Case-control association study of Disrupted-in-Schizophrenia-1 (DISC1) gene and schizophrenia in the Chinese population

JOURNAL OF PSYCHIATRIC RESEARCH

Journal of Psychiatric Research 41 (2007) 428–434

www.elsevier.com/locate/jpsychires

Case-control association study of Disrupted-in-Schizophrenia-1 (DISC1) gene and schizophrenia in the Chinese population Qing-Ying Chen a,b, Qi Chen b,c, Guo-Yin Feng d, Klaus Lindpaintner e, Li-Jun Wang f, Zheng-Xiong Chen g, Zhen-Song Gao g, Ji-Sheng Tang h, Gang Huang i, Lin He b,c,* a

c

Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 319 Yue Yang Road, Shanghai 200031, PR China b Bio-X Life Science Research Center, Shanghai Jiaotong University, P.O. Box 501, Hao Ran Building, 1954 Hua Shan Road, Shanghai 200030, PR China Institute for Nutritional Sciences, SIBS, Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai 200031, PR China d Shanghai Institute of Mental Health, 600 South Wan Ping Road, Shanghai 200030, China e Roche (China) Ltd, 1100 Long Dong Avenue, Pudong New Area, Shanghai 201203, PR China f Shenyang Tiexi Institute of Mental Health, Liaoning, China g Shantou Institute of Mental Health, Guangdong, China h Shandong Institute of Mental Health, Shandong, China i Medical College, Shanghai Jiao Tong University, 1954 Hua Shan Road, Shanghai 200030, PR China Received 11 October 2005; received in revised form 4 January 2006; accepted 10 January 2006

Abstract Disrupted-in-Schizophrenia-1 (DISC1) has first been identified as a candidate gene for schizophrenia through study of a Scottish family with a balanced (1; 11) (q42.1; q14.3) translocation. Lots of linkage and association studies supported DISC1 as a risk factor for schizophrenia. In this study, we genotyped three SNPs in DISC1 using a set of Han Chinese samples of 560 schizophrenics and 576 controls. No positive association was detected in the whole samples but analysis of allele frequencies in female samples showed weak association between SNP rs2295959 and the disease (v2 = 6.188, P = 0.0135, OR = 0.728, 95% CI = 0.567–0.935). Our results provide further evidence for sex difference for the effect of the gene on the aetiology of schizophrenia. Our findings also would encourage further studies, particularly family-based association studies with larger samples, to analyze the association between DISC1 and schizophrenia.  2006 Elsevier Ltd. All rights reserved. Keywords: DISC1; Case-control; Association; Schizophrenia; Chinese

1. Introduction Schizophrenia is a debilitating psychiatric disorder, which is associated with a high rate of morbidity and mortality. A large body of data collected from family,

*

Corresponding author. Tel./fax: +86 21 62822491. E-mail address: [email protected] (L. He).

0022-3956/$ - see front matter  2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2006.01.001

twin, and adoption studies over many years has consistently supported the involvement of a major, complex genetic component in liability to schizophrenia. Heritability estimates for schizophrenia range from 70% to 80% (Gottesman, 1991). While the ultimate biological cause is unknown, schizophrenia is believed to be of neurodevelopmental origin. Disrupted-in-Schizophrenia-1 (DISC1) was identified as the sole gene in which a mutant truncation by

Q.-Y. Chen et al. / Journal of Psychiatric Research 41 (2007) 428–434

a balanced t (1; 11) (p42.1; q14.3) translocation is cosegregated with schizophrenia in a large Scottish family (Millar et al., 2000). Ekelund and colleagues found a microsatellite maker in DISC1 provided strong evidence for linkage to schizophrenia in a Finnish family (Ekelund et al., 2001). Using another set of samples of 70 Finnish families with multiple individuals affected with schizophrenia, they also found that a polymorphic marker and a haplotype in DISC1 showed evidence of association with schizophrenia (Ekelund et al., 2004). Furthermore, a marker located nears the breakpoint of a balanced translocation t (1; 11) (q42.1; q14.3) in DISC1 also showed linkage to schizophrenia in Taiwanese families (Hwu et al., 2003). Recently, Cannon et al. (2005) found a haplotype incorporating 3 single-nucleotide polymorphic markers near the translocation break point of DISC1 associated with schizophrenia in their population-based twin cohort study. Positive associations between DISC1 and both bipolar disorder and schizophrenia were reported in a Scottish population and a North American white population (Thomson et al., 2005; Hodgkinson et al., 2004). Data from biochemical and cellular assays also provided evidences to support the important role of DISC1 in schizophrenia pathogenesis. Results from in situ hybridization assays demonstrate that DISC1 is strongly expressed in mouse hippocampus during all stages of hippocampal development, and suggest that developmental DISC1 dysfunction may lead to defects in hippocampal function that are associated with schizophrenia (Austin et al., 2004). In the primate brain, DISC1 expression is highly localized in the dentategyrus of the hippocampus and lateral septum by in situ hybridization (Austin et al., 2003). The subcellular distribution of a DISC1 isoform is observed significantly changed in the orbitofrontal cortex of brains from patients with SZ and major depression (MD) (Sawamura et al., 2005). Given the importance of these regions in schizophrenia pathogenesis, these results suggest brain circuits with DISC1 truncation may lead to schizophrenia. In addition, two-hybrid and co-immunoprecipitation assays revealed DISC1 interacts with multiple proteins of the centrosome and cytoskeletal system, proteins which localize receptors to membranes, and proteins which transduce signals from membrane receptors (Morris et al., 2003). It is found that DISC1 protein predominantly localizes to mitochondria, deficits in which have been reported in schizophrenia and other psychiatric disorders (James et al., 2004). NudElike (NUDELl), implicated to play a role in neuronal migration, is able to act as a bridge between DISC1 and LIS1, mutations in which cause many of the autosomal dominant forms of lissencephaly, a disease characterized by malformation of the human brain due to a severe disruption in neuronal migration

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(Dobyns et al., 1993; Lo Nigro et al., 1997), to form a trimolecular complex to bind to different cytoskeletal components (Brandon et al., 2004). In vitro, DISC1 is able to competitively inhibit the activity of Nudel as oligopeptidase A (EOPA) that is involved in the regulation of neuropeptide action in the CNS (Hayashi et al., 2005). Moreover, DISC1 participates in neurite outgrowth through its interaction with fasciculation and elongation protein f-1 (FEZ1) that is reported to represent a new protein family involved in axonal outgrowth and fasciculation (Miyoshi et al., 2003). Neurite Outgrowth Assay indicated mutant truncation of DISC1 is associated with shorter neurites and with a decreased percentage of neurons bearing neuritis (Ozeki et al., 2003). In another DISC1 yeast two-hybrid screens, Millar and colleagues identified 21 proteins playing roles in gene transcription, mitochondrial function, modulation of the actin cytoskeleton, neuronal migration, glutamate transmission, and signal transduction (Millar et al., 2003). One of the proteins, WKL1, has previously been found associated with catatonic schizophrenia (Meyer et al., 2001). These data suggested the involvement of DISC1 protein in intracellular transport, neurite architecture and neuronal migration. All this combined evidence suggests that DISC1 as a susceptibility gene for schizophrenia. Given the importance of independent observation of association findings in genetically complex diseases such as schizophrenia, we aimed at investigating the role of DISC1 in the etiology of schizophrenia in an independent sample of schizophrenic patients and controls from China. Three SNP polymorphisms (rs2492367, rs821616 and rs2295959) were genotyped in 560 Chinese patients and 576 Chinese control individuals.

2. Materials and methods 2.1. Subjects All subjects were Han Chinese in origin. A total of 560 unrelated schizophrenic patients (53.4% male) with a mean age 37.3 ± 13.6 years were collected from Liaoning, Guangdong and Shandong province of China. Consensus diagnosis of each patient was made by two independent psychiatrists according to the DSMIV (Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition) (Flaum et al., 1997) criteria for schizophrenia. Subtypes of schizophrenia patients in our study are: SC(6), SH (4), SP(293), SR(58), SS(28), SU(142) and there are 29 cases (<6%) with no subtype data. Five hundred and seventy six unrelated healthy persons (51.9% male) with a mean age 33.2 ± 10.47 years from the same geographical region were used as controls. All of them were interviewed

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to exclude any history of psychiatric disorders. The study was approved by the local psychiatry research ethics committees and informed consent was obtained from all subjects. 2.2. Genotyping In view of the information from dbSNP (http:// www.ncbi.nlm.nih.gov/SNP/) that exon 2, 6, 9, 11 contain several SNPs with more than 10% average estimated heterozygosity, we sequenced these four exons and adjacent introns of the DISC1 gene in 100 healthy Han Chinese (mean age 35.7 ± 8.7 years; 78% male) with ABI Prism 3100 sequencer (Applied Biosystems) and found three SNPs – rs2492367, rs821616 and rs2295959 with more than 5% minor allele frequencies. Therefore, we selected these SNPs for the present study. Rs2492367, rs821616 and rs2295959 are respectively located in exon6, exon11 and intron in the DISC1 gene spanning around 238kb, average intervals of approximately 59.5kb. Genomic DNA was extracted from venous blood collected from subjects by a standard phenol extraction procedure. All SNPs were genotyped by allele-specific PCR, in which primers were designed to specifically amplify the reference allele or its variant in separate PCR reactions (Greenwood et al., 2001). The assay used in this study combines kinetic (real-time quantitative) PCR with allele-specific amplification (Germer et al., 2000). The primers sequences used for three SNPs were as follows: For rs2492367: 5 0 -CTTGCTTGGAGAGCTTCA/G-3 0 (allele-specific primer) and 5 0 -TG-TCTCCTCATTCTCTACAGAAAGA-3 0 (common primer); for rs821616: 5 0 -TGGCTT-CCTGGAGCTGTAGACA/T-3 0 (allelespecific primer) and 5 0 -TGCCTTTGTTTCCTCTCTGTCTC-3 0 (common primer); for rs2295959: 5 0 -GAGGGAAGACCATAAAGTGG- ATC/T-3 0 (allele-specific primer) and 5 0 -GCATTCACATCTTCTACATCATCCT-3 0 (common primer). For real-time PCR, two PCR reactions were performed for each sample, with 10 ng genomic DNA, 0.05 ll DZ05 enzyme (Roche company), 0.2 lM allele-specific primer, 0.2 lM common primer and 0.2 · SYBR Green I (Molecular Probe, Inc.) in a total volume of 25 ll. To reduce well-to-well variability in PCR reaction conditions, an automated dispenser (Hydra microdispenser, Robbins Scientific) and digital multichannel pipettes (Thermo Labsystems) were used. Kinetic PCR reactions were performed on an ABIPRISM 7900 Sequence Detection System (Applied Biosystems). After an initial 2 min incubation step at 50 C to activate the AmpErase uracil-N-glycosylase (UNG) and a step of 12 min at 95 C to deactivate UNG and activate AmpliTaq Gold enzyme, 50 cycles consisting of 15 s at 95 C and 30 s at annealing temperature were performed, followed by a final stage of dissociation for checking PCR product. Allele calling was

manually performed as the previous research of our lab (Tang et al., 2003). 2.3. Statistical analysis Genotype, allele and haplotype frequencies in different groups of subjects were compared using the CLUMP program (version 1.9) (Sham and Curtis, 1995) with 10,000 stimulations. The P values reported are two tailed and significance was accepted at P < 0.05. A P value of 0.05 was considered significant in tests for Hardy–Weinberg equilibrium. The standardized measure of linkage disequilibrium (LD), denoted as ‘‘D 0 ,’’ was estimated with software 2LD (Zapata et al., 2001). Permutation test was performed by COCAPHASE program with 1000 random permutations (Dudbridge, 2003). Haplotype frequencies were estimated by EHPLUS, which performs model-free analysis and permutation tests of allelic association based on EH (Xie and Ott, 1993) R2 values, Odds Ratio and 95% confidence interval were calculated in the website http:// 202.120.7.14/analysis/myAnalysis.php (Shi and He, 2005).

3. Results In our case-control analysis 560 schizophrenics were genotyped and compared with a set of 576 controls. Table 1 gives the allele and genotype frequencies of the three markers. Genotypic distributions of these three polymorphisms did not deviate significantly from Hardy–Weinberg equilibrium. As shown in Table 1, no SNP showed significant difference in allele frequencies between total 576 control and 560 patients individuals. But SNP rs2295959 gave a weak different allele frequencies between cases and controls in female samples (v2 = 6.188, P = 0.0135, OR = 0.728, 95% CI = 0.567–0.935) (shown in Table 2) while not in male samples and permutation test also suggested difference between female patients and female controls (Global significance: P = 0.0399). Also, the genotype frequencies of SNP rs2295959 shown gender difference: in female patients, CC 34.5%, CT 50.8%, TT 14.7%, in female controls, CC 42.4%, CT 49.6%, TT 8.0%, v2 = 7.61, P = 0.022; in male patients, CC 44.2%, CT 45.5%, TT 10.3%, in male controls, CC 39.3%, CT 48.3% TT 12.3%, v2 = 1.65, P = 0.417. After dividing the cases into SP and others, we failed to find any difference in allele frequencies for rs2295959 (in female cases, P = 0.66; in male cases, P = 0.68). However, low LD value revealed that each pair of SNPs was in modest linkage disequilibrium both in the schizophrenic and control groups. R2: rs2492367–rs2295959 0.018, rs2492367–rs821616 0, rs2295959–rs821616 0.001;

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Table 1 Statistical analysis for polymorphisms of the DISC1 gene in total samples Marker

Distancea (kb)

rs2492367 Patients Controls

0

rs2295959 Patients Controls

48.1

rs821616 Patients Controls

238.0

a b c

nb

Genotypec

HWE (v2)

P-value (2df)

Allelec

P-value (1df)

OR (95%CI)

557 560

AA 7(1.3) 7(1.3)

AG 121(21.7) 148(26.4)

GG 429(77.0) 405(72.3)

0.22 2.59

0.1747

A 135(12.1) 162(14.5)

G 979(87.9) 958(85.5)

0.1107

0.827(0.647–1.058)

559 576

CC 222(39.7) 235(40.8)

CT 268(47.9) 282(49.0)

TT 69(12.3) 59(10.2)

0.74 3.68

0.5291

C 712(63.7) 752(65.3)

T 406(36.3) 400(34.7)

0.6280

0.933(0.785–1.108)

560 574

AA 6(1.1) 7(1.2)

AT 114(20.4) 143(24.9)

TT 440(78.6) 424(73.9)

0.21 1.74

0.1827

A 126(11.3) 157(13.7)

T 994(88.7) 991(86.3)

0.0871

0.800(0.623–1.028)

The distance from rs2492367. Number of samples which are well genotyped. Frequencies are shown in parenthesis (%).

Table 2 Statistical analysis for polymorphisms of the DISC1 gene in female and male samples Gender

Marker

Allelea

Female

rs2492367 Patients Controls rs2295959 Patients Controls rs821616 Patients Controls

A 70(13.6) 85(15.8) C 309(59.9) 371(67.2) A 61(11.8) 73(13.3)

G 444(86.4) 453(84.2) T 207(40.1) 181(32.8) T 457(88.2) 477(86.7)

rs2492367 Patients Controls rs2295959 Patients Controls rs821616 Patients Controls

A 65(10.8) 77(12.9) C 403(66.9) 381(63.5) A 65(10.8) 84(14.0)

G 535(89.2) 505(87.1) T 199(33.1) 219(36.5) T 537(89.2) 514(86.0)

Male

a b

v2

P-valueb

OR (95%CI)

0.995

0.3361

0.840(0.597–1.183)

6.188

0.0135

0.728(0.567–0.935)

0.545

0.5139

0.872(0.606–1.254)

1.193

0.2779

0.806(0.567–1.146)

1.571

0.2330

1.164(0.918–1.476)

2.9128

0.0916

0.741(0.524–1.046)

Frequencies are shown in parenthesis (%). P-values shown in bold reach significant level (P < 0.05).

Table 3 Estimated haplotypes in the case-control samples Haplotypea

rs2492367

rs2295959

rs821616

1 2 3 4 5 6

A A G G G G

C T C C T T

T T A T A T

Haplotype frequency (%) Case

Control

47.75(4.3) 76.95(6.9) 70.23(6.3) 583.81(52.3) 43.47(3.9) 281.49(25.2)

63.16(5.6) 76.43(6.8) 71.63(6.4) 570.13(50.9) 60.96(5.4) 256.28(22.9)

Global a

v2

P-value

Odds ratio (95%CI)

2.195 0.004 0.010 0.444 3.009 1.677

0.125 0.934 0.929 0.499 0.075 0.193

1.007(0.627–1.619) 0.912(0.405–2.054) 1.037(0.878–1.225) 0.923(0.663–1.285) 1.023(0.866–1.210) 0.890(0.607–1.305)

8.879

0.175

Haplotypes were omitted from analysis if the estimated haplotype probabilities were less than 1%.

D 0 : rs2492367–rs2295959 0.258, rs2492367–rs821616 0.035, rs2295959–rs821616 0.053. We analyzed the frequencies of the haplotypes of the three SNPs but only those were common (at least 1% frequency in either case

or control groups) (shown in Table 3). There was no difference in frequencies of haplotypes constructed by the three SNPs between cases and controls (global v2 = 8.879, P = 0.175).

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4. Discussion In recent years, many polymorphisms located in regions of chromosome 1 were reported as susceptibility loci for schizophrenia. Positive results of linkage or association studies were found at 1q21-23 (Cai et al., 2002; Chowdari et al., 2002; Wittekindt et al., 1998), 1q22 (Brzustowicz et al., 2000, 2002, 2004), 1q31–32 (Yu et al., 2004), 1q32.2-q41 (Hovatta et al., 1999; Gurling et al., 2001) or 1q42 (Ekelund et al., 2001; St. Clair et al., 1990). However, other studies did not detect polymorphisms associated with increased risk for schizophrenia (Levinson et al., 2002; Maziade et al., 2002; Laurent et al., 2003). Initially 1q42 identified as a susceptible site for schizophrenia is due to a balanced (1; 11) (q42.1; q14.3) translocation in DISC1 that was found to co-segregate with schizophrenia (St. Clair et al., 1990). Later, linkage and association findings of DISC1 at 1q42 were replicated in Finnish and Taiwanese families (Ekelund et al., 2001, 2004; Hwu et al., 2003). These data confirmed the DISC1 gene and the 1q42 locus as candidates closely related to schizophrenia. In this work, we investigate the association of three SNPs – rs2492367, rs821616 and rs2295959 in DISC gene with schizophrenia. Rs821616, a non-synonymous SNP in exon 11, is association with schizophrenia in Caucasian population according a recent report (Callicott et al., 2005). But our data did not confirm the association. The conflicting result may be due to the different ethnic population. Recently, negative association was found between rs2492367 and schizophrenia in Japanese, which is the same result with ours (Zhang et al., 2005). To our knowledge, it is the first time to report the relationship of rs2295959 with schizophrenia. We found a significant difference in allele and genotype frequencies of SNP rs2295959 in DISC1 gene between female case and control samples (v2 = 6.188, P = 0.0135, OR = 0.728, 95%CI = 0.567–0.935). Interestingly, Hennah reported the under-transmission of a haplotype in DISC1 tended to affected females (P = 0.00024) (Hennah et al., 2003). Their study suggested the sex-dependent effect of DISC1 in the pathogenesis of schizophrenia. But the particular allele offered some protection from the development of schizophrenia in their study. The findings of our study implied ‘‘T’’ allele of rs2295959 could raise the risk to suffer schizophrenia. What makes it different may be that: (a) the subjects used are from different population; (b) long distance about 130kb from rs2295959 to the two SNPs of HEP3 studied by Hennah. The possibility exists that rs2295959 is included in another haplotype leading to schizophrenia. Whatever, our results provided further evidence of sex-dependent effect of DISC1 in the genetics mechanism of schizophrenia. What should be mentioned is that variants from other genes also showed sex-specific susceptibility to schizophrenia.

SNP rs165599 in COMT seemed to affect primarily women and SNP rs175174 in ZDHHC8 showed female-specific effect in transmission distortion (Mukai et al., 2004; Shifman et al., 2002). Our findings supported the possibility that there are sex-specific genetic components involved in the pathology of schizophrenia. On the other hand, as case-control studies are susceptible to positive and negative artifacts from unknown population stratifications, further studies, particularly family-based association studies, are needed to confirm the association by genotyping more polymorphisms and haplotypes in DISC1.

Acknowledgements We are deeply grateful to all schizophrenic patients and healthy people who participated in the study, as well as the psychiatrists and mental health workers for their help in the recruitment of schizophrenic patients. We also thank Dr. G. He and Mr. Y.Y. Shi for providing some valuable information of clinical diagnosis and statistics. This work was partially funded by Roche and the Chinese Ministry of Education, the National 863 and 973 Programs of China, the National Natural Science Foundation of China, and the Shanghai Municipal Commission for Sciences and Technology.

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