Neuregulin 3 does not confer risk for schizophrenia and smooth pursuit eye movement abnormality in a Korean population
2011; Wiley; Volume: 10; Issue: 8 Linguagem: Inglês
10.1111/j.1601-183x.2011.00722.x
ISSN1601-1848
AutoresCharisse Flerida A. Pasaje, Joon Seol Bae, B.‐L. Park, Hyun Sub Cheong, Jaehoon Kim, Taeseop Park, J.-S. Lee, Y. Kim, C.-S. Park, B.-J. Kim, Boseok Cha, J. W. Kim, Woojin Choi, T. Shin, Ihn-Geun Choi, Jaeuk Hwang, Hyoung Doo Shin, Sung‐Il Woo,
Tópico(s)Chronic Lymphocytic Leukemia Research
ResumoGenes, Brain and BehaviorVolume 10, Issue 8 p. 828-833 Free Access Neuregulin 3 does not confer risk for schizophrenia and smooth pursuit eye movement abnormality in a Korean population C.-F. Pasaje, C.-F. Pasaje Department of Life Science, Sogang University These authors contributed equally to this work.Search for more papers by this authorJ.-S. Bae, J.-S. Bae Department of Life Science, Sogang University These authors contributed equally to this work.Search for more papers by this authorB.-L. Park, B.-L. Park Department of Genetic Epidemiology, SNP Genetics, Inc., Seoul, Republic of KoreaSearch for more papers by this authorH. S. Cheong, H. S. Cheong Department of Genetic Epidemiology, SNP Genetics, Inc., Seoul, Republic of KoreaSearch for more papers by this authorJ.-H. Kim, J.-H. Kim Department of Life Science, Sogang UniversitySearch for more papers by this authorT.-J. Park, T.-J. Park Department of Life Science, Sogang UniversitySearch for more papers by this authorJ.-S. Lee, J.-S. Lee Department of Life Science, Sogang UniversitySearch for more papers by this authorY. Kim, Y. Kim Department of Life Science, Sogang UniversitySearch for more papers by this authorC.-S. Park, C.-S. Park Department of Psychiatry, College of Medicine, Gyeongsang National UniversitySearch for more papers by this authorB.-J. Kim, B.-J. Kim Department of Psychiatry, College of Medicine, Gyeongsang National UniversitySearch for more papers by this authorB. Cha, B. Cha Department of Psychiatry, College of Medicine, Gyeongsang National UniversitySearch for more papers by this authorJ. W. Kim, J. W. Kim Division of Life Science, Research Institute of Life Science, Gyeongsang National University, Jinju, Gyeongsang Nam Do, Republic of KoreaSearch for more papers by this authorW. H. Choi, W. H. Choi Department of Biomedical Engineering, Yonsei University, Wonju, Republic of KoreaSearch for more papers by this authorT.-M. Shin, T.-M. Shin Department of Biomedical Engineering, Yonsei University, Wonju, Republic of KoreaSearch for more papers by this authorI.-G. Choi, I.-G. Choi Department of Neuropsychiatry, Hallym University, Han-Gang Sacred Heart HospitalSearch for more papers by this authorJ. Hwang, J. Hwang Department of Neuropsychiatry, Soonchunhyang University Hospital, Seoul, Republic of KoreaSearch for more papers by this authorH.-D. Shin, Corresponding Author H.-D. Shin Department of Life Science, Sogang University Department of Genetic Epidemiology, SNP Genetics, Inc., Seoul, Republic of Korea H.-D. Shin, Department of Life Science, Sogang University, Seoul, 121-742, Republic of Korea. E-mail: hdshin@sogang.ac.kr Dr S.-I. Woo, Department of Neuropsychiatry, Soonchunhyang University Hospital, 657, Hannam-dong, Yongsan-gu, Seoul 140-743, Republic of Korea. E-mail: siwoo@hosp.sch.ac.krSearch for more papers by this authorS.-I. Woo, Corresponding Author S.-I. Woo Department of Neuropsychiatry, Soonchunhyang University Hospital, Seoul, Republic of Korea H.-D. Shin, Department of Life Science, Sogang University, Seoul, 121-742, Republic of Korea. E-mail: hdshin@sogang.ac.kr Dr S.-I. Woo, Department of Neuropsychiatry, Soonchunhyang University Hospital, 657, Hannam-dong, Yongsan-gu, Seoul 140-743, Republic of Korea. E-mail: siwoo@hosp.sch.ac.krSearch for more papers by this author C.-F. Pasaje, C.-F. Pasaje Department of Life Science, Sogang University These authors contributed equally to this work.Search for more papers by this authorJ.-S. Bae, J.-S. Bae Department of Life Science, Sogang University These authors contributed equally to this work.Search for more papers by this authorB.-L. Park, B.-L. Park Department of Genetic Epidemiology, SNP Genetics, Inc., Seoul, Republic of KoreaSearch for more papers by this authorH. S. Cheong, H. S. Cheong Department of Genetic Epidemiology, SNP Genetics, Inc., Seoul, Republic of KoreaSearch for more papers by this authorJ.-H. Kim, J.-H. Kim Department of Life Science, Sogang UniversitySearch for more papers by this authorT.-J. Park, T.-J. Park Department of Life Science, Sogang UniversitySearch for more papers by this authorJ.-S. Lee, J.-S. Lee Department of Life Science, Sogang UniversitySearch for more papers by this authorY. Kim, Y. Kim Department of Life Science, Sogang UniversitySearch for more papers by this authorC.-S. Park, C.-S. Park Department of Psychiatry, College of Medicine, Gyeongsang National UniversitySearch for more papers by this authorB.-J. Kim, B.-J. Kim Department of Psychiatry, College of Medicine, Gyeongsang National UniversitySearch for more papers by this authorB. Cha, B. Cha Department of Psychiatry, College of Medicine, Gyeongsang National UniversitySearch for more papers by this authorJ. W. Kim, J. W. Kim Division of Life Science, Research Institute of Life Science, Gyeongsang National University, Jinju, Gyeongsang Nam Do, Republic of KoreaSearch for more papers by this authorW. H. Choi, W. H. Choi Department of Biomedical Engineering, Yonsei University, Wonju, Republic of KoreaSearch for more papers by this authorT.-M. Shin, T.-M. Shin Department of Biomedical Engineering, Yonsei University, Wonju, Republic of KoreaSearch for more papers by this authorI.-G. Choi, I.-G. Choi Department of Neuropsychiatry, Hallym University, Han-Gang Sacred Heart HospitalSearch for more papers by this authorJ. Hwang, J. Hwang Department of Neuropsychiatry, Soonchunhyang University Hospital, Seoul, Republic of KoreaSearch for more papers by this authorH.-D. Shin, Corresponding Author H.-D. Shin Department of Life Science, Sogang University Department of Genetic Epidemiology, SNP Genetics, Inc., Seoul, Republic of Korea H.-D. Shin, Department of Life Science, Sogang University, Seoul, 121-742, Republic of Korea. E-mail: hdshin@sogang.ac.kr Dr S.-I. Woo, Department of Neuropsychiatry, Soonchunhyang University Hospital, 657, Hannam-dong, Yongsan-gu, Seoul 140-743, Republic of Korea. E-mail: siwoo@hosp.sch.ac.krSearch for more papers by this authorS.-I. Woo, Corresponding Author S.-I. Woo Department of Neuropsychiatry, Soonchunhyang University Hospital, Seoul, Republic of Korea H.-D. Shin, Department of Life Science, Sogang University, Seoul, 121-742, Republic of Korea. E-mail: hdshin@sogang.ac.kr Dr S.-I. Woo, Department of Neuropsychiatry, Soonchunhyang University Hospital, 657, Hannam-dong, Yongsan-gu, Seoul 140-743, Republic of Korea. E-mail: siwoo@hosp.sch.ac.krSearch for more papers by this author First published: 18 July 2011 https://doi.org/10.1111/j.1601-183X.2011.00722.xCitations: 10 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Located on chromosome 10q22-q23, the human neuregulin3 (NRG3) is considered to be a strong positional and functional candidate gene for schizophrenia pathogenesis. Several case–control studies examining the association of polymorphisms in NRG3 with schizophrenia and/or related traits such as delusion have been reported recently in cohorts of Han Chinese, Ashkenazi Jews, Australians and white Americans of Western European ancestry. Thus, this study aimed to comprehensively investigate the association of NRG3 genetic variations with the risk of schizophrenia and smooth pursuit eye movement (SPEM) abnormality in a Korean population. Using TaqMan assay, six single-nucleotide polymorphisms (SNPs) in the intronic region of NRG3 were genotyped and two major haplotypes were identified in 435 patients with schizophrenia as cases and 393 unrelated healthy individuals as controls. A total of 113 schizophrenia patients underwent an eye tracking task, and degree of SPEM abnormality was measured using the logarithmic values of the signal/noise (Ln S/N) ratio. Differences in frequency distributions were analyzed using logistic and regression models following various modes of genetic inheritance and controlling for age and sex as covariates. Subsequent analysis revealed that the frequency distributions of NRG3 polymorphisms and haplotypes were similar between schizophrenia patients and healthy controls of Korean ethnicity. Furthermore, no significant differences were observed between the genetic variants tested for SPEM abnormality. By elucidating a lack of association in a Korean population, findings from this study may contribute to the understanding of the genetic etiology focusing on the role of NRG3 in schizophrenia pathogenesis. Introduction Schizophrenia is a severe mental disorder characterized by positive symptoms such as delusion and hallucination, negative symptoms and cognitive symptoms. This condition affects about 4–7 per 100,000 people in the general population (McGrath et al. 2008; Torrey 1987), and disease pathogenesis is attributable to combined effects of environmental and genetic risk factors. In the etiology of schizophrenia, the 10q22-q23 locus has shown linkage to the disease in various populations (Fallin et al. 2003; Faraone et al. 2006), and recurrent deletions in this region have been associated with neurodevelopmental disorders, including developmental delay and cognitive impairment (Balciuniene et al. 2007), key features shared by schizophrenia. Results from previous copy number variant studies have identified the 10q22-q23 region in psychiatric disorders (Chen et al. 2009; Saus et al. 2010), providing further evidence that the locus harbors genetic mechanisms important in schizophrenia pathophysiology. Mapped to the 10q22-q23 schizophrenia susceptibility locus and spanning over 1.11 kb, the human neuregulin 3 (NRG3) gene is, thereby, regarded as a strong positional and functional candidate gene for disease pathogenesis. Previous case–control studies investigating the association of NRG3 genetic polymorphisms with schizophrenia and/or related traits including delusional behaviors have been reported in cohorts of Han Chinese, Ashkenazi Jews, Australians and white Americans of Western European ancestry (Chen et al. 2009; Kao et al. 2010; Morar et al. 2010; Wang et al. 2008). However, in one of the studies, fine mapping of the 10q22-23 region in schizophrenia has identified genome-wide significant association of polymorphisms in a 13-kb interval of intron 1 of NRG3 (rs10883866, rs10748842 and rs6584400) with delusion severity, but not with the disease status (Chen et al. 2009). The neuregulin family of growth and differential factors (NRG1–4) and their cognate ErbB4 receptor tyrosine kinases play multiple roles in brain development and in maturation and function of neurons and glial cells. NRG1 is involved in the formation and maintenance of radial glial cells guiding radial migration of neurons, tangential migration of GABAergic interneurons in the cortical region, oligodendrocyte development, myelination of axons and synapse formation in the central nervous system (CNS), suggesting a link between neuregulin 1 perturbation and schizophrenia (Mei & Xiong 2008). In contrast, the biological roles of NRG3 remain unclear and relatively few genetic studies were performed. NRG3 gene spans approximately 1.2 Mb genomic region and its full-length human protein, 720 amino acids in length, has an extracellular epidermal growth factor (EGF)-like domain of 31% identity with the EGF-like domain of NRG1. So, NRG3 is a neural-enriched member of the EGF family and the only known binding receptor for NRG3 is erbB4, although NRG1 binds to both erbB3 and erbB4. Smooth pursuit eye movement (SPEM) is one of the most consistent neurophysiological endophenotype in schizophrenia, which can be measured objectively and quantitatively. Patients with schizophrenia tend to exhibit difficulty in pursuing fast targets and objects moving at a predictable velocity, which may reflect lack of cohesion of brain circuits (Avila et al. 2006). The current authors have revealed significant association between ZDHHC8 genetic variations in the 22q11 deleted region with SPEM abnormality (Shin et al. 2010), novel findings that need to be replicated in further studies. Since deletion of chromosome 10q22-q23 is associated with neurodevelopmental disorders and cognitive impairment, there is also a need to perform association analysis of SPEM abnormality with NRG3. Taken together, the NRG3 gene might be a candidate gene for schizophrenia and/or related traits, but studies verifying its association with the disease were rarely performed. In the present study, the association of NRG3 genetic variations with the risk of schizophrenia and SPEM abnormality is comprehensively investigated in a Korean population. Materials and methods Study subjects We recruited patients with schizophrenia from Jinju Mental Hospital, Soonyoung Hospital, Hadong Wooridle Hospital (Gyeongsang Nam Do, Korea) and Keyo Hospital (Kyunggi-Do, Korea). The protocols were approved by the Institutional Review Board of the each hospital, and the experiments were undertaken with the understanding and written informed consent of each subject. Diagnosis of the disorder was carried out by trained psychiatrists based on the guidelines of Diagnostic Statistical Manual of Mental Disorders IV (DSM-IV). Exclusion criteria for the case group include complicating diagnoses of mental retardation, organic brain damage, drug or alcohol abuse, neurological disorders, autoimmune disorders and low comprehension skills. The control group which was composed of unrelated healthy employees from two hospitals in Korea underwent crucial evaluation by a trained clinician using the Structured Clinical Interview for DSM-IV, non-patient edition (SCID-NP). Measurement of SPEM Schizophrenia patients who were able to understand the procedure of the experiment underwent an eye tracking task as described previously (Park et al. 2009). Electrooculographic (EOG) recordings of eye movement were used to quantify SPEM abnormality and calculate the natural logarithmic values of the signal/noise (Ln S/N) ratio. The electrophysiological analog signals of SPEM were amplified and sampled at 400 Hz and converted into digitized files. A measurement period of 15 seconds during the SPEM task was resampled at 4 Hz and passed through a 2 Hz low-pass filter. With an Ln S/N ratio of 3.97, subjects were categorized into 'good' and 'poor' performers according to their SPEM function. We did not perform association analysis of SPEM function abnormality in normal controls considering that there are low incidences of SPEM impairment in healthy subjects (<10%) and association analysis could not retain statistical power. Single-nucleotide polymorphism selection and genotyping NRG3 single-nucleotide polymorphisms (SNPs) were screened from polymorphisms relevant to schizophrenia pathogenesis and related conditions (P < 0.05) in the literature (Chen et al. 2009; Kao et al. 2010; Wang et al. 2008). Commercially available predesigned TaqMan® probes and primers (Applied Biosystems, Foster City, CA, USA) were used in genotyping, and assay IDs of each SNP are shown in Table S1, Supporting information. Genotype data quality was assessed by duplicate DNA checking (n = 10; rate of concordance in duplicates >99%). SNPs that did not meet the following criteria were excluded from association analyses: (1) a minimum call rate of 95%; (2) no duplicate error; (3) Hardy-Weinberg equilibrium (HWE) of P > 0.05. Haplotypes were inferred from the genotyped SNPs using the PHASE algorithm ver. 2.0 (Stephens et al. 2001), and those with frequency of over 0.05 were included in the association analysis. Statistical analyses Linkage disequilibrium (LD) between all pairs of biallelic loci were determined using Lewontin's D′ (|D′|) and LD coefficient r2, which were examined using Haploview algorithm (Barrett et al. 2005). Odds ratio (95% confidence interval) and corresponding P values were calculated using logistic model with adjusted age (continuous value) and sex (male = 0, female = 1) as covariates. Ln S/N ratio was calculated from analysis of the power spectrum curves, and results were used in multiple regression analysis of SPEM abnormality, controlling for age and sex as covariates. Results A total of 435 schizophrenia cases (247 males and 188 females) and 393 normal controls (222 males and 171 females) of Korean ethnicity were recruited for this study. The mean age of the subjects in the case and control groups were 44.78 (range = 23–76) and 54.62 (range = 28–80), respectively. For analysis of SPEM abnormality, 113 schizophrenia patients participated in an eye tracking task and were then stratified into two groups, 'good' and 'poor,' when their Ln S/N ratios (mean ± SD) were 4.35 ± 0.29 and 3.20 ± 0.70, respectively. Six SNPs (rs6584400, rs1080293, rs1764072, rs1937970, rs677221 and rs12416489) localized in the intronic region of NRG3 were successfully genotyped in a total of 828 subjects (Fig. 1a and Table S2, Supporting information). Except for one rare polymorphism (rs1764072; P = 0.028), none of the variants showed significant departure from Hardy-Weinberg equilibrium (HWE; P > 0.05; Table S2). A haplotype block (Fig. 1b) was constructed from pairwise comparisons of two genotyped SNPs (rs1937970 and rs677221), and two major haplotypes with frequencies over 0.05 (NRG3_ht1 and NRG3_ht2; Fig. 1c) were obtained and included in the association analysis with the risk of schizophrenia and SPEM abnormality. Figure 1Open in figure viewerPowerPoint Physical map, LD and haplotypes of the NRG3 gene. (a) Schematic gene map and SNPs of NRG3 on chromosome 10q22-q23 (1.11 kb). Black blocks represent coding exons. The first base of translation site was denoted as nucleotide +1. (b) LD coefficient (|D′|) among NRG3 SNPs in a Korean population. UTR, untranslated region. (c) Haplotypes of NRG3. Results from logistic analysis showed no significant associations between NRG3 variations and the risk of schizophrenia (Table 1; P > 0.05). Since SPEM is considered as a physiologic abnormality associated with schizophrenia, association analysis was further performed. Similarly, results reveal no statistically significant associations between SPEM abnormality and the tested NRG3 polymorphisms and haplotypes (Table 2). Table 3 summarizes the genetic association of NRG3 polymorphisms with schizophrenia and/or related traits in various populations. Table 1. Association analysis of NRG3 variations with schizophrenia Loci MAF Codominant Dominant Recessive Schizophrenia Control OR (95% CI) P * OR (95% CI) P * OR (95% CI) P * rs6584400 0.226 0.242 0.93 (0.72–1.20) 0.58 1.01 (0.74–1.39) 0.93 0.61 (0.32–1.15) 0.13 rs1080293 0.455 0.491 0.85 (0.68–1.06) 0.14 0.88 (0.63–1.25) 0.48 0.72 (0.49–1.04) 0.08 rs1764072 0.421 0.416 1.02 (0.82–1.26) 0.86 0.95 (0.69–1.31) 0.77 1.15 (0.77–1.71) 0.49 rs1937970 0.397 0.389 1.10 (0.88–1.37) 0.42 1.14 (0.83–1.57) 0.43 1.11 (0.73–1.71) 0.63 rs677221 0.393 0.366 1.14 (0.91–1.44) 0.25 1.17 (0.85–1.60) 0.35 1.25 (0.80–1.95) 0.34 rs12416489 0.189 0.195 0.87 (0.66–1.14) 0.31 0.78 (0.56–1.08) 0.13 1.28 (0.61–2.69) 0.52 NRG3_ht1 0.579 0.592 0.90 (0.72–1.12) 0.34 0.84 (0.55–1.28) 0.42 0.88 (0.64–1.22) 0.45 NRG3_ht2 0.356 0.335 1.11 (0.89–1.39) 0.35 1.16 (0.85–1.58) 0.36 1.14 (0.72–1.81) 0.57 Logistic regression analyses was used to calculate odds ratios (95% confidential interval) controlling for age (continuous value) and sex (male = 0, female = 1). MAF, minor allele frequency; CI, confidence interval; OR, odds ratio. * P values at 0.05 level of significance. Table 2. Regression analysis of NRG3 variations with SPEM abnormality in a Korean population Loci C/C C/R R/R P * † P * ‡ P * § rs6584400 60 (3.72 ± 0.69) 45 (3.69 ± 0.73) 8 (3.79 ± 0.80) 0.92 0.84 0.89 rs1080293 35 (3.68 ± 0.80) 53 (3.74 ± 0.66) 22 (3.75 ± 0.67) 0.65 0.63 0.80 rs1764072 45 (3.63 ± 0.77) 48 (3.82 ± 0.62) 20 (3.64 ± 0.77) 0.60 0.24 0.63 rs1937970 45 (3.74 ± 0.67) 49 (3.72 ± 0.70) 19 (3.61 ± 0.85) 0.68 0.85 0.59 rs677221 46 (3.86 ± 0.59) 47 (3.62 ± 0.73) 17 (3.68 ± 0.87) 0.28 0.16 0.86 rs12416489 71 (3.78 ± 0.68) 38 (3.59 ± 0.75) 4 (3.63 ± 0.87) 0.22 0.20 0.69 NRG3_ht1 21 (3.64 ± 0.82) 50 (3.69 ± 0.73) 42 (3.78 ± 0.63) 0.59 0.71 0.61 NRG3_ht2 54 (3.75 ± 0.67) 44 (3.68 ± 0.69) 15 (3.65 ± 0.92) 0.67 0.66 0.81 C/C, C/R and R/R refer to major homozygote, heterozygote and minor homozygote, respectively. Mean SD of S/N ratio values of each genotype are shown in parenthesis. Multiple linear regression analysis in †codominant,‡dominant and§recessive models with adjusted age and sex as covariates.*P values at 0.05 level of significance. Table 3. Genetic associations of NRG3 polymorphisms with schizophrenia and/or related traits (statistical significance, P value) Population Reference Study design SNP and locus rs658440−15280A>G rs1080293−7747C>A rs1764072−1290G>A rs1937970 +809A>G rs677221 +1782G>A rs12416489 +21025A>C Ashkenazi Jewish Chen et al. (2009) 458 cases and 487 controls 8.46 × 10−6* (A: 0.13)† 8.43 × 10−3 — — — 3.78 × 10−2‡ (A:0.14 [0.00–0.27])§ Australian Morar et al. (2010) 411 cases and 223 controls 0.031 (G:0.169 vs. 0.123)¶ — — — — — Han Chinese Wang et al. (2008) 270 cases and 235 controls — — NS 0.02 (G:0.655 vs. 0.585)¶ 0.002 (A:0.667 vs. 0.569)¶ — White Americans of Western European ancestry Kao et al. (2010) 537 cases and 538 controls 0.01 — 0.01 NS NS — Korean This study 435 cases and 393 controls NS** NS** NS** NS** NS** NS** P values were not corrected for multiple testing. NS, not significant; – , not performed. * P value of association with delusional behavior. †Frequency of the risk allele. ‡ P value of association with scholastic performance. §Estimated additive genetic value for the risk allele compared with the non-risk allele, assuming a normally distributed trait and small deviations from the mean. ¶Over-represented alleles in patients with schizophrenia (frequencies among cases vs. controls). **Association analysis with schizophrenia and SPEM abnormality. Discussion The NRG3 as a candidate gene for schizophrenia was suggested by recent genetic mapping studies and case–control analyses. Among the intronic SNPs analyzed in this study (Table 3), rs1080293 has been previously depicted to be marginally associated with schizophrenia in Ashkenazi Jews, a signal that failed to maintain significance after either stringent or Bonferroni corrections (Chen et al. 2009). In a study involving Australians (Morar et al. 2010), rs6584400 was associated with schizophrenia (P = 0.03 for minor allele) and rs10883866 showed a trend in the same direction without reaching nominal significance, consistent with a family-based study of white Americans of Western European ancestry wherein a significant association between rs6584400 and the risk of schizophrenia was detected (Kao et al. 2010). In contrast, rs6584400 and rs12416489 were found to be significantly associated with delusional behaviors and poor scholastic performance, respectively, but not with schizophrenia status per se in Ashkenazi Jews (Chen et al. 2009). Kao et al. (2010) also reported a marginal association with rs1764072, and no relationships of NRG3 rs677221 and rs1937970 with the risk of schizophrenia, in contrast to the findings of Wang et al. (2008), who found statistically significant correlations between the later two polymorphisms and the disease, but no association with rs1764072 in a Han Chinese population. This follow-up study in a Korean population, therefore, was initiated in the context of prior inconsistent reports (Table 3) on the role of various NRG3 polymorphisms in the risk of schizophrenia. Results from logistic analysis revealed that the frequency distributions of NRG3 polymorphisms and haplotypes were similar between schizophrenia patients and healthy controls of Korean ethnicity via codominant, dominant and recessive modes of genetic inheritance. This finding replicates the lack of association between rs1764072 and the risk of schizophrenia reported in a Chinese cohort, but contradicts the results for rs677221 and rs1937970 which were correlated with the disease in the latter population (Wang et al. 2008). As demonstrated previously, two polymorphisms analyzed in this study, the rs6584400 and rs12416489, may be closely linked to certain traits associated with schizophrenia rather than to the disease itself (Chen et al. 2009) (Table 3). In this study, an association analysis was further performed between NRG3 and SPEM abnormality, one of the most consistent neurocognitive endophenotype that might be under a more direct genetic control compared to traits such as delusional behavior analyzed in previous studies. In the present study, results from regression analysis do not support a major role of NRG3 in SPEM abnormality among Korean schizophrenia patients. The significant statistical interaction of the two associated SNPs with signal/noise discrimination on the traits by continuous performance teat (CPT) reported by Morar et al. (2010) might turn out to be relevant to the current SPEM analysis resulting in the Ln S/N index of 4.35 for the 'good' performers compared to 3.20 for the 'poor' performers. Since reduction in the sample size of the participants (N = 113) for the SPEM task might have weakened the ability to detect any significant results in this study, we suggest that the effects of NRG3 in the other biological traits of schizophrenia still need to be elucidated further. The genetic makeup of various ethnic groups varies according to geographical and racial differences, thereby discrepancies between our data and previous studies may be a manifestation of differences in the effects of polymorphisms in different populations. Furthermore, findings from case–control analyses are subject to genotyping errors. Indeed, one of the SNPs analyzed in this study has a HWE of 0.02, identifying low sample size as one of the study limitations. Moreover, although adjusting for age and gender as covariates may increase the credibility of the findings, doing so could also blunt the ability to detect significant associations. To address these limitations and to determine reliable associations in the future, replication studies should be performed with substantially larger sample sizes in independent sample groups. To conclude, findings from this study provide evidence that NRG3 is not a genetic risk factor for schizophrenia susceptibility and SPEM abnormality in a Korean population. To our knowledge, this study is the first to investigate the relationship of schizophrenia and SPEM as a presumed endophenotype with disease candidate gene NRG3 in a Korean population. Findings from this study may be useful in directing future researches of schizophrenia pathophysiology. Supporting Information Supporting Information Additional Supporting Information may be found in the online version of this article: Table S1: Assay IDs of NRG3 SNPs. Table S2: Genotype and allele frequency distribution of NRG3 polymorphisms. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer-reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Filename Description GBB_722_sm_st1_st2.doc48.5 KB Supporting info item Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. References Avila, M.T., Hong, L.E., Moates, A., Turano, K.A. & Thaker, G.K. (2006) Role of anticipation in schizophrenia-related pursuit initiation deficits. J Neurophysiol 95, 593– 601. CrossrefPubMedWeb of Science®Google Scholar Balciuniene, J., Feng, N., Iyadurai, K., Hirsch, B., Charnas, L., Bill, B.R., Easterday, M.C., Staaf, J., Oseth, L., Czapansky-Beilman, D., Avramopoulos, D., Thomas, G.H., Borg, A., Valle, D., Schimmenti, L.A. & Selleck, S.B. (2007) Recurrent 10q22-q23 deletions: a genomic disorder on 10q associated with cognitive and behavioral abnormalities. Am J Hum Genet 80, 938– 947. CrossrefCASPubMedWeb of Science®Google Scholar Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263– 265. CrossrefCASPubMedWeb of Science®Google Scholar Chen, P.L., Avramopoulos, D., Lasseter, V.K., McGrath, J.A., Fallin, M.D., Liang, K.Y., Nestadt, G., Feng, N., Steel, G., Cutting, A.S., Wolyniec, P., Pulver, A.E. & Valle, D. (2009) Fine mapping on chromosome 10q22-q23 implicates Neuregulin 3 in schizophrenia. Am J Hum Genet 84, 21– 34. CrossrefCASPubMedWeb of Science®Google Scholar Fallin, M.D., Lasseter, V.K., Wolyniec, P.S., McGrath, J.A., Nestadt, G., Valle, D., Liang, K.Y. & Pulver, A.E. (2003) Genomewide linkage scan for schizophrenia susceptibility loci among Ashkenazi Jewish families shows evidence of linkage on chromosome 10q22. Am J Hum Genet 73, 601– 611. CrossrefCASPubMedWeb of Science®Google Scholar Faraone, S.V., Hwu, H.G., Liu, C.M., Chen, W.J., Tsuang, M.M., Liu, S.K., Shieh, M.H., Hwang, T.J., Ou-Yang, W.C., Chen, C.Y., Chen, C.C., Lin, J.J., Chou, F.H., Chueh, C.M., Liu, W.M., Hall, M.H., Su, J., Van Eerdewegh, P. & Tsuang, M.T. (2006) Genome scan of Han Chinese schizophrenia families from Taiwan: confirmation of linkage to 10q22.3. Am J Psychiatry 163, 1760– 1766. CrossrefPubMedWeb of Science®Google Scholar Kao, W.T., Wang, Y., Kleinman, J.E., Lipska, B.K., Hyde, T.M., Weinberger, D.R. & Law, A.J. (2010) Common genetic variation in Neuregulin 3 (NRG3) influences risk for schizophrenia and impacts NRG3 expression in human brain. Proc Natl Acad Sci U S A 107, 15619– 15624. CrossrefCASPubMedWeb of Science®Google Scholar McGrath, J., Saha, S., Chant, D. & Welham, J. (2008) Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol Rev 30, 67– 76. CrossrefPubMedWeb of Science®Google Scholar Mei, L. & Xiong, W.C. (2008) Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci 9, 437– 452. CrossrefCASPubMedWeb of Science®Google Scholar Morar, B., Dragovic, M., Waters, F.A., Chandler, D., Kalaydjieva, L. & Jablensky, A. (2010) Neuregulin 3 (NRG3) as a susceptibility gene in a schizophrenia subtype with florid delusions and relatively spared cognition. Mol Psychiatry 16, 860– 866. CrossrefCASPubMedWeb of Science®Google Scholar Park, B.L., Shin, H.D., Cheong, H.S., Park, C.S., Sohn, J.W., Kim, B.J., Seo, H.K., Kim, J.W., Kim, K.H., Shin, T.M., Choi, I.G., Kim, S.G. & Woo, S.I. (2009) Association analysis of COMT polymorphisms with schizophrenia and smooth pursuit eye movement abnormality. J Hum Genet 54, 709– 712. CrossrefCASPubMedWeb of Science®Google Scholar Saus, E., Brunet, A., Armengol, L., Alonso, P., Crespo, J.M., Fernandez-Aranda, F., Guitart, M., Martin-Santos, R., Menchon, J.M., Navines, R., Soria, V., Torrens, M., Urretavizcaya, M., Valles, V., Gratacos, M. & Estivill, X. (2010) Comprehensive copy number variant (CNV) analysis of neuronal pathways genes in psychiatric disorders identifies rare variants within patients. J Psychiatr Res 44, 971– 978. CrossrefPubMedWeb of Science®Google Scholar Shin, H.D., Park, B.L., Bae, J.S., Park, T.J., Chun, J.Y., Park, C.S., Sohn, J.W., Kim, B.J., Kang, Y.H., Kim, J.W., Kim, K.H., Shin, T.M. & Woo, S.I. (2010) Association of ZDHHC8 polymorphisms with smooth pursuit eye movement abnormality. Am J Med Genet B Neuropsychiatr Genet 153B, 1167– 1172. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Stephens, M., Smith, N.J. & Donnelly, P. (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68, 978– 989. CrossrefCASPubMedWeb of Science®Google Scholar Torrey, E.F. (1987) Prevalence studies in schizophrenia. Br J Psychiatry 150, 598– 608. CrossrefCASPubMedWeb of Science®Google Scholar Wang, Y.C., Chen, J.Y., Chen, M.L., Chen, C.H., Lai, I.C., Chen, T.T., Hong, C.J., Tsai, S.J. & Liou, Y.J. (2008) Neuregulin 3 genetic variations and susceptibility to schizophrenia in a Chinese population. Biol Psychiatry 64, 1093– 1096. CrossrefCASPubMedWeb of Science®Google Scholar Acknowledgments This study was supported by a grant of the Korea Healthcare technology R&D Project, Ministry of Health & Welfare, Republic of Korea (No. A101023). The authors declare no competing interests. Citing Literature Volume10, Issue8November 2011Pages 828-833 FiguresReferencesRelatedInformation
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