Possible linkage of schizophrenia and bipolar affective disorder to chromosome 3q29

Journal of Psychiatric Research 38 (2004) 357–364 www.elsevier.com/locate/jpsychires

Possible linkage of schizophrenia and bipolar affective disorder to chromosome 3q29: a follow-up Alexandra Schossera,*, Karoline Fuchsb, Friedrich Leischc, Ursula Bailera, Kurt Meszarosa, Elisabeth Lenzingera, Ulrike Willingera, Rainer Strobld, Angela Heidena, Christian Gebhardta, Siegfried Kaspera, Werner Sieghartb, Kurt Hornike, Harald N. Aschauera a

Department of General Psychiatry, University Hospital for Psychiatry, A-1090 Vienna, Austria Brain Research Institute of the University of Vienna, Division of Biochemistry and Molecular Biology, A-1090 Vienna, Austria c Institut fu¨r Statistik und Decision Support Systems, University Wien, A-1010 Vienna, Austria d Department of Social Psychiatry and Evaluation Research, University Hospital for Psychiatry, A-1090 Vienna, Austria e Institut fu¨r Statistik und Wahrscheinlichkeitstheorie, University of Technology, A-1040 Vienna, Austria

b

Received 13 May 2003; received in revised form 31 October 2003; accepted 12 November 2003

Abstract The present linkage study is a follow-up within the chromosome 3q29 region in schizophrenia and bipolar affective disorder families, based on our recently published genome scan, resulting in evidence for linkage of both disorders to this region (marker D3S1265: NPL [non parametric lod] score Zall=3.74, P=0.003). Using the same family sample (five pedigrees with schizophrenic index patients and three pedigrees with index bipolar disorder patients N=86; 50 of them were available for genotyping), genotyping of eight additional markers close to D3S1265 was done. Five of those new markers (three centromeric and two telomeric of D3S1265) spanning 4.14 cM (centiMorgan) could be used for statistical analyses (‘‘new markers’’). Moreover, marker D3S1265, genotyped within the published genome scan, was used for additional calculations. Linkage analysis was performed using the GENEHUNTER program version 2.1r3. Within newly genotyped markers the highest NPL score Zall observed was 1.93296 with the telomeric SNP (single nucleotide polymorphism) rs1835669, corresponding to P=0.032166. Statistical analysis including D3S1265, located in between the newly genotyped markers, resulted in a peak NPL score Zall=4.00179 with marker D3S1265, that is P=0.000128. Doing subset analyses of the bipolar disorder and schizophrenia families separately with new markers and D3S1265, linkage signals arose substantially from bipolar disorder families, with contribution from schizophrenia families, too. The results of our follow-up study support our previous linkage finding of schizophrenia and bipolar affective disorder to chromosome 3q29. # 2003 Elsevier Ltd. All rights reserved. Keywords: Schizophrenia; Bipolar disorder; Linkage; Chromosome 3q29

1. Introduction Schizophrenia and bipolar disorder have been considered as nonoverlapping nosologic entities, with distinctive clinical characteristics, unique treatment regimens, and separate etiologies. A review of genetic * Corresponding author. Tel.: +43-1-40400-3575; fax: +43-140400-3629. E-mail address: [email protected] (A. Schosser). 0022-3956/$ - see front matter # 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2003.11.004

epidemiology and recent molecular linkage studies, however, reveals a surprising degree of concordance for schizophrenia genetics and bipolar disorder genetics, raising the hypothesis that these two diagnostic categories may share some genetic susceptibility factors. Curiously, despite of the widely accepted view that schizophrenia and bipolar disorder exhibit independent modes of inheritance, some regions that are reported as positive for linkage in relation to schizophrenia overlap with regions of positivity for affective disorder: 18p11.2

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(Berrettini et al., 1994, 1997; No¨then et al., 1999; Schwab et al., 1998; Stine et al., 1995), 13q32 (Blouin et al., 1998; Detera-Wadleigh et al., 1999; Lin et al., 1997), and 22q11 (Detera-Wadleigh et al., 1999; Gill et al., 1996; Kelsoe et al., 2001; Lachman et al., 1997; Saito et al., 1999). There are three additional reasons arguing against the concept that schizophrenia and bipolar disorder are distinct illnesses. First, in phenomenology, a bimodal separation of schizophrenic and affective symptoms has not been demonstrated (Kendell and Gourlay, 1970). Second, no clear separation can be demonstrated in terms of treatment response, and the overlap in indications of neuroleptics provides some support for the unitary psychosis concept (Kuhne et al., 1988; Tsuang, 1975). Neuroleptic medication is antipsychotic rather than antischizophrenic, because it can be used in unipolar and bipolar affective as well as in schizophrenic psychosis. Neuroleptics are the treatment of second choice in acute mania (Bowden, 2000; Post et al., 1996). Furthermore there is accumulating evidence for beneficial effect of new atypical neuroleptics in treatment of acute mania and prophylactic treatment for bipolar affective disorder. Some of the atypical neuroleptics are on the market under this indication, too. In addition, antidepressants can be beneficial in schizophrenia (Angst et al., 1970; Johnstone et al., 1988; Klein et al., 1981). Third, family studies have failed to demonstrate a natural point of cleavage on the basis of risk to relatives, and first-degree relatives of schizophrenic patients also have a higher risk for bipolar disorder (Gershon et al., 1988; Henn et al., 1995; Kendler et al., 1985; Maier et al., 1993; Taylor et al., 1993). The same holds true for relatives of bipolar patients (Weissman et al., 1984). After finding suggestive evidence for linkage with marker D3S1265, mapping to chromosome 3q29, within our recently published genome scan (Bailer et al., 2002), further studies were conducted in order to add further support to our findings. The NPL score Zall for D3S1265 was 3.74 (P=0.003). Within the current analysis, we established fine mapping of the 3q29 region by linkage study, in order to narrow down a possible susceptibility locus for schizophrenia and bipolar affective disorder. Kelsoe et al., (2001) reported suggestive evidence for linkage of bipolar disorder to 3q27 with marker D3S2398. Meanwhile marker D3S2398 is known not to be located on 3q27, but on 3q29 (6.1 cM centromeric of marker D3S1265, the marker of highest linkage within our genome scan). The present study provides evidence for linkage of both schizophrenia and bipolar affective disorder to 3q29. The dopamine 3 receptor gene (DRD3) is located on the long arm of chromosome 3, but at 3q13.3, far away from the locus identified in this study. Dopamine neurotransmission has long been implicated in the pathogenesis of schizophrenia and, more recently, affective disorder (Dikeos et al., 1997).

Concerning bipolar affective disorder, suggestive evidence for linkage was obtained using markers D3S2403 and D3S3038, both located on the short arm of chromosome 3, among families investigated as part of the National Institute of Mental Health Genetics Initiative of Bipolar Disorder (Foroud et al., 1997; Nimgaonkar et al., 1998). Within the present report, we describe the results of genotyping eight new SNP markers spanning 4.14 cM at the telomere of chromosome 3.

2. Materials and methods 2.1. Families Within this study, DNA of the same family-sample as in the recently published genome scan (Bailer et al., 2002) was genotyped. Five pedigrees with schizophrenic index patients and three pedigrees with index bipolar disorder patients (N=86; 50 of them were available for genotyping; Fig. 1) were investigated in Vienna. Hospitalized and outpatient individuals with a DSM-III-R (Diagnostic and Statistical Manual of Mental Disorders; American Psychiatric Association, 1987) diagnosis of schizophrenia or bipolar disorder were identified as index patients at the Department of Psychiatry at the University of Vienna, Austria. A patient was accepted as schizophrenia index patient if she or he suffered from DSM-III-R schizophrenia and had at least one available sibling with a nonaffective, nonorganic psychosis. A patient was accepted as bipolar index patient if she or he suffered from DSM-III-R bipolar I disorder and had at least one available sibling with an affective, nonorganic or schizoaffective psychosis. The families were ethnically homogenous of Austrian origin. The disease model (affected individuals) of the current analysis included schizophrenia, schizophrenia spectrum disorders (i.e., schizophreniform disorder, delusional disorder, atypical psychosis, schizoaffective disorder), bipolar affective disorder, and recurrent unipolar depression. All participants gave written informed consent. The study was approved by the ethical committee of the Faculty of Medicine at the University of Vienna. Of the genotyped affected, 70% were women; on average, they were 41.59 (S.D. 18.86) years of age at interview. The mean age at onset was 26.33 (S.D. 10.87) years. Age at onset was defined as age at first hospitalization for the disorder. All 27 patients had been hospitalized during the course of their illness. 2.2. Diagnostic procedure The diagnostic process included: A face-to-face interview with all available living individuals utilizing the Schedule for Affective Disorders and Schizophrenia,

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Fig. 1. Structures of schizophrenia (SCH) and bipolar (MDK) families. The eight pedigrees used in this study are shown. Genotyped individuals (n=50) are indicated by an asterisk (*) to the right. Fully shaded symbols represent individuals with a diagnosis of DSM-III-R schizophrenia, schizoaffective disorder, bipolar disorder, other nonaffective psychoses, and recurrent unipolar depression who were considered affected in the linkage analysis. There were 27 such cases for whom DNA was available. Slanted lines through a circle (female) or square (male) indicate a deceased individual. Below each symbol, the DSM-III-R code numbers are presented: V71.09: no diagnosis or condition on Axis I or II; 799.90: diagnosis or condition deferred on Axis I, II; 294.8: dementia, not otherwise specified (NOS); 295.12: schizophrenia, disorganized, chronic; 295.32: schizophrenia, paranoid, chronic; 295.40: schizophreniform disorder; 295.62: schizophrenia, residual, chronic; 295.70: schizoaffective disorder, bipolar type; 296.2: major depression, single episode; 296.3: major depression, recurrent; 296.4: bipolar I disorder, manic; 296.5: bipolar I disorder, depressed; 296.54: bipolar I disorder, most recent episode depressed, severe with psychotic features; 296.70: bipolar disorder, NOS; 300.01: panic disorder, without agoraphobia; 300.29: simple phobia; 300.3: obsessive-compulsive disorder; 300.40: dysthymia; 301.13: cyclothymia; 303.90: alcohol dependence; 305.00: alcohol abuse; 309.00: adjustment disorder, with depressed mood; 309.82: adjustment disorder with physical complaints; 309.89: posttraumatic stress disorder; 311.00: depressive disorder, NOS; 299.00: Axis II: autistic disorder; 301.00: Axis II: paranoid personality disorder; 301.22: Axis II: schizotypal personality disorder; 301.82: Axis II: avoidant personality disorder.

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Lifetime version (Spitzer and Endicott, 1987). Parts of the International Personality Disorder examination (IPDE; Loranger et al., 1987) were applied for Axis II diagnoses. In addition, an unstructured psychiatric interview and a family history evaluation were completed for each subject. Clinical data were obtained from medical records, and the interviewer prepared a written anonymous case report. Using all available data, blind consensus diagnoses were made by at least two independent psychiatrists according to DSM-III-R (American Psychiatric Association, 1987) Axis I and II without knowledge of marker status or family relationship. 2.3. Laboratory work and genotyping After obtaining written informed consent, 20 ml of venous blood from 50 participating subjects was collected in vacutainers containing EDTA (ethylenediamine-tetraacetic acid). High molecular weight DNA was extracted from blood, using the Nuncleon BACC3 kit (Amersham Biosciences), and was used for genotyping. SNPs were selected by means of ‘NCBI-GENBANK’ (http://www.ncbi.nlm.nih.gov ). The following primer pairs were used: SNP rs1873405: 50 -CTCATGTCTTCTGACTCCAAGTCC30 and 50 -GAAGCAAGTCCTGGTCTTCTTACC-30 ;

SNP rs2368036: 50 -GACAGATGAGCAACATTCTTATCACTC-30 and 50 -GGTTATTAGAGAAGGGTCTCAGATTCAC-30 ; SNP rs2368041: 50 -GAGCTCCCGTGATAGGATGAGTG-30 and 50 -CATCCCAGTCTCCTTACTGCACAG-30 ; SNP rs2341399: 50 -CTGCTGCCTGAAGAACTGCCTG-30 and 50 -GCCCTGTGAGACAACCCAGATC-30 ; SNP rs1835669: 50 -GATGCAGCTGGGGAGTAGGAG-30 and 50 -CAGAGCAGTTTCTTGGGTCCTTC- 30 ; In this study, restriction endonuclease cleavage (the restriction enzymes were: SNP rs1873405: Ban I, SNP rs2368036: Blp I, SNP rs2368041: BsmB I, SNP rs2341399: Hind III, SNP rs1835669: BsiHKA I) was used to distinguish between the two alleles of SNPs. Exchange of a single nucleotide within this recognition site generates or abolishes a restriction enzyme recognition site. A total of eight SNPs were genotyped. Five of the genotyped SNPs could be used for statistical analysis (rs1835669, rs1873405, rs2368041, rs2368036, and rs2341399). In case of the other SNPs (rs1317196, rs1996904, and rs2368047), they were not informative, since all patients were either all homozygous or all heterozygous for the respective SNPs. Table 1 contains the five newly genotyped markers used in analysis, spanning a 4.14 cM region on chromosome 3q29.

Table 1 (a) Results of GENEHUNTER multilocus linkage analysis, on chromosome 3q29 with eight families (schizophrenia and bipolar affective disorder), and five newly genotyped SNP markersa; (b) subset GENEHUNTER linkage analysis of three bipolar affective disorder families and five schizophrenia families separately done with five newly genotyped markers Marker

Position (centiMorgan)

LOD score

NPL score

P

Info.Cont.

190.75 190.82 190.88 192.20 194.89

0.009268 0.012826 0.015347 0.317712 0.800668

1.52257 1.52250 1.52308 1.65000 1.93296

0.069797 0.069835 0.069797 0.055605 0.032166

0.823209 0.827299 0.830315 0.823785 0.677195

(b) Bipolar affective disorder families rs1873405 190.75 rs2368036 190.82 rs2368041 190.88 rs2341399 192.20 rs1835669 194.89

0.563246 0.565184 0.566867 0.584780 0.555624

1.59799 1.60261 1.60718 1.61225 1.50316

0.080383 0.080383 0.078918 0.078918 0.091370

0.753030 0.759109 0.763041 0.764638 0.620760

0.572514 0.578010 0.582214 0.267069 0.245044

0.68811 0.68446 0.68164 0.83826 1.28069

0.254517 0.254517 0.254517 0.188843 0.107056

0.865317 0.868213 0.870680 0.859273 0.711057

(a) rs1873405 rs2368036 rs2368041 rs2341399 rs1835669

Schizophrenia families rs1873405 rs2368036 rs2368041 rs2341399 rs1835669

190.75 190.82 190.88 192.20 194.89

LOD score=likelihood of linkage, logarithm of the odds; NPL score=non parametric lod score Zall; P=value of statistical significance; Info.Cont.=information content. a SNPs were selected by means of ‘NCBI-GENBANK’ (http://www.ncbi.nlm.nhi.gov). Map position was derived from ‘NCBI-GENBANK’ (Contig numbers NT_005571+12, NT_033013+2, NT_029920+7, and NT_022508+10).

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2.4. Statistical analysis Linkage was performed using the GENEHUNTER program version 2.1r3 to compute both the usual parametric logarithm of the likelihood of linkage (LOD) scores (a dominant model was used), as well as the nonparametric multipoint linkage (NPL) score Zall (for details, see Kruglyak et al., 1996). Information content mapping was computed within GENEHUNTER, too. For the parametric LOD scores, a disease allele frequency of 0.05, phenocopy rate of 0.01, homozygous penetration of 0.7, and heterozygous penetrance of 0.7; all 50 genotypings were used, assuming affected or nonaffected status. The nonparametric linkage analysis does not require these assumptions, and here only the 27 affected cases, according to our model of disease, were used for calculation. The map position of the markers were derived from ‘NCBI-GENBANK’ (Contig numbers NT_005571, NT_033013, NT_029920, and NT_022508). The map position of D3S1265 and the five newly genotyped markers used for statistical analysis are listed in Table 1b and 2b. Three markers were situated centromeric of D3S1265, and two markers telomeric. D3S1265 had been the marker of strongest linkage

within our previous genome scan (Bailer et al., 2002), resulting in a NPL score Zall of 3.74 (P=0.003). Linkage analyses were performed for the newly genotyped markers, for new markers plus D3S1265, and in addition for bipolar and schizophrenia families combined on one hand, and separately on the other hand. The traditional Transmission Disequilibrium Test (Spielman et al., 1993) was also computed within GENEHUNTER.

3. Results In our analysis, among the 5 newly genotyped markers (Table 1a, Fig. 2), the highest NPL score Zall observed was 1.93296 with SNP rs1835669 situated at the telomeric end of chromosome 3q29, corresponding to P=0.032166. This result supports our previous significant linkage finding of the genome scan. In the parametric analysis of SNP rs1835669 a LOD score of 0.800668 resulted. The NPL score Zall observed with SNP rs2341399—2.69 cM centromeric of SNP rs1835669— was 1.65000 (P=0.055605). The other three SNPs—1.45 cM, 1.32 cM, and 1.38 cM centromeric of SNP

Table 2 (a) Results of GENEHUNTER multilocus linkage analysis on chromosome 3q29 with eight families (schizophrenia and bipolar affective disorder), and five newly genotyped markers plus marker D3S1265;a (b) subset GENEHUNTER linkage analysis of three bipolar affective disorder families and five schizophrenia families separately done with five newly genotyped markers plus D3S1265 Marker

Position (centiMorgan)

LOD score

NPL score

P

Info.Cont.

(a) Five newly genotyped SNP markers plus D3S1265 Bipolar affective disorder families rs1873405 190.75 rs2368036 190.82 rs2368041 190.88 D3S1265 191.25 rs2341399 192.20 rs1835669 194.89

1.594311 1.596941 1.599381 1.611930 1.602683 1.526849

3.46428 3.47492 3.49368 3.56441 3.49130 3.17520

0.001038 0.001038 0.001038 0.001038 0.001038 0.005005

0.914636 0.921636 0.921800 0.926845 0.888503 0.722350

Schizophrenia families rs1873405 rs2368036 rs2368041 D3S1265 rs2341399 rs1835669

0.017210 0.013757 0.010816 0.356281 0.353040 0.551871

1.57005 1.57015 1.57013 2.30093 2.19593 2.05256

0.049683 0.049683 0.049683 0.009155 0.023575 0.024414

0.934110 0.938625 0.943120 0.932470 0.943871 0.775340

1.611521 1.610698 1.610197 1.968212 1.955722 2.078720

3.36266 3.36926 3.38073 4.00179 3.87401 3.56709

0.000999 0.000985 0.000965 0.000128 0.000200 0.000534

0.926807 0.932254 0.935125 0.930361 0.923108 0.755469

190.75 190.82 190.88 191.25 192.20 194.89

(b) Five newly genotyped SNP markers plus marker D3S1265 rs1873405 190.75 rs2368036 190.82 rs2368041 190.88 D3S1265 191.25 rs2341399 192.20 rs1835669 194.89

LOD score=likelihood of linkage, logarithm of the odds; NPL score=non parametric lod score Zall; P=value of statistical significance; Info.Cont.=information content. a SNPs were selected by means of ‘NCBI-GENBANK’ (http://www.ncbi.nlm.nhi.gov). Map position was derived from ‘NCBI-GENBANK’ (Contig numbers NT_005571+12, NT_033013+2, NT_029920+7, and NT_022508+10).

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rs2341399—resulted in NPL scores Zall > 1.5 each, corresponding to P values of 0.069797 and 0.069835, respectively. In addition, statistical analyses were conducted including marker D3S1265 (0.9 cM centromeric of SNP rs2341399; Table 2a, Fig. 3), genotyped within the previous genome scan (Bailer et al., 2002), resulting in a NPL score Zall=4.00179 with marker D3S1265, that is p=0.000128. In the parametric analysis for D3S1265 a

LOD score of 1.968212 was observed. In short, within this study, all NPL scores Zall increased substantially, and LOD scores increased markedly, too. Conducting subset analyses of the bipolar disorder and schizophrenia families separately, including marker D3S1265 (Table 2a), within the bipolar disorder families we found NPL scores Zall > 3 with all markers, corresponding to P values of 0.001038 and 0.005005, respectively. Within the schizophrenia families, the highest

Fig. 2. Results of GENEHUNTER multilocus linkage analysis, on chromosome 3q29 with eight families (schizophrenia and bipolar affective disorder), and five newly genotyped SNP markers: x-axis: position in cM; y-axis: LOD/NPL score.

Fig. 3. Results of GENEHUNTER multilocus linkage analysis, on chromosome 3q29 with eight families (schizophrenia and bipolar affective disorder), and five newly genotyped SNP markers plus marker D3S1265: x-axis: position in cM; y-axis: LOD/NPL score.

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NPL score Zall was observed with marker D3S1265 (2.30093), corresponding to a P value of 0.009155. As for the LOD score, the highest were found with marker D3S1265 (1.611930) and SNP rs2341399 (1.602083) in the subset of bipolar disorder families. In short, linkage signals arise substantially from bipolar disorder families, additionally with contribution from schizophrenia families. The subset analyses of bipolar disorder and schizophrenia families separately excluding marker D3S1265 are shown in Table 1b. Obviously, there seems to be a trend for a higher linkage signal toward the centromeric direction within bipolar families, whereas within schizophrenia families the trend increases in telomeric direction. The traditional Transmission Disequilibrium Test resulted in a P value of 0.045500, corresponding to Chi2=4.00 (two-point analysis) with marker D3S1265, the same P value and Chi2 value were found within haplotype analyses (markers SNP rs2368041 and D3S1265; and markers D3S1265 and SNP rs2341399).

4. Discussion The results of our follow-up linkage analysis of the chromosome 3q29 region support our previous finding of possible linkage of schizophrenia and bipolar affective disorder to the long arm of chromosome 3 (Bailer et al., 2002). In the present study, we examined the same family sample as in the genome scan, but genotyping new markers, spanning 4.14 cM around marker D3S1265 (marker of highest linkage within the recently published genome scan). Calculations could be performed with five informative SNPs. The appropriate P values for declaring linkage to be significant are not universally agreed upon. As for genome scans, the significance level is very stringent. Lander and Kruglyak (1995) proposed that a nominal P value of 2.2105 is needed to declare linkage in a whole genome scan. A P value of 1102 is needed to declare a replication of linkage (confirmation of previous findings) within a genome scan. Within the current study, we did not perform a genome scan, rather followed up on a finding of suggestive linkage of our previous genome scan on chromosome 3q29. However, as markers were chosen (very) close to the marker with the most significant result in our previous study, and as the same people were used, there is obviously a dependency between the results, and Pvalues must be taken with care. With our five newly genotyped markers, the best P values obtained were 0.032166 and 0.055605 with SNP rs1835669 and SNP rs2341399 respectively. Consequently, when calculating the newly genotyped DNA markers, again a signal for linkage was found within the chromosome 3q29 region, even without including the previously used markers.

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This supports our finding of possible linkage with marker D3S1265 (NPL score Zall=3.74, P=0.003) within the genome scan. When performing linkage analyses with newly genotyped markers and marker D3S1265 together, our results even stronger provide evidence for linkage of both disorders to chromosome 3q29 at the locus D3S1265 (P value of 0.000128), rs2341399 (P value of 0.000200), and rs1835669 (P value of 0.000534). Note that in this case P-values should be read as if having been part of the original genome scan. In general, the results of linkage analysis of the markers genotyped within the current study show a tendency for linkage in the 3q29 region with P < 0.05. We can conclude that at least in our family sample we have a possible susceptibility locus for both disorders in this region. Conducting linkage analysis including the marker of strongest linkage within the previous genome scan, D3S1265, the P values markedly decreased (from P=0.003 to P=0.000128). One possible reason for the weaker linkage signal of the newly genotpyed markers could be, that they only had two alleles, whereas e.g. D3S1265 had more power with 10 alleles. As a result of this follow-up study, there seems to be a candidate gene located around or telomeric of marker D3S1265 in both schizophrenia and bipolar disorder.

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