two-point LOD scores >2.0. When family P101 was excluded from the analyses, the chromosomal regions 4q32, 12q23 and 16p12 provided suggestive evidence for linkage. Statistical evidence for the X-chromosomal region (Xq25) was mostly contributed by family P101, and this particular region has been reported in our previous paper (28). Hence, three chromosomal regions on 4q32, 12q23 and 16p12 were further analyzed in the second stage of the genome-wide scan with denser marker maps, using two-point linkage analyses, three-point analyses and association analyses.


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  		Table 4. Maximum two-point linkage results from the fine mapping stage as well as Dunn–Sidák corrected association results
 
The results of these analyses are presented in Table 4. All the fine mapped regions gained further, albeit modest, support from the additional markers in the two-point analyses. The most significant two-point LOD scores were again observed with marker D16S769. In the association analyses, which have been corrected for multiple testing, only markers on chromosomes 4 and 16 showed any trend of putative association, D4S3049 (P=0.0319) and D16S403 (P=0.0680). The three-point analyses for chromosome 4 resulted in the best maximum LOD score of 3.6 between markers D4S3049 and D4S1629, located 3 cM apart from each other. The second best three-point LOD score was obtained for chromosome 16 between markers D16S769 and D163093 (Zmax=2.7; Fig. 2A and B). To evaluate statistical significance of the best LOD scores obtained on chromosomes 4q32 (D4S1629) and 16p12 (D16S679), we performed a simulation study estimating type I error rates. For marker D4S1629 the LOD score 2.6 was once retrieved in the analysis of 10.000 replicates, producing a Dunn–Sidák corrected empirical P-value<0.0009. For marker D16S769 the LOD score 3.4 was also obtained once in the analysis of 10.000 replicates, producing a similar Dunn–Sidák corrected empirical P-value.



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  		Figure 2. (A) Three-point linkage results for chromosome 4 presented when all families are included and when pedigree P101 is excluded from analyses (40 families). (B) Three-point linkage results for chromosome 16 presented when all families are included and when pedigree P101 is excluded from analyses (40 families).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
MATERIALS AND METHODS
 REFERENCES
 
The two-stage genome-wide scan performed here was attempted to identify loci predisposing to bipolar disorder by utilizing the benefits of an isolated population and a nationwide Finnish family-set. To our knowledge, this is one of the largest genome-wide scans targeted on narrowly diagnosed bipolar disorder. Furthermore, we have followed a strict family ascertainment strategy, e.g. by ascertaining the probands nationwide using criteria of an early age-of-onset (first bipolar episode under 31 years of age) and requiring two or more hospitalizations due to BPD-I or SA-BPD. We have thus made an effort to include more genetically loaded BPD cases in this study sample. A total of 27 markers showed a maximum two-point LOD score of 1.0, three of which produced an LOD score >2.0 (4q32, 12q23 and Xq25), and one >3.0 (16p12). Regions on 4q32, 12q23 and 16p12 were fine mapped by including additional unaffected family members. One extended pedigree (family P101) was systematically analyzed separately from the remaining 40 families due to its significantly larger impact in statistical analyses. This family alone could exert a major influence on the linkage results, possible outweighing the contribution of other families. Nonetheless, it did not seem to have a major effect on autosomal locus findings. This particular family P101 was ascertained decades ago and has ever since been the primary family included in our genetic studies. Through these studies significant evidence of linkage to Xq24–q27 was found (27,28). Family P101 was included here in the statistical analyses of the genome-wide scan, since multiple affected individuals provided significant linkage and phase information for putative additional loci. However, the X-chromosomal locus seems to be the major genetic BPD locus in this particular family since no additional loci were identified in the genome-wide scan (28).

On 4q32 an interesting locus emerged from our study. Marker D4S1629 (157.99 cM) produced the best evidence for linkage when all 41 families were included in the analyses using the broad diagnostic category and dominant mode of inheritance. Three-point and association analyses further supported this finding and provided significant evidence of linkage for this particular region (Zmax=3.6 and P=0.0319, respectively). Numerous linkage findings for affective disorder have been reported on 4q (6–8), although they have been scattered over a wide region (Fig. 3). Adams et al. (7) reported a locus on 4q35 (D4S1652: 208.07 cM) with a maximum LOD score of 2.39, using a dominant model and when subjects diagnosed with BPD-I, BPD-II, SA-BP and unipolar disorder were coded as affected. Further analysis of this peak region produced significant evidence of linkage (Zmax=3.6) with marker D4S2924 (199 cM), located 41 cM away from our best marker. Recently, a genome-wide scan with 65 multiplex bipolar families, using broad diagnostic criteria, produced suggestive evidence of linkage over a 10 cM broad region flanking the same marker, D4S1629, that gave the strongest result in our study (8). Additionally, in an association study between bipolar disorder and the MN blood groups, it has been shown in several studies that the blood group NN is less frequent in bipolar patients (37–41). Significant deviation of the allele frequencies for glycophorin A (4q28.2–q31.1), located 13 Mb from our peak marker, was reported in bipolar patients when compared with unipolar, schizophrenia and control groups (P=0.006) (6). All these findings would seem to imply an important BPD locus on 4q32 (Fig. 3).



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  		Figure 3. Schematic presentation of the linkage findings reported on the chromosomal regions identified in this study. (A) Chromosome 4: Ekholm (Zmax=2.5), Adams (Zmax=3.57), Alda (P=0.006), McInnis (NPLmax=2.8). (B) Chromosome 12: Ekholm (Zmax=2.0), Craddock (Zmax=2.11), Barden (Zmax=4.9), Ewald (Zmax=3.37), Morissette (Zmax=1.46), Detera-Wadleigh (Zmax=1.24). (C) Chromosome 16: Ekholm (Zmax=3.4), Ewald (Zmax=2.5), McInnes (Zmax=1.47), Dick (Zmax=2.8).

 
For chromosome 12 our genome-wide scan produced the best LOD score for the (PAH) phenylalanine hydroxylase (PAH, 109 cM) gene, obtained using a broad diagnostic category in the affected sib-pair (ASP) analysis. 12q had attracted considerable attention because of numerous linkage reports associating it with certain psychiatric disorders (9–12,42,43). Major interest has focused on Darier's gene, ATP2A2 (ATPase, Ca2+-transporting, slow-twitch) on 12q23–q24.1, located 7 Mb telomeric from the PAH gene. In 1994, Craddock et al. (9) were the first to show evidence of linkage between bipolar disorder and ATP2A2. Barden et al. (43) confirmed the finding when obtaining a significant LOD score of 4.9 in an extended family from Quebec, while Ewald et al. (11) recorded a maximum LOD score of 3.37 in their analysis of two Danish pedigrees. Since then, several groups have provided supporting evidence in independent studies (12,42). Although Jacobsen et al. (44) recently excluded Darier's gene in their study material, this region still remains interesting in psychiatric disorders (Fig. 3).

The most significant two-point LOD score (Zmax=3.4) in our study was obtained on 16p12 with marker D16S769 (50.6 cM), using a dominant mode of inheritance and the narrow diagnostic category. Markers over a 30 cM wide chromosomal region around our linkage peak on 16p exceeded an LOD score of 0.4. This finding was further supported by the three-point analyses (Zmax=2.7) and by the suggestive association (P=0.0680). The 16p region has recently become a very prominent candidate region in bipolar disorder, even though the linkage findings are once again scattered over a relatively large region. In 1995, Ewald et al. (13) were the first to report linkage between bipolar disorder and the chromosomal region 16p13. They analyzed two extended Danish families and recorded an LOD score of 2.5 with a recessive mode of inheritance at marker D16S510 (10.36 cM). Another group, McInnes et al. (22), reported linkage among a Costa Rican family at marker D16S521 (1.08 cM) in the parametric analyses, with a maximum LOD score of 1.46. The most recent evidence of linkage in this region in bipolar disorder comes from the NIMH Study Group (14). Using affected relative pairs, Dick et al. (14) observed a 25 cM-wide peak region (D16S748, S16S2619, D16S764, D16S749) yielding maximum LOD scores above 2.0. The most distal marker, D16S749 (39.04), is located only 10 cM telomeric from our peak marker D16S769 (Fig. 3).

To summarize our results, markers on 4q32 and 16p12 provided most promising results in all the analyses conducted, the latter exceeding the level of significance for a genome-wide scan in the two-point analyses (45). Moreover, both chromosomal regions have been reported in several earlier independent bipolar linkage studies, e.g. both regions were replicated in the recent bipolar genome-wide scan conducted by NIMH (8,14). Although some of the other overlapping linkage findings, especially on chromosome 16p, are more distally scattered from our region of interest, the underlying locus might still be the same. It has been demonstrated in several simulation studies that the position of the linkage peak for complex-trait susceptibility loci is influenced by factors like adopted mode of inheritance, incomplete penetrance, locus heterogeneity and sample size. Even with 1000 sib-pairs, there is considerable error in the position of the maximum LOD scores peaks (46–48). It seems plausible that some of the findings on 16p may in fact be detecting the same susceptibility locus, despite the large variation in the location estimates in individual studies. The degree of variation in location estimates is consistent with what one might expect for linkage studies of susceptibility loci with a relatively weak effect.

One additional locus in our genome-wide scan that remains interesting, even though it failed to exceed the threshold we set for including loci in the second stage of the genome-wide scan (Z>2.0), was found on the long arm of chromosome 1 (1q31.1). Here, we observed a maximum LOD score of 1.9 with both narrow and broad diagnostic categories for marker D1S1660 (212 cM) in the ASP analysis. There are two other independent reports in this region of bipolar findings exceeding a maximum LOD score of 2.0 (Zmax=2.67, 2.42) (7,42). This chromosomal region has also received much attention in schizophrenia research. Two of the most significant schizophrenia findings on chromosome 1 were made in Finnish study samples (Zmax=3.82, 2.65) (33,49). This might imply for the presence of a ‘common psychosis gene’ enriched in the Finnish study samples. Furthermore, 3q13.1–q13.3 (10 cM) and 5p13.2–p13.1 (7 cM), as well as 1q31, showed evidence of linkage (Zmax=1.0) over extended chromosomal regions, although also not exceeding the threshold set for the second stage of the genome-wide scan. These regions therefore remain interesting as putative sites predisposing to bipolar disorder.

The two most promising results on 4q and 16p were obtained with different diagnostic categories, which indicates that the possible underlying genes might predispose to different traits of the bipolar spectrum. The most significant finding on 16p12 was obtained with the narrow diagnostic category, including only BPD-I and SA-BPD as affected. It may be that this particular locus in our families discloses underlying susceptibility alleles for a more ‘pure’ bipolar disorder, perhaps with increased risk for psychotic symptoms. Nonetheless, the results concerning this region are contradictory, some groups retrieve evidence of linkage with the broad diagnostic spectra, and some using the narrow ones. On the other hand, 4q32 has showed evidence of linkage for broader diagnostic categories in the vast majority of studies conducted, including ours. Our results agree with the view of bipolar disorder as a complex disease with several genes predisposing to it. These genes are likely to influence different traits of the disorder; those concerning the broad spectrum may predispose to affective ability in particular and those with influence on the narrow spectrum to psychotic symptoms in specific.

Although, genome-wide scans in bipolar disorder have so far indicated several regions on the genome that have met the criteria for genome-wide signifiance proposed by Lander and Kruglyak (45), only a few of these significant findings have been replicated in other studies with independent study samples (50). Our genome-wide scan revealed three chromosomal regions on 4q32, 12q23 and 16p12, which all replicated earlier linkage findings in BPD, implying their general significance (6–14). Chromosomal regions 4q32 and 16p12 are emerging as the most interesting loci and will thus be further analyzed with single nucleotide polymorphisms in the search for underlying genetic factors predisposing to bipolar disorder.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
REFERENCES
 
Family and phenotype ascertainment
The detailed ascertainment strategy is described elsewhere (28). Briefly, prior to ascertainment, two hierarchical diagnostic categories were formed: (i) BPD-I and SA-BPD; and (ii) BPD-II, bipolar NOS, cyclothymic disorder and rMDD. With permission from the Ministry of Social Affairs and Health, national medical registers were used to collect all bipolar families nationwide that included at least two subjects diagnosed with diagnostic category I. Two psychiatrists, unaware of the family relationships, made independent diagnoses of the subjects based on all available case notes according to DSM-IV diagnostic criteria. Altogether, 41 Finnish bipolar families, of which four were extended, were analyzed in this study.

Genotyping
The 389 microsatellite markers genotyped in the first stage of the genome-wide scan were all di-, tri- or tetranucleotide repeats selected from the Marshfield Medical Research Foundation (Weber sets 6 and 9). The average intermarker interval was ~7.7 cM and the maximum 20 cM. Map positions were derived primarily from the Marshfield integrated map.

Genomic DNA was extracted from venous blood samples using a standard protocol. The fluorescently labeled PCR products were electrophoretically separated, either with an automated laser fluorescence DNA sequencer ABI 377 (Perkin-Elmer), using GENESCAN (version 2.1) fragment analysis software, or with an LI-COR DNA 4200 Genetic Analyzer (LI-COR Biosciences). The alleles were identified using the GENOTYPER program (version 2.0; Perkin-Elmer) or genotyping software SAGA version 5.1 (LI-COR Biosciences).

Statistical analyses
Prior to statistical analyses, extended mendelian error-checking with PedCheck (51) and genotyping error-checking were performed with SimWalk2 using the genotype mistyping option (52) and Mendel (53). SimWalk2 programs utilize the Markov chain Monte Carlo algorithm in order to report the overall probability of mistyping at each observed genotype.

The data were analyzed using the affected only (AO) model with the two different diagnostic categories: (i) BPD-I, and SA-BP; and (ii) BPD-I, SA-BP, BPD-II, BPD-NOS, cyclothymic disorder and rMDD. In the AO model all linkage information on the affected individuals was extracted in order to avoid problems caused by incomplete penetrance of the disease and genetic ambiguity of the unaffected phenotype. Both dominant and recessive modes of inheritance were tested, with penetrance of the disease allele set at 0.9. In the narrow diagnostic category a disease allele frequency of 1% and a phenocopy rate of 0.1% were used, and for the broader spectrum a disease allele frequency of 5% and a phenocopy rate of 4.5% were used. We also analyzed one particularly extended pedigree (family P101) separately from the other 40 families, because of its significantly larger size (n=64).

In the first stage of the genome-wide scan the preferred primary analyses methods were two-point linkage analyses with locus homogeneity, which were carried out using the MLINK program from FASTLINK 4.1P package (54), as well as locus heterogeneity using the HOMOG program (55). In addition two-point non-parametric statistics were also calculated by adopting the ASP analysis. This calculates a likelihood-based test statistic almost equivalent to an LOD score calculated with a simple recessive inheritance model in nuclear families, and it also assumes that segregation from both parents is independent. Sib-pair analysis was performed by means of the SIBPAIR program (30). For the genome-wide analysis of genotype data we utilized the AUTOSCAN 1.0 program (56) to automate the use of the ANALYZE package.

In the fine mapping stage the association analyses and three-point analyses were performed for these selected regions. The association analyses were performed using the PSEUDOMARKER program (57), which is a linkage analysis software for joint linkage and/or linkage disequilibrium analysis. We utilized linkage disequilibrium given linkage statistics of the program, which calculates association free of linkage. The association results were corrected for multiple testing using the Dunn–Sidák correction [{alpha}'=1-(1-{alpha})k] (58). The MLINK program was also used to perform three-point analysis. This analysis was not performed with flanking markers moving the disease across the map, because of the known propensity for false exclusions in that method (59). To avoid the known negative side effects of multipoint analysis, we performed a multipoint analysis in which the markers were placed in a fixed order and in which the disease locus was allowed to vary outside the map of markers (60). Using this method, we found that meioses uninformative for some markers can be scored for nearby markers, thus allowing all meioses in all families to be scored in the analyses. A simulation study estimating type I error rates was carried out by the SLINK program for markers D4S1629 and D16S769 (61,62). The exact same condition under which the best LOD scores were obtained for these two markers were reproduced in the simulations, e.g. the same family structures, statistical models and allele frequencies were used. The markers were simulated 10 000 times under null-hypothesis ({theta}=0.5), subsequently it was elucidated how many times the same or exceeding maximum LOD scores were retrieved by analyzing these 10 000 replicates using the ANALYZE program. The empirical P-values obtained were then Dunn–Sidák corrected.


   ACKNOWLEDGEMENTS
 
We are very grateful to the members of the families who participated in the study. We also thank Mari Sipilä, Carina von Schantz, Elli Kempas, Maria Lindfors, Kristina Pelli and Maija Parkkonen for their excellent technical assistance. This study was supported by grants from the Academy of Finland, the Finnish Cultural Foundation (Jenny Ekholm) and Emil Aaltonen Foundation (Tero Hiekkalinna), which are gratefully acknowledged.


   FOOTNOTES
 
* To whom correspondence should be addressed. Tel: +358 947448393; Fax: +358 947448480; Email: leena.peltonen{at}ktl.fi Back


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 

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