Human Molecular Genetics, 2001, Vol. 10, No. 15 1611-1617
© 2001 Oxford University Press
Chromosome 1 loci in Finnish schizophrenia families
1Department of Molecular Medicine and 2Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland, 3Millennium Pharmaceuticals Inc., Cambridge, MA, USA, 4Department of Human Genetics and 5Department of Biomathematics, UCLA, Los Angeles, CA, USA
Received April 23, 2001; Revised and Accepted May 23, 2001.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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We have earlier reported evidence for linkage to two regions on chromosome 1q32–q42 in schizophrenia families collected for two separate studies in Finland. Here we report the results of a fine mapping effort aimed at further definition of the chromosomal region of interest using a large, population-based study sample (221 families, 557 affected individuals). Most affecteds (78%) had a DSM-IV schizophrenia diagnosis and the remaining had schizophrenia spectrum disorders. We genotyped a total of 147 microsatellite markers on a wide 45 cM region of chromosome 1q. The results were analyzed separately for families originating from an internal isolate of Finland and for families from the rest of Finland, as well as for all families jointly. We used traditional two-point linkage analysis, SimWalk2 multipoint analysis and a novel gamete-competition association/linkage method. Evidence for linkage was obtained for one locus in the combined sample (Zmax = 2.71, D1S2709) and in the nuclear families from outside the internal isolate (Zmax = 3.21, D1S2709). In the families from the internal isolate the strongest evidence for linkage was obtained with markers located 22 cM centromeric from this marker (Zmax = 2.30, D1S245). Multipoint analysis also indicated these loci. Some evidence for association with several markers was observed using the gamete-competition method. Interestingly, the strongest evidence for linkage in the combined study sample was obtained for marker D1S2709, which is an intragenic marker of the DISC1 gene, previously suggested as a susceptibility gene for schizophrenia. These results are consistent with the presence of susceptibility gene(s) in this chromosomal region, a result also implied in other recent family studies of schizophrenia.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Schizophrenia is a severe mental disorder with a lifetime prevalence of
1% in most studied populations. The disorder has been shown to have a high heritability, 80% in the Finnish population (1). We previously reported linkage of schizophrenia to chromosome 1q32.2–q41 in families collected from a sub-isolate within the late settlement region of Finland (2), and similarly in a separate study sample consisting of affected sib-pairs across Finland (3). Chromosome 1q is emerging as a highly interesting candidate region for psychosis-predisposing loci. A recent report indicated linkage of bipolar disorder to 1q32 (4). For schizophrenia Brzustowicz et al. (5) reported strong evidence for linkage to chromosome 1q21–q22 and more recently, Gurling et al. (6) also reported evidence for linkage of schizophrenia to marker D1S196, which in the genetic map is in the immediate vicinity of the linkage marker reported by Brzustowicz et al. (5). Further, a balanced translocation between chromosome 1q43 and 11q21 has been shown to co-segregate with schizophrenia in a Scottish kindred (7). In our genetic studies of Finnish schizophrenia families (2,3) the regions showing strongest evidence for linkage were relatively broad with markers over a 15 cM region of chromosome 1 showing evidence for linkage both in the multiplex families collected from an internal sub-isolate and in the nationwide sib-pair collection. Further, the markers revealing strongest evidence for linkage in the internal isolate and in the sib-pair collection were some 19 cM apart. To restrict the critical chromosomal region we genotyped a dense marker map (average spacing <0.5 cM, Table 1) over the 45 cM region on 1q in a larger study sample of schizophrenia families collected from Finland.
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Isolated populations like the Finnish (8,9) have been shown to offer a definitive advantage in the identification of monogenic trait loci (10,11). Several studies carried out in this population suggest that this may also be the case for some genetically complex diseases (12–15). Because of the small number of founders and genetic isolation, genetic homogeneity of a given complex trait is expected to be higher than in an admixed population and the interval of shared allelic haplotype is assumed to be detectable—at least in sub-isolates and in a sub-fraction of disease alleles originating from a common ancestor.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Two-point linkage analyses
The results are presented separately for three different study samples: (i) extended families with well established genealogical data from the internal isolate of the late settlement region of Finland; (ii) the generally smaller families originating from the rest of Finland (referred to as ‘nuclear families’ hereafter); and (iii) the two study samples combined.
The results of the two-point analyses for 94 of the 147 analyzed markers are given in Figures 1–3 for the model giving the strongest evidence for linkage in each study sample. The results for all markers and all inheritance models are provided at our website (www.ktl.fi/lmgo/lmgo_wwwpub.htm).
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For the combined sample, the highest LOD score was obtained for marker D1S2709 (LOD = 2.71), adopting the dominant inheritance model and treating individuals with schizophrenia spectrum disorders (LC3) as affected. Several markers in a 2 cM region around this marker gave two-point LOD scores >1 (Fig. 1).
For the families from the internal isolate of Finland, marker D1S245 gave a LOD score of 2.30, again adopting the dominant model classifying all individuals with schizophrenia spectrum disorders as affected (LC3; Fig. 2). This region is the same as the one identified in the previously published genome-wide scan in this sub-isolate (2). Evidence for co-segregation was also seen for marker D1S1728 (LOD = 2.44, dominant model, LC3, not shown in figure), which is >100 cM proximal of D1S245.
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For the nuclear families from the rest of Finland, marker D1S2709 gave the strongest evidence for linkage (LOD = 3.21), using a dominant model treating individuals with spectrum diagnoses as affected (LC3; Fig. 3). This marker is within 3 cM of the peak identified in our previously published sib-pair genome-wide scan (3). No evidence for linkage to the position identified in the internal isolate was found in these families.
The gamete-competition model showed results significant at the 5% level for 17% of the markers, whereas this would have been expected for only 4% of the markers by chance based on a gene-dropping simulation. The strongest evidence for association and linkage for the combined study sample was seen with marker D1S225 (P = 0.009). The evidence for association and linkage to this marker emerged exclusively from the nuclear families (P = 0.005), whereas the families from the internal isolate showed no evidence for association. Marker D1S251, which is closely linked to D1S225, also showed some evidence of association and linkage in both samples separately (P = 0.041 and 0.052 in the internal isolate and nuclear families, respectively), but not in the combined sample (P = 0.222). This marker showed over-transmission of a different allele in the internal isolate to that in the nuclear families. These two markers, D1S255 and D1S251, are within 1 cM of marker D1S2709, which gave the strongest evidence for linkage in this study. The results of the gamete-competition test for all 147 markers can be found on our homepage (www.ktl.fi/lmgo/lmgo_wwwpub.htm).
One of the markers we genotyped (D1S484) is within 2 cM of the marker that gave the strongest evidence for linkage to schizophrenia in a recent study performed in Canadian families (5). This particular marker provided only weak evidence for linkage (LOD = 0.88) in our combined sample for the dominant model treating schizophrenia and schizoaffective disorder as the affected phenotype (LC2, not shown in figure). The same marker resulted in weakly positive LOD scores both in nuclear families and in families from the internal isolate when analyzed separately (LOD = 0.64 and 0.29, respectively). For this marker the gamete-competition model showed some evidence for association and linkage in the families from the internal isolate (P = 0.02), but not in the rest of the study sample.
Multipoint analyses
The results for the SimWalk2 multipoint analyses are shown in Figures 4 and 5. For the 10 markers around D1S245 that showed evidence for linkage in the two-point analysis of the families from the internal isolate, statistic B of SimWalk2 gave the strongest evidence for linkage close to marker D1S245 [–log10(P) = 3.46; Fig. 4] in families from the internal isolate. Statistic A of SimWalk2 gave somewhat weaker evidence for linkage in this region [–log10(P) = 1.98]. For this region the nuclear families from the rest of Finland did not show evidence for linkage. The largest pedigree from the internal isolate, with 31 affected family members, provided the majority of the statistical evidence for linkage, while the rest of the families from this restricted geographical area contributed very little.
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For the 10 markers flanking marker D1S2709, which gave the strongest evidence for linkage for the total study sample in the two-point analysis, statistic B of SimWalk2 showed the strongest evidence for linkage close to marker D1S2709 (–log10(P) = 1.94). The evidence for linkage was obtained almost exclusively from the nuclear families. Statistic A provided slightly less evidence for linkage.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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We have genotyped a dense marker map, consisting of 147 markers with an average intermarker distance <0.5 cM, in a 45 cM region of chromosome 1 previously identified by our two genome-wide scans (2,3). The present study was carried out in 221 extended families consisting of 284 nuclear families. Of these nuclear families, 136 had been represented in the previous genome scans (2,3), whereas 148 nuclear families have not been included in the previous studies. However, even for the previously included families, additional individuals have been genotyped for this study. Specifically, the number of genotyped individuals is 1250, while the previous studies used 550 and 160 individuals, respectively. Thus, we do not separate our data sets into ‘original’ and ‘replication’ partitions.
The results from the combined study sample of 221 extended families showed linkage to an 8 cM region on chromosome 1q flanked by markers D1S439 and D1S446. This is consistent with the finding from the previously published genome-wide scan performed in a sib-pair sample collected from the whole geographical region of Finland (3). The sample size in the present study is substantially larger than in the previous study, and the evidence for linkage is somewhat stronger even though genetic heterogeneity of the study sample is most probably increased since the analyzed families were collected more evenly from all regions of Finland than in either of the previous studies. Any putative gene in this chromosomal region therefore seems to be a susceptibility gene distributed in most geographical regions of Finland and not only a gene enriched in a specific sub-isolate. Importantly, the marker providing the strongest evidence for linkage (D1S2709) is located within an intron of DISC1, a gene previously suggested as a candidate gene for schizophrenia (16).
Analysis of only nuclear families from all over Finland yielded results similar to those for the combined sample, indicating that most of the statistical power of our sample is produced by these widely dispersed families. The strongest evidence for linkage was seen for the dominant model treating all schizophrenia spectrum conditions as affected. This is consistent with the published genome-wide scan results in schizophrenic sib-pairs from Finland (3).
When only the families from the internal isolate were analyzed, the strongest evidence for linkage was observed some 21 cM centromeric to the peak in the combined sample. This again is consistent with the results from the original genome-wide scan in a smaller set of families from the internal isolate (2). In this region the dominant model treating all schizophrenia spectrum conditions as the affected phenotype gave the strongest evidence for linkage.
The present results produced in a large, population-wide study sample using a dense set of markers on 1q provide support for the original reports from two independent genome-wide scans of familial schizophrenia in the Finnish population (2,3). There are two regions that show evidence for linkage over several adjacent markers, and the regions are 21 cM apart on the genetic map of 1q. The evidence for the more centromeric locus comes almost exclusively from families of the young, inbred internal isolate, whereas evidence for the other, more distal, locus comes predominantly from families ascertained outside this isolate. Further, as most of the linkage evidence for the more centromeric locus comes from a single large pedigree from the internal isolate, the loci might truly represent two separate predisposing loci or alternatively reflect the well known feature of the variation in the LOD score peak in complex traits due to incorrect inheritance parameters or hidden genotyping errors (17,18). We presently favor an interpretation of our data as reflecting one schizophrenia locus on chromosome 1 in our population-wide study sample. However, we cannot exclude the possibility of two susceptibility loci on 1q, one of them being enriched in the regional subisolate. Unfortunately, this being the case, the present study did not further narrow the critical chromosomal region on 1q, but did slightly increase statistical evidence for linkage despite the likely increase in heterogeneity introduced into our study sample.
Several interesting findings on chromosome 1 in schizophrenia and related phenotypes have been reported recently. Brzustowicz et al. (5) reported linkage to schizophrenia 75 cM centromeric from our strongest linkage signal and this genetic region was also supported by linkage evidence in the study by Gurling et al. (6). Our results provide only weak evidence for linkage to this particular region, being substantially weaker than for the more telomeric region described above. Further, St Clair et al. (7) reported a balanced (1;11)(q43;q21) translocation which cosegregates with schizophrenia (LOD = 6.0) in a large Scottish family, and a gene disrupted by this translocation was recently identified and named Disrupter in schizophrenia (DISC1) (16). Interestingly, this breakpoint colocalizes with the region showing the strongest linkage in our study sample (D1S2709). Finally, Detera-Wadleigh et al. (4) reported linkage of bipolar disorder to the same region where we observe the strongest evidence for linkage for schizophrenia in the internal isolate study sample. Although these linkage reports span a wide chromosomal region (80 cM), it is still possible that two or more of the findings reflect the effect of the same genetic locus. Simulation-based studies have shown that the maximal evidence for linkage in any genome-wide scan can occur at a considerable distance from the true genetic locus (
30 cM according to some simulations) (17,18), due to stochastic sampling variation and incorporation of incorrect assumptions in the inheritance model used in linkage analysis. Pooled analyses of large study samples, diagnostic refinement, assessment of endophenotypes and quantitative measures of disease liability may all be necessary to restrict the region of interest in future studies, and ultimately determine whether there are one or several schizophrenia/psychosis susceptibility genes on the long arm of chromosome 1q.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Study sample
Using three nationwide registers as described earlier (19,20), we identified 29 124 individuals born between 1940 and 1969 with a register diagnosis of schizophrenia in Finland. By linking the unique identifiers of these individuals with the national population register we were able to construct pedigrees. Probands were contacted by the treating physician most familiar with the proband. Additional family members were contacted only if the proband provided written informed consent. Collection of blood samples was carried out as recommended in the Helsinki declaration. Permissions for the collection were obtained from the Ministry of Social Affairs and Health and from the institutional review board. The study sample consisted of 221 families with 558 affected individuals and 1206 unaffected family members (of which DNA was available for 692/1206). The 221 families included 284 nuclear families, of which 23 had been previously presented in one publication (2), and 113 in another (3). The 148 most recently collected families have not been included in previous analyses. Of the 221 families, 53 were from the internal isolate. One of the pedigrees from the internal isolate was very large containing 161 individuals (24 with LC 1, 6 with LC 2, 1 with LC 3, 47 unaffected and 83 untyped ancestors), and can be expected to contribute most of the statistical power of this sub-sample.
Laboratory methods
DNA was extracted from EDTA blood according to a standard procedure (21). PCR was performed according to standard procedures and electrophoresis was done on an ABI 377 sequencer (Applera Corporation, Norwalk, CT).
Marker sequences were obtained from The Genome Database (www.gdb.org), and marker order and inter-marker distances were obtained by RH mapping and by utilizing the Human Genome Project sequence data. When sequence data were used, the genetic distance was estimated from the physical distance assuming the equivalence of one million bp to 1 cM.
Diagnostic assessment
All available inpatient and outpatient records were collected for probands and relatives with a diagnosis of psychosis in any of the registers. Two psychiatrists who were blind to family structure and register diagnosis independently assessed a consensus best estimate lifetime diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders, fourth Edition (DSM-IV). One of them also filled out the Operational Criteria (OPCRIT) checklist (22). Whenever the two psychiatrists disagreed on a diagnosis, a consensus diagnosis was obtained using a third reviewer. The register diagnosis of schizophrenia has been shown, in several studies, to have high reliability (1,23–25), and agreement between different psychiatrists on lifetime diagnosis has been shown to be good using the method described above (2,3).
Genealogical data
The first Finnish immigrants to the internal isolate arrived in 1676. This migration originated mainly from Ostrobothnia and South Kainuu, both of these groups having originated in Savo. This internal migration resulted in the permanent settlement in the internal isolate of 60–70 Finnish families in 1687. The great famine of 1695–1697 killed about half of the Finns in the region. When parish registers were established in 1718, the population of the region numbered 615 in 165 households. In the 18th and 19th centuries, population growth in the internal isolate was rapid; population expansion to the present level of about 18 700 produced an inbred population structure resembling an immense pedigree with few ancestors. Since the settlers originated from a Finnish sub-population, it would be expected that a subset of the alleles present in the general Finnish population will be present in the sub-isolate, but potentially at different frequencies.
Because of the population history of the internal isolate it can be assumed that genetic heterogeneity is reduced in this population, and that only a small number of the genes that influence susceptibility to schizophrenia worldwide have been introduced into this population some 320 years ago. In both two-point and multipoint analyses, we therefore analyzed families from the internal isolate and families from the rest of Finland separately, as well as jointly.
Statistical methods
In all analyses, we classified subjects as either affected or unknown. We did not classify anyone as unaffected because unaffected family members were not systematically assessed. Therefore all the results are based on ‘affected only’ analysis. We divided subjects into three increasingly inclusive diagnostic classes. Diagnostic class I included schizophrenia, class II included class I plus schizoaffective disorder, and class III included class II plus the following psychotic disorders: schizophreniform, delusional, brief psychotic, and psychotic, not otherwise specified (NOS), as well as the following personality disorders: paranoid, schizoid and schizotypal. These conditions have consistently been shown to aggregate in families of probands with schizophrenia (26), and can therefore be regarded as belonging to a schizophrenia spectrum that is based on a common genetic background.
In both two-point and multipoint analyses, we wanted to minimize the problem of type 1 errors due to multiple testing. To this end, we used oversimplified inheritance models in all analyses. In two-point analyses one ‘recessive’ and one ‘dominant’ model were analyzed (see details below). Correspondingly, in multipoint analyses we considered only SimWalk’s statistics A and B, the two statistics that are the most powerful at detecting linkage to a recessive trait and a dominant trait, respectively. Several liability classes were analyzed for all inheritance models and both the pedigree and nuclear family structures were analyzed. The analysis of several different liability classes for one inheritance model are not independent tests, but still, the obtained results have to be interpreted with due caution because of the multiple tests performed.
Two-point linkage analyses
It has been demonstrated that the sib-pair mean test is statistically equivalent to linkage analysis under a recessive mode of inheritance with no phenocopies allowed, and infinitesimally rare disease allele (27). As implemented in the SIBPAIR program (12), this has been shown to be one of the more reliable approaches to affected sib-pair analysis, especially when extended to sibships with two or more affecteds (28). This ‘recessive’ model was therefore used in the two-point analysis of the data. However, it is also possible to perform a corresponding analysis assuming that the sib-pair is sharing alleles identical by descent (IBD) from one of the parents, but not the other. Such a model has been shown to be equivalent to linkage analysis with a dominant model, rare disease allele, and no phenocopies (13,29–31). Therefore, such a ‘dominant’ affected relative pair analysis was performed using the MLINK program of the LINKAGE package, with technical details described elsewere (13,29,30).
We used a generalization of the transmission disequilibrium test (TDT), the gamete-competition model, for association analyses (32). The gamete-competition model can be used to test for biased transmission of marker alleles to affected individuals. Because the null hypothesis is no association and no linkage, the method is not purely a test of association as linkage alone affects the observed P value.
Multipoint linkage analyses
Owing to the great complexity of some of our pedigrees, most currently available software packages for multipoint analysis cannot take the full pedigree structure into account, but rather must simplify it in some way. To our knowledge, the only available program that can utilize all of the information available from such complex pedigrees is SimWalk2 (33), which uses a likelihood-based approach for sampling from all possible configurations on general pedigrees. We considered statistics ‘A’ and ‘B’ of SimWalk2. The statistics measure the degree of clustering among the affecteds of the founder alleles, i.e. the marker alleles descending from the founders. Specifically, ‘Statistic A’ is based on the number of different founder-alleles contributing alleles to the affecteds. ‘Statistic B’ is based on the maximum number of alleles among the affecteds descended from any one founder allele. Since SimWalk2 uses all available pedigree information, calculation time for the complex pedigrees in our study sample is in the order of months when analyzing all available markers simultaneously (using a Compaq Alpha Server DS-10). We therefore selected two different subsets of the genotyped markers, containing 10 markers each, to be analyzed by this method. One subset consisted of markers around the marker that gave the strongest two-point evidence for linkage in the families from the internal isolate, and the other subset consisted of markers around the marker that gave the strongest two-point evidence for linkage in the nuclear families from all over Finland. We performed identical analyses in five different subsets of the families, i.e. families from the internal isolate, the same families without the largest pedigree, the largest pedigree separately, the nuclear families from all over Finland, and all families combined. We treated individuals with schizophrenia spectrum disorders (LC3) as affected in the multipoint analyses, since this model showed the strongest evidence for linkage in two-point analyses. In all analyses, we used the non-parametric analysis alternative to SimWalk2. The number of replicates was 10 000 in all analyses.
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ACKNOWLEDGEMENTS |
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We wish to thank Drs Maria Muhonen and Jaana Suokas for their important role in the diagnostic work. The work was supported in part by Millennium Pharmaceuticals Inc., Finska Läkaresällskapet, the Finnish Foundation for Medicine, the Juselius Foundation, the Ahokkaan Säätiö foundation and the Center of Excellence for Disease Genetics of the Academy of Finland.
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FOOTNOTES |
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+ To whom correspondence should be addressed at present address: Department of Human Genetics, UCLA School of Medicine, 33-257 CHS, Box 851737, Los Angeles, CA 90095-1737, USA. Tel: +1 310 794 5631; Fax: +1 310 794 5446; Email: lpeltonen@mednet.ucla.edu
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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