Trend for an Association Between Schizophreniaand D3S1310, a Marker in Proximity to theDopamine D3 Receptor Gene

E.G. Jonsson,1* V.L. Nimgaonkar,2,3 X.R. Zhang,2 S.H. Shaw,4 E. Burgert,5 M.-A. Crocq,6A. Chakravarti,4 and G.C. Sedvall1

1Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institute, Stockholm, Sweden2Department of Psychiatry, University of Pittsburgh, Western Psychiatric Institute and Clinic,Pittsburgh, Pennsylvania

3Department of Human Genetics, University of Pittsburgh, Western Psychiatric Institute and Clinic,Pittsburgh, Pennsylvania

4Department of Genetics, Case Western Reserve University, Cleveland, Ohio5Institute of Human Genetics, University of Freiburg, Freiburg, Germany6Centre Hospitalier, Rouffach, France

There is considerable controversy regard-ing a putative association between schizo-phrenia and a biallelic BalI polymorphismin the first exon of the dopamine D3 recep-tor gene (DRD3), although meta-analyses ofpublished data suggest an association. Ifsuch an association exists, it may be detect-able at markers physically close to DRD3.Accordingly, we conducted a case-controlassociation study using D3S1310, a shorttandem repeat polymorphism located ap-proximately 700 kb telomeric to DRD3 onchromosome 3q13.3. The subjects wereSwedish patients with schizophrenia (DSMIII-R criteria, n = 110) and screened adultcontrols (n = 83). A trend for a negative as-sociation with the 141 bp allele was detected(x2 = 7.6, d.f. = 1, P = 0.006; odds ratio 0.46,95% confidence intervals 0.26, 0.81). How-ever, following corrections for multiplecomparisons using subgroups (n = 15) thedifference was not significant. Also, due tothe risk for population stratification incase-control association studies the resultsmust be treated as tentative. If replicatedthe results may lend further support for theproposition of an association betweenschizophrenia and DRD3 or a gene in close

proximity to DRD3 on chromosome 3q. Am.J. Med. Genet. (Neuropsychiatr. Genet.) 88:352–357, 1999. © 1999 Wiley-Liss, Inc.

KEY WORDS: schizophrenia; genetics; as-sociation; dopamine D3 re-ceptor gene locus; dopaminereceptors

INTRODUCTION

From family, twin, and adoption studies it has beenproposed that genetic factors play a role in the etiologyof schizophrenia [Kendler and Diehl, 1993]. However,no specific hereditary mechanism has yet been conclu-sively identified for the disease. Alterations in dopa-mine transmission and dopamine receptors have longbeen hypothesized in the pathophysiology of schizo-phrenia [Davis et al., 1991; Haracz, 1982; van Rossum,1967]. Thus, dopamine receptor genes are plausiblecandidates in the search for the genetic etiology ofschizophrenia.

All antipsychotic drugs used in clinical practice haverelatively high affinities for the dopamine D3 receptor(DRD3), especially some of the ‘‘atypical’’ and disinhibi-tory neuroleptic drugs [Sokoloff et al., 1992]. The DRD3mRNA is almost exclusively expressed in limbic areasof the brain [Bouthenet et al., 1991]. Hence, both theanatomical distribution and the pharmacological pro-file of the D3 receptor makes it a possible site for an-tipsychotic drug action. Consequently, DRD3 is a suit-able candidate for involvement in the pathogenesis ofschizophrenia. A biallelic BalI polymorphism of theDRD3 gene, caused by a basepair shift that substitutesa serine for a glycine amino acid residue, has recentlybeen described [Lannfelt et al., 1992]. The DRD3 genehas been mapped to chromosome 3q13.3 by in situ hy-bridization [Le Coniat et al., 1991].

Contract grant sponsor: Swedish Medical Research Council;Contract grant number: 03560; Contract grant sponsor: NationalInstitute of Mental Health; Contract grant numbers: 44814,00966, 53459; Contract grant sponsor: NARSAD; Contract grantsponsor: Soderstrom-Konigska Foundation.

*Correspondence to: E.G. Jonsson, Department of Clinical Neu-roscience, Psychiatry Section, Karolinska Hospital, SE-171 76Stockholm, Sweden. E-mail: erikj@psyk.ks.se

Received 28 January 1998; Accepted 17 September 1998

American Journal of Medical Genetics (Neuropsychiatric Genetics) 88:352–357 (1999)

© 1999 Wiley-Liss, Inc.

Crocq and his colleagues reported an association be-tween schizophrenia and homozygosity for the BalIpolymorphism in a combined French and Britishsample [Crocq et al., 1992]. These results have beenreplicated in enlarged case-control samples from bothgroups [Asherson et al., 1996; Griffon et al., 1996; Mantet al., 1994], in a European collaborative study [Spur-lock et al., 1998], and in a family based associationstudy [Williams et al., 1998]. Other groups have de-tected association between schizophrenia and the Ser-allele or Ser/Ser-genotype [Nimgaonkar et al., 1996;Shaikh et al., 1996; Spurlock et al., 1998; Williams etal., 1998] or Gly-allele [Ebstein et al., 1997; Kennedy etal., 1995]. Although no overall association with schizo-phrenia has been detected in several other studies,such studies have nevertheless suggested that sub-groups of schizophrenic patients may be associatedwith DRD3 BalI alleles/genotypes. These subgroups in-clude male gender [Asherson et al., 1996; Griffon et al.,1996; Mant et al., 1994], response to medication [Du-rany et al., 1996; Ebstein et al., 1997; Jonsson et al.,1993; Krebs et al., 1997; Mant et al., 1994; Shaikh etal., 1996], a family history of schizophrenia [Mant etal., 1994; Nimgaonkar et al., 1993; Nimgaonkar et al.,1996], age of onset [Durany et al., 1996; Ebstein et al.,1997; Griffon et al., 1996; Mant et al., 1994; Maziade etal., 1997; Nimgaonkar et al., 1996], alcohol or sub-stance abuse [Krebs et al., 1997], tardive orofacialmovements [Macciardi et al., 1997], and a diagnosis ofdisorganized or undifferentiated schizophrenia [Du-rany et al., 1996].

On the other hand, several linkage and associationstudies have yielded nonsignificant results [Ashersonet al., 1996; Chen et al., 1997; Coon et al., 1993; DiBella et al., 1994; Dollfus et al., 1996; Dourado et al.,1997; Durany et al., 1996; Gaitonde et al., 1996; Hawiet al., 1998; Hovatta et al., 1994; Inada et al., 1995;Jonsson et al., 1993; Kalsi et al., 1997; Karayiorgou etal., 1994; Krebs et al., 1997; Laurent et al., 1994; Mac-ciardi et al., 1994; Maziade et al., 1997; Nanko et al.,1993; Nanko et al., 1994; Nothen et al., 1993a; Nothenet al., 1993b; Ohara et al., 1996; Rietschel et al., 1996;Rothschild et al., 1996; Sabate et al., 1994; Saha et al.,1994; Tanaka et al., 1996; Wiese et al., 1993]. Many ofthese studies also investigated the aforementionedsubgroups, but significant associations were not de-tected.

To synthesize the discrepant results, meta-analyseson all published data have been reported. All suchanalyses have supported an association betweenschizophrenia and DRD3 [Nimgaonkar et al., 1996;Shaikh et al., 1996; Dubertret et al. 1998; Williams etal., 1998]. Even so, considerable skepticism about theputative association remains. This may be attributedto the large body of nonsignificant results.

Another explanation for the discrepancies may be anassociation for another DRD3 polymorphism in linkagedisequilibrium with the BalI polymorphism. However,a thorough search for coding sequences in DRD3 failedto identify sufficiently informative markers [Ashersonet al., 1996]. This leaves the less desirable alternativeof investigating a distant, but more informativemarker. Accordingly, we conducted a case-control asso-

ciation study using D3S1310. This short tandem repeatpolymorphism (STRP) was estimated to be approxi-mately 700 kb telomeric to DRD3 using radiation hy-brid mapping [Shaw et al., 1995].

MATERIALS AND METHODSHuman Subjects

All subjects were unrelated Caucasian individualsliving in Stockholm. They were assessed by clinicaland/or structural interviews [Spitzer et al., 1986],medical records, and parish register data for psychiat-ric diagnosis, family history of psychosis in first or sec-ond degree relatives, and geographical origin as previ-ously described [Jonsson et al., 1993; Jonsson, 1997].Patients were also evaluated regarding age at first hos-pitalization; abuse of alcohol, solvents, or drugs; previ-ous suicide attempts; response to neuroleptic drugtreatment; extrapyramidal side effects (EPS); andtreatment with anticholinergic drugs. All 110 patients,72 men and 38 women, fulfilled Diagnostic and Statis-tical Manual of Mental Disorders (DSM-III-R) criteriafor schizophrenia [American Psychiatric Association,1987] with the following subdiagnosis: disorganized (n4 23), catatonic (n 4 9), paranoid (n 4 10), and un-differentiated (n 4 68). Their age range was 20 to 90years (mean 45.5). They had their first hospitalizationbetween the ages of 15 to 56 (mean 25.8). Twenty-sixhad a history of concomitant abuse of alcohol or drugssometime during their lifes. Seventy-nine and 31 wereestimated to have had an optimum/partial or negligibleresponse to neuroleptic treatment, respectively. Of theschizophrenic subjects 45 had attempted suicide,whereas 126 had not. A family history of schizophreniaspectrum disorders in first degree relatives were re-ported by 30 subjects, whereas 78 lacked such a familyhistory.

There were 83 control subjects, 49 men and 34women. All were free from current or previous psychi-atric morbidity. The age range was 26 to 56, with amean of 38.1 years. Genealogical reports suggested nosignificant difference in the national ancestry of casesor controls.

Methods

Genomic DNA was extracted from venous blood [Gei-jer et al., 1994]. For the molecular genetic analysis,polymerase chain reaction (PCR) based assays wereused. The BalI polymorphism was analyzed as previ-ously described [Lannfelt et al., 1992]. For theD3S1310 polymorphism the following procedure wasused: briefly, 100 ng genomic DNA of each sample wasamplified in a total reaction volume of 50 mL containing50 pmol of each primer, 0.125 mM dNTPs, and 1 U Taqpolymerase. The PCR buffer contained 10 mM Trisbase (pH 9), 50 mM KCl, 1.5 mM MgCl2, 0.1% TritonX100, and 0.01% gelatin. The primer sequences were asfollows: (AFM242xh2a) CAT TAT TGT CAA AGC AACACA C and (afm242XH2M): AAT GAG TTT TGG CAGAGG GT. Amplification consisted of 35 cycles of dena-turation (94°C for 40 sec), and annealing (55°C for 30sec). An elongation step (72°C for 2 min) concludes the

Schizophrenia and D3S1310 353

PCR. Taq polymerase is added only after a first dena-turation step of 5 min at 96°C. The amplified productswere visualized following silver staining [Bassam etal., 1991]. Their size was estimated in comparison withbands from two Centre d’Etude du Polymorphisme Hu-main (CEPH) individuals (1333-11 [# 7049] and 1347-02), whose allelic status (147 bp homozygotes) wasknown. Amplified DNA from such individuals was runevery 15 wells on each gel. Genotypes were examinedtwice by an individual blind to the clinical status of thesamples.

Statistical Calculations

The allele frequencies among cases and controls werecompared using contingency x2-tests. Due to smallnumbers in some cells a Monte Carlo method, as imple-mented in the CLUMP program [Sham and Curtis,1995], was used to assess the statistical significance ofthe results if the expected number of $25% of the cellswas <5. Individual allele frequencies were comparedusing 2 × 2 x2-tests. Odds ratios and confidence inter-vals were estimated in accordance with Woolf [1955].Power was estimated in accordance with publishedmethods [Cohen, 1988; Erdfelder et al., 1996]. Morethan 15 different analyses were performed when thepatient material was divided into different clinical sub-groups, reducing the significance level to 0.003 (0.05/15). Survival analysis (Kaplan-Meyer) was used to ex-amine possible association between the 141 bp alleleand age at onset of illness, defined here as the age atfirst hospitalization. Survival curves for patients sub-divided on the basis of presence or absence of the 141bp allele were compared following stratification by gen-der. As no linkage disequilibrium was detected it wasconsidered appropriate to use logistic regression tocompare combined DRD3 BalI and D3S1310 genotypes.Statistical analyses were conducted using the packagesStatView and JMP.

RESULTS

There was a difference in the overall allele (Table I;x2 4 11.9, d.f. 4 5, P 4 0.036) and genotype distribu-tions (Table II; x2 4 24.8, d.f. 4 16, P 4 0.036) whenpatients with schizophrenia were compared with con-trol subjects. The 141 bp allele was less common amongschizophrenic patients than control subjects (x2 4 7.6,

d.f. 4 1, P 4 0.006; odds ratio 0.46, 95% confidenceintervals 0.26, 0.81).

There was no significant difference in age at firsthospitalization between schizophrenic patients dividedwith regard to presence or absence of the D3S1310 141bp allele (data not shown). When considering only malesubjects the observed frequencies for D3S1310*141 al-lele for schizophrenic and control subjects were 0.097and 0.143, respectively (x2 4 1.19, d.f. 4 1, P 4 0.276).The 141 allele frequencies for schizophrenic and con-trol women were 0.132 and 0.309, respectively (x2 46.67, d.f. 4 1, P 4 0.010). The 141 allele frequencies forthe different schizophrenic subdiagnosis were (com-parisons versus controls in paranthesis): disorganized0.043 (x2 4 7.00, d.f. 4 1, P 4 0.008), catatonic 0.278(x2 4 0.43, d.f. 4 1, P 4 0.570), paranoid 0.150 (x2 40.41, d.f. 4 1, P 4 0.605), and undifferentiated 0.103(x2 4 6.40, d.f. 4 1, P 4 0.011), respectively. Whencomparing schizophrenic subjects with family historyversus controls, the observed 141 allele frequencieswere 0.150 and 0.211, respectively (x2 4 1.04, d.f. 4 1,P 4 0.308). The 141 allele frequencies in schizophrenicsubjects lacking a family history were 0.096 (compari-sons versus controls: x2 4 8.07, d.f. 4 1, P 4 0.005).Comparisons were also performed between controls (al-lele 141 frequency 0.211) and schizophrenic subjectswith optimum/partial (0.108; x2 4 6.41, d.f. 4 1, P 40.011) or negliable (0.113; x2 4 2.88, d.f. 4 1, P 40.090) response to neuroleptic drugs, respectively. Con-sidering only schizophrenic patients who had at-tempted suicide and control subjects the 141 allele fre-quencies were 0.033 and 0.211, respectively (x2 414.55, d.f. 4 1, P 4 0.0001). Schizophrenic patientswho had not attempted suicide had a 141 allele fre-quency more similar to controls (0.167; x2 4 0.90, d.f.4 1, P 4 0.342). Controls (141 allele frequency 0.211)were also compared with schizophrenic subjects with(0.058; x2 4 6.45, d.f. 4 1, P 4 0.011) and without(0.125; x2 4 4.41, d.f. 4 1, P 4 0.036) alcohol/substance abuse.

TABLE I. D3S1310 Allele Distribution in Percentages andCounts in Schizophrenic Patients (n 4 110) and Control

Subjects (n 4 83)

Allele Schizophrenic patients Control subjects

Total samplea % # alleles % # alleles

137 15.9 35 19.9 33139 7.3 16 3.6 6141b 10.9 24 21.1 35143 54.1 119 45.8 76145 10.0 22 9.0 15147 1.8 4 0.6 1

ax2 4 11.9, d.f. 4 5, P 4 0.036.bx2 4 7.6, d.f. 4 1, P 4 0.006.

TABLE II. D3S1310 Genotype Distribution in Percentages andCounts in Schizophrenic Patients (n 4 110) and Control

Subjects (n 4 83)

Genotype Schizophrenic patients Control subjects

Total samplea % # genotypes % # genotypes

137/137 8.2 9 6.0 5137/139 0.9 1 0.0 0137/141 2.7 3 8.4 7137/143 10.0 11 15.7 13137/145 1.8 2 3.6 3139/139 1.8 2 2.4 2139/141 1.8 2 1.2 1139/143 7.3 8 1.2 1139/145 0.9 1 0.0 0141/141 6.4 7 9.6 8141/143 4.5 5 13.3 11143/143 40.9 45 25.3 21143/145 3.6 4 9.6 8143/147 0.9 1 1.2 1145/145 6.4 7 2.4 2145/147 0.9 1 0.0 0147/147 0.9 1 0.0 0

ax2 4 24.75, d.f. 4 16, P 4 0.036.

354 Jonsson et al.

Part of the material has been published previouslywith regard to the DRD3 BalI genotypes [Jonsson etal., 1993]. DRD3 BalI results of all the subjects in thepresent study are presented in Table III. There was nosignificant difference between patients and controlswith regard to allele (x2 4 0.13, d.f. 4 1, P 4 0.715) orgenotype distribution (x2 4 0.17, d.f. 4 2, P 4 0.918).No significant difference was detected with regard tohomozygosity distribution between patients and con-trols (x2 4 0.14, d.f. 4 1, P 4 0.710).

Significant evidence for linkage disequilibrium be-tween the D3S1310 marker and the DRD3 exon 1 Ballpolymorphism was not detected in the present sample(data not shown). In view of the previous reports of anassociation between schizophrenia and the BalI DRD3polymorphism, it would be of interest to examine in-teractions between D3S1310 and the BalI polymor-phism. Multivariate analysis was therefore performed.Using illness status as the outcome variable, logisticregression was used to examine the individual andjoint effects of DRD3 and D3S1310 genotypes, the lat-ter based on presence or absence of the 141 bp allele.Only D3S1310 genotypes predicted illness status. TheDRD3 genotypes were removed from the regressionequation, without significantly altering the goodness offit (results not shown).

The power to detect an overall difference (a 4 0.05)between schizophrenic patients and control subjectswas 1.00 and 0.91 assuming ‘‘large’’ (w 4 0.5) or ‘‘me-dium’’ (w 4 0.3) effect sizes, respectively. However,assuming a ‘‘small’’ (w 4 0.1) effect size the power(0.15) was not sufficient. The effect size of the presentassociation with regard to the D3S1310 141 bp allelewas 0.14, giving a power of 0.79 and 0.50 comparingalleles and genotypes, respectively.

DISCUSSION

In the present study a trend for an association wasfound between schizophrenia and D3S1310. Pendingreplication, these results must be considered tentative,because case-controls studies are prone to populationstratification artefacts. It should also be noted that theresults miss statistical significance, using a conserva-tive correction for multiple comparisons. Also, takingthe low effect size into account, the power was subop-timal, giving a possibility for a false positive finding.

Linkage disequilibrium between D3S1310 and theDRD3 BalI polymorphism could not be detected in thepresent sample. This may seem surprising in view of

the relatively small genetic distance between the BalIand the D3S1310 polymorphism. However, linkage dis-equilibrium is not always present even for closely situ-ated polymorphisms, e.g., the −141 Ins/Del promoterand the TaqIA polymorphisms separated by more than270 kb in the dopamine D2 receptor gene [Arinami etal., 1997]. In addition, there appeared to be no signifi-cant interaction in the risks conferred individually bythe 141 bp allele at D3S1310 and the DRD3 BalI poly-morphism. Taken together, these results suggest thatrisk for schizophrenia is conferred independently byboth loci, or other loci in physical proximity to them. Amore parsimonious explanation may be the presence ofa third locus, with which both DRD3 and D3S1310 arein linkage disequilibrium. This would also provide areasonable explanation for the negative association inthe present study.

ACKNOWLEDGMENTS

We thank Alexandra Tylec and Kjerstin Lind, De-partment of Clinical Neuroscience, for technical assis-tance.

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