Association study between the TNXB locus and schizophrenia in a Japanese population.код для вставкиСкачать
American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 144B:305 –309 (2007) Association Study Between the TNXB Locus and Schizophrenia in a Japanese Population Mamoru Tochigi,1 Xuan Zhang,2,3 Jun Ohashi,2 Hiroyuki Hibino,1 Takeshi Otowa,1 Mark Rogers,1 Tadafumi Kato,4 Yuji Okazaki,5 Nobumasa Kato,1 Katsushi Tokunaga,2 and Tsukasa Sasaki1,6* 1 Department of Neuropsychiatry, Graduate School of Medicine, University of Tokyo, Bunkyo, Tokyo, Japan Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Bunkyo, Tokyo, Japan 3 Jilin University Research Center for Genomic Medicine, National Center of Human Genome Research, Jilin, P.R. China 4 Laboratory for Molecular Dynamics of Mental Disorders, Brain Science Institute, RIKEN, Wako-City, Saitama, Japan 5 Department of Neuropsychiatry, Faculty of Medicine, Mie University, Edobashi, Tsu City, Mie, Japan 6 Health Service Center, University of Tokyo, Bunkyo, Tokyo, Japan 2 The chromosome 6p21–24 region, which contains the human leukocyte antigen (HLA) region, has been suggested as an important locus for a susceptibility gene for schizophrenia. Recently, a significant association between schizophrenia and the TNXB locus, located immediately telomeric of the NOTCH4 locus in the HLA region, was observed. Few studies have further investigated the region in schizophrenia. In the present study, we investigated the region in a Japanese population. Subjects included 241 patients with schizophrenia and 290 controls. Twenty-six single nucleotide polymorphisms (SNPs) and the corresponding haplotypes were analyzed. As a result, exactly the same SNPs in the TNXB locus (rs1009382 and rs204887) as in the previous study were associated with schizophrenia (P ¼ 0.034 and 0.034, respectively, uncorrected). A SNP (rs2071287) in the NOTCH4 locus and haplotype around it were also suggested to associate with the disease, consistent with another previous study (P ¼ 0.041 and permutation P ¼ 0.024, respectively, uncorrected). Although these associations became insignificant after Bonferroni correction, the findings might provide support for the association of the TNXB locus or its adjacent region of the NOTCH4 locus with schizophrenia. ß 2006 Wiley-Liss, Inc. KEY WORDS: tenascin X (TNXB); NOTCH4; chromosome 6; schizophrenia; association study Please cite this article as follows: Tochigi M, Zhang X, Ohashi J, Hibino H, Otowa T, Rogers M, Kato T, Okazaki Y, Kato N, Tokunaga K, Sasaki T. 2007. Association Study Between the TNXB Locus and Schizophrenia in a Japanese Population. Am J Med Genet Part B 144B:305–309. *Correspondence to: Dr. Tsukasa Sasaki, M.D., Ph.D., Associate Professor, Associate Director, Health Service Center, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. E-mail: email@example.com Received 28 March 2006; Accepted 14 August 2006 DOI 10.1002/ajmg.b.30441 ß 2006 Wiley-Liss, Inc. INTRODUCTION Linkage studies have indicated that the chromosome 6p21– 24 region may contain a susceptibility locus of schizophrenia [Schwab et al., 1995; Straub et al., 1995; Wang et al., 1995; Schizophrenia Linkage Collaborative Group for Chromosomes 3, 6, and 8, 1996]. The human leukocyte antigen (HLA) region, located at 6p21.3, has been suggested as a particularly important locus for a candidate gene for schizophrenia (reviewed by Wright et al. ). In a previous study, Wei and Hemmings  observed that the NOTCH4 locus, located at the centromeric end of the HLAclass III region, was strongly associated with schizophrenia by using five markers. However, subsequent studies using mainly the same markers failed to replicate the initial findings [McGinnis et al., 2001; Sklar et al., 2001; Fan et al., 2002; Tochigi et al., 2004]. Nor did a meta-analysis of the association studies of these five markers find a significant association [Glatt et al., 2005]. Zhang et al. , however, observed an association of rs520692; not one of the five original markers employed by Wei and Hemmings , in 141 Han Chinese trios (P ¼ 0.017). Recently, linkage disequilibrium (LD) mapping was conducted in the region immediately telomeric of the NOTCH4 locus [Wei and Hemmings, 2004]. As a result, an association between two single nucleotide polymorphisms (SNPs) in the tenascin X (TNXB) locus (rs1009382 and rs204887) and schizophrenia was observed in 122 family trios recruited in the UK (P ¼ 0.00047 and 0.007, respectively). The tenascins are a family of large multimeric extracellular matrix proteins [Bristow et al., 1993]. There have been at least three family members identified in humans [Erickson, 1993], including tenascin R (TNR) located in 1q24, tenascin C (TNC) in 9q33 and tenascin X (TNXA and TNXB) in 6p21.3. The TNXB gene spans approximately 68.2 kb of DNA and consists of 45 exons [Yang et al., 1999]. The TNXA gene is a partially duplicated segment corresponding to intron 32 to exon 45 of the TNXB gene. The tenascins are known to be involved in the morphogenesis, migration, and growth of many organs and tissues. TNR and C are prominent in the nervous system and have an impact on neurite outgrowth and synaptic functions [Fuss et al., 1993; Gotz et al., 1996]. TNX, structure of which shows a striking similarity to TNR and C, is important for the proper deposition of collagen fibers in dermis. TNX deficiency causes an autosomal recessive form of Ehlers-Danlos syndrome, which is a connective tissue disorder characterized by hyperextensive skin, hypermobile joints, and tissue fragility [Burch et al., 1997; Schalkwijk et al., 2001]. TNX is also known to be associated with growth of central and peripheral nerves [Geffrotin et al., 1995; Tucker et al., 2001]. Thus, the TNXB 306 Tochigi et al. locus has been suggested to be a candidate gene for schizophrenia. To our knowledge, the initial study [Wei and Hemmings, 2004] has been followed by only one replication study from the same group, which observed no association between TNXB and schizophrenia in 136 Chinese family trios [Liu et al., 2004]. Further investigation of additional sites throughout the NOTCH4 and TNXB loci should be conducted. In the present study, we investigated the 6p21.3 region, mainly the TNXB locus and the adjacent region of the NOTCH4 locus, in Japanese patients with schizophrenia. A greater number of SNPs were investigated than in the previous studies [Liu et al., 2004; Wei and Hemmings, 2004; Zhang et al., 2004]. To our knowledge, this is the first study which investigated the region in a Japanese population. SUBJECTS AND METHODS Japanese patients and control subjects were recruited in the vicinity of Tokyo, Japan. Subjects were 241 unrelated patients with schizophrenia diagnosed by the DSM-IV criteria (137 males and 104 females; age, 46.2 14.8 years, mean SD) and 290 sex-matched unrelated healthy volunteers (165 males and 125 females; age, 41.6 11.6 years). The objective of the present study was clearly explained and written informed consent was obtained from all subjects. The study was approved by the Ethical Committee of the Faculty of Medicine, the University of Tokyo. Genome-DNA was extracted from leukocytes by using the standard phenol-chloroform method. We genotyped 26 SNPs as detailed in Table I. SNPs 1–9, 11, 12, 14–20, and 22 were analyzed by using the fluorescence correlation spectroscopysequence specific primer-PCR (FCS-SSP-PCR) protocols [Bannai et al., 2004]. SNPs 10, 13, 21, and 23–26 were selected form the list of the Assay-on-DemandTM Products for ABI PRISM 7900HT and analyzed by using the ABI PRISM 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA). SNPs 9, 12, 14, 17, 19, 20, and 22 were in common with Wei and Hemmings  and we covered all the SNPs which showed a significant association with schizophrenia in that study (SNPs 12, 17, and 19). A chi-square test was used to compare the SNP frequencies between the patients and the controls. Haplotypes of the SNPs and their frequencies were estimated by the maximumlikelihood method with an expectation–maximization algorithm [Excoffier and Slatkin, 1995]. The pairwise LD was measured by using r2. The results of pairwise r2 were visualized by using the GOLD program [Abecasis and Cookson, 2000]. Permutation P values were calculated in comparison of haplotype frequencies between patients and controls [Fallin et al., 2001]. The SNPAlyze 3.0Pro software (DYNACOM, Yokohama, Japan) was used to estimate haplotype frequencies, LD, and permutation P values. RESULTS Genotypic distributions and allelic frequencies of the 26 SNPs compared between patients and controls are shown in Table II. In the patients, the distributions of SNPs 17 and 19 deviated significantly from Hardy–Weinberg equilibrium (P ¼ 0.044 and 0.044, respectively, uncorrected), while the distributions of the other 24 SNPs were within the values expected from the Hardy–Weinberg equilibrium. In the controls, the distribution of SNP 21 deviated significantly (P ¼ 0.008, uncorrected), while the distributions of the other 25 SNPs were within the values expected. Allelic frequencies of SNPs 8 and 10 were significantly different between the TABLE I. Profile of SNPs Located at 6p21.3, Genotyped in the Present Study SNP ID dbSNP ID Alleles (major/minor) Amino acid change Locus Size of interval (add up) (bp) 1 2 3 4 5 6 7 8 9 10 11 12a 13 14 15 16 17a 18 19a 20 21 22 23 24 25 26 rs447459 rs915894 rs2071282 rs2071284 rs520688 rs520692 rs422951 rs2071287 rs8365 rs1061808 rs204999 rs8283 rs2071293 rs204900 rs185819 rs2269428 rs204887 rs2269429 rs1009382 rs6472 rs6474 rs641153 rs7887 rs644827 rs660594 rs480092 C/T C/A C/T G/A A/G A/G A/G G/A G/C C/A A/G T/C C/T T/G G/A C/A C/T G/A A/G C/G G/A C/T A/C C/T A/G A/G — Gln/Lys Pro/Leu — Pro/Pro Asp/Gly Ala/Thr — — — — — — Ser/Ala Arg/His Pro/His — Gly/Ser Glu/Gly Ser/Thr Arg/Lys Arg/Gln — — — — — NOTCH4 NOTCH4 NOTCH4 NOTCH4 NOTCH4 NOTCH4 NOTCH4 AGER AGPAT1 — CREBL1 TNXB TNXB TNXB TNXB TNXB TNXB TNXB CYP21A2 CYP21A2 BF BAT8 C6orf29 C6orf29 LSM2 0 (0) 18,283 (18,283) 1,447 (19,730) 216 (19,946) 85 (20,031) 2 (20,033) 257 (20,290) 17,950 (38,240) 22,030 (60,270) 11,856 (72,126) 26,568 (98,694) 26,679 (125,373) 20,613 (145,986) 6,107 (152,093) 6,513 (158,606) 19,867 (178,473) 974 (179,447) 43 (179,490) 3,076 (182,566) 18,257 (200,823) 963 (201,786) 92,706 (294,492) 49,633 (344,125) 26,106 (370,231) 1,191 (371,422) 72,351 (443,773) AGER, advanced glycosylation end product-specific receptor; AGPAT1, 1-acylglycerol-3-phosphate O-acyltransferase 1; CREBL1, cAMP responsive element binding protein-like 1; CYP21A2, cytochrome P450, family 21, subfamily A, polypeptide 2; BF, B-factor, properdin; BAT8, HLA-B associated transcript 8; C6orf29, chromosome 6 open reading frame 29; LSM2, LSM2 homolog; U6 small nuclear RNA associated (S. cerevisiae). a Significant associations with schizophrenia were observed in Wei and Hemmings . TNXB and Schizophrenia in Japanese 307 TABLE II. Genotypic Distributions and Allelic Frequencies of 26 SNPs Genotyped in the Present Study Genotypic distributiona Schizophrenia Controls SNP ID AA Aa aa AA Aa aa 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 136 62 202 202 123 149 149 113 206 51 214 154 117 200 91 202 105 202 105 202 109 209 118 106 106 131 87 121 36 36 90 80 80 103 35 114 25 75 100 39 107 38 97 37 97 37 99 31 101 104 104 95 18 58 3 3 28 12 12 25 0 76 2 12 24 2 43 1 39 2 39 2 33 1 22 31 31 15 172 79 241 241 137 172 172 116 246 82 254 166 137 236 117 244 126 236 126 237 140 250 137 119 118 156 105 151 48 48 121 101 101 129 44 137 35 106 123 54 136 46 135 54 135 53 107 40 123 128 129 113 13 60 1 1 32 17 17 45 0 70 1 18 30 0 36 0 29 0 29 0 41 0 28 41 41 18 a b Minor allele frequency P-valueb P-value for recessive model (aa vs. AA þ Aa)b Schizophrenia Controls P-valueb 0.33 0.64 0.44 0.44 0.59 0.81 0.81 0.12 0.98 0.072 0.64 0.29 0.95 0.24 0.22 0.55 0.077 0.19 0.077 0.21 0.65 0.52 0.94 0.80 0.76 1.00 0.14 0.35 0.23 0.23 0.83 0.66 0.66 0.081 1.00 0.061 0.46 0.54 0.88 0.12 0.083 0.27 0.034 0.12 0.034 0.12 0.86 0.27 0.82 0.65 0.65 0.98 0.255 0.492 0.087 0.087 0.303 0.216 0.216 0.317 0.073 0.552 0.060 0.205 0.307 0.089 0.400 0.083 0.363 0.085 0.363 0.085 0.342 0.068 0.301 0.344 0.344 0.259 0.226 0.467 0.086 0.086 0.319 0.233 0.233 0.378 0.076 0.479 0.064 0.245 0.316 0.093 0.360 0.079 0.333 0.093 0.333 0.091 0.328 0.069 0.311 0.365 0.366 0.260 0.26 0.43 0.96 0.96 0.57 0.51 0.51 0.041 0.84 0.019 0.81 0.13 0.77 0.83 0.18 0.83 0.30 0.65 0.30 0.72 0.63 0.97 0.73 0.49 0.46 0.99 ‘‘A’’ and ‘‘a’’ represent major and minor alleles at each SNP site, respectively. Uncorrected values. Significant values are shown in italics. controls and patients (P ¼ 0.041 and 0.019, respectively, uncorrected). No significant difference was observed in the allelic frequencies of the other SNPs between the two groups. No significant difference was observed in the genotypic distributions between patients and controls (2 3 comparison). However, when analyzed in the recessive model, genotypic distributions of SNPs 17 and 19 differed significantly between the controls and patients (P ¼ 0.034 and 0.034, respectively, uncorrected). No significant difference was observed in the recessive-model genotypic distributions of the other SNPs between the two groups. The pairwise r2 between the 17 SNPs with a high-frequency (>20%) minor allele in the patients is shown in Figure 1. There was no significant difference in r2 between the controls and patients (data not shown). Figure 1 suggests the presence of two blocks of strong LD, roughly coinciding with the NOTCH4 (SNPs 5–8) and TNXB (SNPs 13–21) genes, respectively. In each LD block, haplotypes and their frequencies were estimated. Table III shows estimated frequencies of the haplotypes consisting of SNPs 5–8. A significant difference was observed in the frequency of one of the haplotypes (‘‘0-0-0-1’’) between the controls and patients (0.145 vs. 0.102, permutation P ¼ 0.024, uncorrected). No significant difference was observed in frequencies of other estimated haplotypes or in distributions of all estimated haplotypes between the controls and patients (global permutation P ¼ 0.10). With respect to the haplotypes consisting of SNPs 13–21, no significant difference was observed in the frequencies of any estimated haplotype or in distributions of all estimated haplotypes between the controls and patients (global permutation P ¼ 0.24). Further haplotype estimation of the LD block including SNPs 13–21 was conducted by selecting five SNPs with a high-frequency (>30%) minor allele (SNPs 13, 15, 17, 19, and 21). However, no significant difference was observed (global permutation P ¼ 0.22). Fig. 1. Pattern of LD in the telomeric region of the NOTCH4 locus in the patients. Pairwise LD between SNPs, as measured by r2, is represented. Regions of high and low degrees of LD are shown in red and blue, respectively. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.] 308 Tochigi et al. TABLE III. Estimated Frequencies of the Haplotypes Consisting of SNPs 5–8 Haplotype Frequency SNP 5 6 7 8 0 1 0 1 0 1 0 0 0 1 1 0 0 1 0 0 Schizophrenia Control 0.595 0.216 0.102 0.087 0.536 0.233 0.145 0.087 w2 Permutation P-value 3.75 0.44 4.48 0.0029 0.06 0.52 0.024 0.91 Haplotypes whose frequencies were estimated >3% were described. In each SNP, 0 and 1 correspond to the major allele and the minor allele, respectively. DISCUSSION In the present study, we investigated the association of 26 SNPs in the telomeric region of the NOTCH4 locus and schizophrenia. LD analysis suggests the presence of two LD blocks in the region, roughly coinciding with the NOTCH4 (SNPs 5–8) and TNXB (SNPs 13–21) genes, respectively. In the block including SNPs 5–8, allelic frequency of SNP 8 was significantly different between the controls and patients (P ¼ 0.041, uncorrected). Analysis of haplotype consisting of SNPs 5–8 also showed a significant difference in the frequency of one of the estimated haplotypes between the two groups (permutation P ¼ 0.024, uncorrected). In the block including SNPs 13–21, significant differences were observed in recessive-model genotypic distributions of SNPs 17 and 19 between the controls and patients (P ¼ 0.034 and 0.034, respectively, uncorrected). In the region between the two LD blocks, there was a significant difference in allelic frequency of SNP 10 between the two groups (P ¼ 0.019, uncorrected). Since all these differences were insignificant after Bonferroni correction, these results must be interpreted with caution. The possibility of type I error could be considered. However these non-significant trends do point to SNPs 17 and 19; the SNPs which showed a significant association in the previous Caucasian study, with the same excessive alleles observed in the present study (P ¼ 0.007 and 0.00047, respectively, uncorrected; Wei and Hemmings, 2004). Both the present and previous studies observed low frequencies of heterozygotes in the patients, resulting in deviation from Hardy–Weinberg equilibrium in SNP 19 in the present and previous study (P ¼ 0.044 and 0.01, respectively, uncorrected) and in SNP 17 in the present study (P ¼ 0.044, uncorrected). SNP 19 is a missense mutation located in exon 24 of the TNXB gene, changing glutamic acid into glycine. These results suggest that SNP 19 might be a candidate of susceptible variants of schizophrenia. SNP 19 or other variants at strong LD with it might affect the function of the TNXB gene, although no study has investigated the effect of SNP 19 to our knowledge. SNP 17 is a synonymous SNP located about 3 kb away from SNP 19. The association of SNP 17 may be due to complete LD with SNP 19. Estimated frequencies of the haplotype consisting of SNPs 13–21, however, showed no significant difference between the controls and patients. It would be interesting to examine whether the estimated haplotype is associated with schizophrenia in a recessive model by a permutation procedure, although the available software does not allow us to conduct the calculation at present. The deviation from Hardy–Weinberg equilibrium in SNP 21 in the controls might be a chance observation, although other possibility could not be totally ruled out. The haplotype consisting of SNPs 5–8 showed a significant association with schizophrenia. SNP 8, which also showed a significant association, has not been investigated in previous studies, to our knowledge. Zhang et al. , using 141 Han Chinese trios, observed the association of the haplotype consisting of SNPs 6 and 7, a part of the haplotype consisting of SNPs 5–8 in the present study (global P ¼ 0.018, uncorrected). SNP 6 was by itself associated with schizophrenia in Zhang et al.  (P ¼ 0.017, uncorrected) and the excessive allele of the SNP in their patients was in LD with that of SNP 8 in the present study. The LD block containing SNPs 5–8 might be worth further investigation. In contrast, SNP 10 showed the association independently with the two LD blocks. To our knowledge, SNP 10 has not been investigated in the previous studies. SNP 10 is in the gene encoding 1-acylglycerol-3-phosphate O-acyltransferase 1 (AGPAT1), an enzyme that converts lysophosphatidic acid (LPA) into phosphatidic acid (PA) in the endoplasmic reticulum [Leung, 2001]. Replication studies with a larger sample set may be needed to confirm the association. In conclusion, we might provide support for an association between the TNXB locus or its adjacent region of the NOTCH4 locus and schizophrenia in Japanese subjects. Two SNPs (SNP 17 and 19 or rs204887 and rs1009382) in the TNXB locus were significantly associated with schizophrenia in agreement with previous research [Wei and Hemmings, 2004]. An association between schizophrenia and SNP 8 and haplotype analysis around it (SNPs 5–8) was also suggested, consistent with another previous study [Zhang et al., 2004]. 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