Genetic association between schizophrenia and the DISC1 gene in the Scottish population.код для вставкиСкачать
American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 141B:155 –159 (2006) Genetic Association Between Schizophrenia and the DISC1 Gene in the Scottish Population Feng Zhang,2 Jane Sarginson,1,2 Caroline Crombie,2 Nick Walker,3 David St. Clair,2 and Duncan Shaw1* 1 School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland, UK Department of Mental Health, Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland, UK 3 Ravenscraig Hospital, Greenock, Scotland, UK 2 Several lines of evidence support the involvement of the disrupted in schizophrenia 1 (DISC1) gene in schizophrenia susceptibility, including its original identification in a schizophrenia family with a chromosome translocation, several genetic association studies, and functional characterization of the gene product. In the present study, we have genotyped multiple SNP and microsatellite markers in a large Scottish case-control sample. We identified two SNPs and one microsatellite that show significant association with schizophrenia. The strongest association is with a haplotype of SNPs rs751229 and rs3738401, located at the 50 end of the gene; the C-A haplotype of these SNPs is associated with a relative risk of schizophrenia of 5 in our population. We also observe association with a microsatellite in intron 7, but no association with markers toward the 30 end of the gene. The results are in broad agreement with those of other genetic studies, but there are differences in terms of the precise patterns of association. This analysis further strengthens the candidacy of DISC1 as a risk factor for schizophrenia in the general population, and suggests that more intensive searching for causative variants is justified. ß 2006 Wiley-Liss, Inc. KEY WORDS: Schizophrenia; DISC1; association; haplotype; Scotland INTRODUCTION There is little doubt that schizophrenia has a significant genetic component. However, it has been difficult to identify the predisposing genes. The approaches taken have included family-based linkage, case-control and family-based association, cytogenetic abnormality studies, genome-wide scans, and candidate gene studies. These have recently led to the identification of plausible candidate genes including neuregulin [Stefansson et al., 2002, 2003], G72 and D-amino acid oxidase [Chumakov et al., 2002], and dysbindin [Straub et al., Jane Sarginson and Feng Zhang made equal contributions to this study. Grant sponsor: University of Aberdeen. *Correspondence to: Prof. Duncan Shaw, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK. E-mail: email@example.com Received 22 July 2005; Accepted 10 November 2005 DOI 10.1002/ajmg.b.30274 ß 2006 Wiley-Liss, Inc. 2002]. For a recent review of schizophrenia genetics, see Owen et al. . A Scottish family in which the balanced translocation t(1;11)(q42;q14.3) cosegregates with major mental disorders with maximum LOD ¼ 6.0 [St. Clair et al., 1990; Blackwood et al., 2001], was the starting point for the identification of the disrupted in schizophrenia 1 (DISC1) gene at 1q42.1 [Millar et al., 2000a]. It encodes a protein of 854 amino acids, with no obvious homology to other proteins of known function [Millar et al., 2001]. The DISC1 locus is transcriptionally complex, with a small, apparently non-translated gene DISC2 that overlaps one of the exons of DISC1, and the TSNAX (TRAX, or translin-associated factor X) gene that is involved in intergenic splicing with DISC1 [Millar et al., 2000b]. Linkage and association studies with DISC1 have since then been carried out worldwide. Linkage analysis in Finnish families indicated 1q42 as a possible locus for schizophrenia and the strongest linkage signal was obtained from marker D1S2709, which is located within the DISC1 gene [Ekelund et al., 2001, 2004]. Haplotype transmission analysis also yielded positive evidence, but showed sex differences [Hennah et al., 2003]. Positive associations have also been found in North American studies [Hodgkinson et al., 2004; Callicott et al., 2005]. Furthermore, Sachs et al.  reported a frameshift mutation at the extreme 30 end of exon 12 of DISC1 in a familial case of schizophrenia. As well as the evidence from genetics, recent functional studies of the cell biology of DISC1 also add to our understanding of how it may be involved in schizophrenia. Morris et al.  and Brandon et al.  showed that it interacts with several proteins of the cytoskeletal system and centrosome, including Nudel. The interaction with Nudel is through the DISC1–Nudel–LIS1 complex, which is disrupted in the form of DISC1 truncated by the translocation. The DISC1– Nudel–LIS1 complex is also involved in the Reelin-related signaling pathway [Assadi et al., 2003]. All of these phenomena may be directly or indirectly associated with schizophrenia or other cortical developmental disorders [Impagnatiello et al., 1998; Guidotti et al., 2000; Hong et al., 2000; Eastwood and Harrison, 2003]. Mutant DISC1 is proposed to contribute to schizophrenia susceptibility by disrupting intracellular transport, neurite modeling, and neuronal migration [Morris et al., 2003; Ozeki et al., 2003]. These functional studies further strengthen the candidacy of this gene as a genetic risk factor. In the present study, we have analyzed a series of markers along the length of the DISC1 gene for association with schizophrenia in a Scottish case-control sample set. We selected four SNPs, in intron 1, exon 2, intron 9, and exon 11, and three microsatellites, in introns 7, 9, and 10, for genotyping for association with schizophrenia. We analyzed the markers individually and as haplotypes. The results provide further evidence of the involvement of the DISC1 gene in schizophrenia. 156 Zhang et al. MATERIALS AND METHODS Patients and Controls Unrelated schizophrenics (n ¼ 677; mean age 37, range 17– 66) of apparent European ancestry were recruited from the Scottish population, all meeting the DSM IV criteria for schizophrenia or schizoaffective disorder, and reassessed using the OPCRIT system. Diagnosis was based on psychiatric case note inspection and, when appropriate, through the use of the lifetime version of the Schizophrenia and Affective Disorders Schedule. Diagnosis was confirmed by consensus of two senior psychiatrists. Control individuals (n ¼ 648; mean age 36, range 18–58) of Scottish origin were obtained from the Aberdeen blood Transfusion Service (ABTS). The ABTS controls were not specifically screened for the presence of schizophrenia but individuals on long-term medication do not donate blood, which excludes major psychiatric illness. The study was approved by Grampian Regional Ethics Committee (LREC) and Multi-Regional Ethics Committee (MREC), Scotland. Genetic Markers SNPs were obtained from public databases, and were genotyped as follows. Marker rs821616 (exon 11) was genotyped by using dynamic allele-specific hybridization [DASH; Prince and Brookes, 2001]. The primers were GAAGCTTGTCGATTGCTTATC and TTATCCAGAGCCTACAG. The DASH probes were TTATCCAGTGCCTACAG (T allele) and TTATCCAGAGCCTACAG (A allele). Markers rs751229 (intron 1) and rs1984895 (intron 9) were genotyped by K-Biosciences (Cambridge, UK) using AmplifluorTM chemistries. For rs751229, the allele-specific forward primers were GAAGGTCGGAGTCAACGGATTAGGCATGAGCCACTGCGCCT and GAAGGTGACCAAGTTCATGCTGCATGAGCCACTGCGCCC, and the reverse primer was TTGAGCTATGATGGCTCTT. For rs1984895, the allele-specific forward primers were GAAGGTGACCAAGTTCATGCTTTTCATAGGGTGATAACCTATAGAACC and GAAGGTCGGAGTCAACGGATTGTTTCATAGGGTGATAACCTATAGAACT, and the reverse primer was CTGCCATGTTGCTATAGCAGATGGATAA. Marker rs3738401 (exon 2) was genotyped by restriction digestion with enzyme DbeI. The forward primer was GGTCCCCCCAACCCCTCC, and the reverse primer CATCCCCGGAGCCGCTGC. The PCR reaction produces a 386 bp product containing two DbeI restriction sites, one of which is constant, and the other is cut when allele A is present, but uncut with allele G. The results were scored by electrophoresis using a 4% agarose gel. Microsatellite markers were identified by inspection of the genomic DNA sequence, and were given names reflecting the nature of the repeat, and the position in the sequence relative to an arbitrary origin (e.g., CA95066 is a (CA)n dinucleotide repeat at position 95066). Their absolute positions on chromosome 1 in the UCSC Genome Browser (genome.cse.ucsc.edu; May 2004 data release) and the PCR primers used were as follows. CA95066: position 228240406-228240690 (intron 7); primers TGCACAGACACGAATGTG and TAATGAGTGCAAGGAAGG. AT157017: position 228395133-228395320 (intron 9); primers TGAAATCACCTTGGCCTATTG and ATTGCAAAGACCAGCCATCA. CA212755: position 228444954-228445242 (intron 10); primers CGAGATGTCTTTCTGTGGGTG and CATGCCTCCCCCTCTCTAGTC. These markers were genotyped by using fluorescently labeled PCR primers and analysis on an ABI automated DNA sequencer with appropriate size markers. Statistical Analysis For SNPs, association between disease and allele or haplotype frequencies was tested by Chi-square test. Haplotype frequencies were estimated from genotype data using the software Phase [Stephens et al., 2001], kindly made available by the authors (www.stat.washington.edu/stephens/software. html). For microsatellites, the significance of allele distribution differences between cases and controls was assessed using the Clump Monte Carlo simulation method [Sham and Curtis, 1995]. RESULTS Microsatellite Analysis In a preliminary study using pooled DNA samples from 200 patients and controls, nine microsatellites distributed among introns 4–12 of the DISC1 gene were tested for association with schizophrenia (J. Sarginson, PhD thesis, University of Aberdeen, 2003). Those showing evidence of association were then tested by individual genotyping. The marker CA95066 in intron 7 showed a significantly different allele distribution between cases and controls (P < 0.01; n ¼ 200 each). Markers AT157017 in intron 9, and CA212755 in intron 10, showed no significant association (P ¼ 0.211, n ¼ 600; P ¼ 0.518, n ¼ 200, respectively). Individual SNP Marker Genotyping Four SNPs in the DISC1 gene were genotyped in this study: rs751229, a C/T change in intron 1; rs3738401, a G/A change in exon 2 causing a Arg/Gln substitution; rs1984895, a G/A change in intron 9; and rs821616, an A/T change in exon 11 causing a Ser/Cys substitution. The results of the analysis for genetic association with schizophrenia are shown in Table I. Two of the polymorphisms (rs751229 and rs3738401) showed statistically significant association (P < 0.05) with schizophrenia, when analyzed by genotype or by allele frequency. The remaining SNPs, rs1984895 and rs821616, showed no significant association. None of the genotype frequencies showed significant deviations from the Hardy–Weinberg expectation, but there was a non-significant excess of heterozygotes for rs751229 among the patient group. Haplotype Analysis The two SNPs that showed association with schizophrenia (rs751229 and rs3738401) were found to be in linkage disequilibrium with each other, in the patients (D ¼ 0.124; r2 ¼ 0.277; P < 0.0001) and controls (D ¼ 0.06; r2 ¼ 0.079; P < 0.0001). These two SNPs were used for haplotype estimation in both the case and control populations. The results are shown in Table II. For the 2-marker haplotypes of rs751229 and rs3738401, there is an excess of C-A, and a deficit of T-A, in the cases relative to the controls. For the haplotypes of the three SNPs rs751229, rs3738401, and rs821616, those most over-represented in the cases are C-A-G and C-A-A. For both 2and 3-marker haplotypes including rs751229 and rs3738401, the overall association with disease was highly significant (P < 1050). The addition of the third SNP to the haplotype partitions the numbers in accordance with its allele frequencies; no new associations are revealed, and the relative risks are little changed by the addition of the third SNP. The same Association Between Schizophrenia and DISC1 Gene TABLE I. Genotype and Allele Numbers and Frequencies for Four SNPs in DISC1 in Schizophrenia Cases and Controls, and P Values for Association With Disease rs751229 TT CT CC T C rs3738401 GG GA AA G A rs1984895 GG GA AA G A rs821616 AA AT TT A T P Cases Controls 153 (0.32) 250 (0.52) 76 (0.16) 556 (0.58) 402 (0.42) 134 (0.40) 162 (0.49) 38 (0.11) 430 (0.64) 238 (0.36) 0.029 252 (0.43) 260 (0.45) 72 (0.12) 764 (0.65) 404 (0.35) 302 (0.53) 230 (0.40) 41 (0.07) 834 (0.73) 312 (0.27) 0.0006 337 (0.59) 204 (0.36) 30 (0.05) 878 (0.77) 264 (0.23) 344 (0.63) 177 (0.32) 27 (0.05) 865 (0.79) 231 (0.21) 0.434 317 (0.52) 241 (0.40) 48 (0.08) 875 (0.72) 337 (0.28) 294 (0.51) 223 (0.39) 61 (0.10) 811 (0.70) 345 (0.30) 0.293 0.010 0.0001 0.245 0.273 was found when the fourth SNP was added to the haplotype (data not shown). Two-marker haplotype frequencies were also estimated for the pair rs1984895 and rs821616. These showed no significant differences between the disease and control populations (P ¼ 0.317). DISCUSSION Millar et al. [2000a] first reported that DISC1 was disrupted by a chromosome translocation in a family with numerous cases of schizophrenia and other mental illnesses. Linkage of schizophrenia in Finnish families to D1S2709, which is located within DISC1, was reported by Ekelund et al. . More recently, Thomson et al.  showed that SNPs in DISC1 are associated with both schizophrenia and bipolar disorder in a 157 Scottish population. Thus, the role of DISC1 in schizophrenia is supported by several lines of evidence. The main conclusions from this study are that we find further evidence for the involvement of DISC1 in genetic susceptibility to schizophrenia, that the important variants are most likely in the 50 region of the gene, but that we have not established that any particular variant is directly responsible. We also found association with a microsatellite in intron 7, in the middle of the gene, but no association with markers at the 30 end. A Finnish study [Hennah et al., 2003] showed undertransmission of haplotypes containing the T allele of rs751229 and the A allele of rs3734801 to affected individuals in families. Hodgkinson et al. , using a North American patient cohort of white European origin, also reported undertransmission of a DISC1 haplotype including the A allele of rs3738401. Using a case-control study design, we have found that the T-A haplotype is less than half as frequent in schizophrenics as it is in controls, which is in broad agreement with the Finnish and American findings. Only one of these SNPs, rs3738401, causes an amino-acid substitution (Gln/Arg in exon 2). Rs751229 is in a non-conserved region of intron 1 and is unlikely to be functional. The relative risks of schizophrenia associated with haplotypes of these two SNPs are: C-A fivefold higher; T-A threefold lower; C-G and T-G, little change. The effect of rs751229 is therefore dependent on the presence of the A allele of rs3734801. There seems to be no simple explanation for the effects of these SNPs. Presumably they are acting as markers for other, nearby variants that are causative. The only common non-synonymous SNP in the database in this region of the gene is in exon 1 (rs3738400, ValGly). It is possible that this SNP, promoter variants, or other undiscovered mutations are functionally involved in the susceptibility to schizophrenia. The HapMap database for linkage disequilibrium in the human genome (www.hapmap. org) does not help to distinguish between these possibilities, because different SNPs have been used. However, HapMap does indicate that the 50 end of the gene, including the region 50 to exon 1, exon 1 itself, and part of intron 1 are within the same LD block. Regions of the gene 30 to these markers are in separate LD blocks. Callicott et al.  reported a significant over-transmission of the A allele at rs821616 close to the 30 end of the gene, and a modest (non-significant) over-transmission of the C allele of rs751229, to schizophrenics in a North American familybased study. Our study found no association with rs821616. Thomson et al.  analyzed a large number of SNPs from DISC1 for association with schizophrenia and bipolar disorder, TABLE II. Two- and Three-Marker Haplotype Estimated Frequencies and Relative Risks in Schizophrenia Cases and Controls for Haplotypes Involving SNPs in DISC1 that Individually Show Association With Disease SNPs rs751229-rs3738401-rs1984895 rs751229-rs3738401 Haplotype C-A-G C-A-A C-G-G C-G-A T-A-G T-A-A T-G-G T-G-A C-A C-G T-A T-G Frequency in cases 0.208 0.065 0.106 0.036 0.064 0.010 0.391 0.119 0.269 0.151 0.079 0.501 Frequency in controls 0.044 0.012 0.133 0.032 0.152 0.045 0.460 0.121 0.068 0.201 0.204 0.527 P value 19 6.3 10 8.3 107 0.136 0.764 2.2 107 0.00012 0.011 0.959 2.4 1022 0.017 4.5 1011 0.352 Relative risk 5.71 5.72 0.77 1.13 0.38 0.21 0.75 0.98 5.04 0.71 0.33 0.90 P values for the Chi-square test for overall association of haplotypes with disease are 3 1056 for the 3-marker haplotypes, and 2 1052 for the 2-marker haplotypes. 158 Zhang et al. including rs751229, rs3738401, and rs821616. In their study, none of these three SNPs was associated with schizophrenia, but they instead found association with SNPs in intron 4, exon 6, and intron 6, closer to the central part of the gene. These discrepancies may be the result of different haplotype structures and/or heterogeneity of causative alleles in different populations. Sachs et al.  have found a frameshift mutation in DISC1 in an American schizophrenia family; further screening studies on a large scale might reveal more such novel mutations. The biochemical interactions of DISC1 have been studied by Morris et al. . The C- and N-terminal regions of the protein interact with different protein partners in the cell. In the truncated DISC1 protein predicted to occur in patients with the translocation [Millar et al., 2000a], the C-terminal portion of the protein, which interacts with ATF5 and NUDEL, would be lost. However, in the present study, the association is with markers in the 50 region of the gene, corresponding to the N-terminal portion. This part of DISC1 interacts with MAP1A, the light chain of the MAP microtubule-associated protein. The latter is involved in microtubule networks in mature neurons, influencing cell shape and intracellular transport. If there are variants in DISC1 that alter the N-terminal domain of the protein’s structure or function, in LD with the markers rs751229 or rs3738401, it could be that the effect on schizophrenia is mediated via the interaction of DISC1 and MAP1A. Alternatively (or additionally), variants in the promoter region might adversely affect gene expression, leading to the increase in susceptibility to schizophrenia. Kockelkorn et al.  reported promoter polymorphisms in DISC1 that initially showed association with schizophrenia in a Japanese population, but that this association failed to be replicated in a second sample. 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