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Association study of monoamine oxidase A/B genes and schizophrenia in Han Chinese

Association study of monoamine oxidase A/B genes and schizophrenia in Han Chinese Background: Monoamine oxidases (MAOs) catalyze the metabolism of dopaminergic neurotransmitters. Polymorphisms of isoforms MAOA and MAOB have been implicated in the etiology of mental disorders such as schizophrenia. Association studies detected these polymorphisms in several populations, however the data have not been conclusive to date. Here, we investigated the association of MAOA and MAOB polymorphisms with schizophrenia in a Han Chinese population. Methods: Two functional single nucleotide polymorphisms (SNPs), rs6323 of MAOA and rs1799836 of MAOB, were selected for association analysis in 537 unrelated schizophrenia patients and 536 healthy controls. Single-locus and Haplotype associations were calculated. Results: No differences were found in the allelic distribution of rs6323. The G allele of rs1799836 was identified as a risk factor in the development of schizophrenia (P = 0.00001). The risk haplotype rs6323T-rs1799836G was associated with schizophrenia in female patients (P = 0.0002), but the frequency difference was not significant among male groups. Conclusions: Our results suggest that MAOB is a susceptibility gene for schizophrenia. In contrast, no significant associations were observed for the MAOA functional polymorphism with schizophrenia in Han Chinese. These data support further investigation of the role of MAO genes in schizophrenia. Background often present with additional conditions such as major Schizophrenia is a chronic mental disorder characterized depression and anxiety disorders [6]. by abnormalities in the perception or expression of rea- Monoamine oxidase (MAO), a mitochondrial enzyme, lity. Onset of symptoms typically occurs in young adult- plays a vital role in the inactivation of neurotransmitters. hood. Global estimates for lifetime prevalence of MAOA and MAOB are two biochemically distinct forms schizophrenia are 4.0‰-7.0‰ [1,2]. The disease has of this enzyme that are encoded by distinct genes been ascertained with a high level of heritability by located adjacently on the X chromosome in opposite twins and adoption studies [3]. Many candidate genes direction [7]. While MAOA and MAOB are different in have been found, such as DAOA (G72), DTNBP1 (dys- metabolic substrates and inhibitor specificities, they bindin), COMT, with each having small effects in gen- equally contribute to the deamination of dopamine. ome-wide association studies. Many of these genes have According to the dopamine theory on the pathogenesis also been implicated in the etiology of bipolar disorder, of schizophrenia, low activity of MAO is a risk factor in as both diseases have some manifestations in common the development of the disorder [8,9]. [4,5]. Schizophrenic patients display increased dopamine Polymorphisms of the MAOA gene have been investi- activity in the mesolimbic pathway of the brain, and gated in several psychiatric illnesses including schizo- phrenia [10], major depressive disorder (MDD) [11] and * Correspondence: liuyao1123@yahoo.cn; hulan328@yahoo.com bipolar affective disorder (BPD) [12]. Examples of Department of Forensic Science, School of Medicine, Xi’an Jiaotong MAOA polymorphisms include rs6323, rs1800466, University/Key Laboratory of Ministry of Public Health for Forensic Science, rs1799835, and rs1465108. The functional polymorph- Xi’an 710061, PR China Institute of Forensic Science, Ministry of Public Security, Beijing 100038, PR ism (rs6323), located in exon 8, is associated with China altered enzyme activity and has been extensively Full list of author information is available at the end of the article © 2011 Wei et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Wei et al. Behavioral and Brain Functions 2011, 7:42 Page 2 of 6 http://www.behavioralandbrainfunctions.com/content/7/1/42 investigated in association studies. Synonymous substitu- to variations in genetic background or linkage disequili- tion of T to G at this location promotes MAOA activity brium (LD) patterns. As significant genetic difference [13,14]. MDD patients with genotype G or G/G at this between European and East Asian populations exist site have a significantly lower magnitude of placebo (Figure 1; δ = 0.225, δ =0.330), we have rs6323 rs1799836 response than those with T, G/T or T/T [15]. A recent limited our investigation to Han Chinese. Accounting study implied that the T allele was associated with schi- for these parameters, a case-control study was proposed zophrenia in Chinese males [16], however this associa- to investigate the associations of rs6323 and rs1799836 tion was not confirmed in a meta-study comprising polymorphisms with schizophrenia, and to generate a Caucasian, Japanese, and Han Chinese [17]. comparison of the relative contribution of each gene. MAOB, located adjacent to MAOA on the opposite Genetic association was examined simultaneously on strand at chromosome Xp11.23, is involved in the alleles, genotypes and haplotypes. breakdown of dopamine in the brain. A non-coding sin- gle nucleotide polymorphism (SNP) (rs1799836) in Material and methods intron 13 is associated with Parkinson’sdisease [18], Sample collection and is also significantly associated with reduced negative Han Chinese subjects (n = 537 patients diagnosed with emotionality [19]. This A/G (A644G) substitution is schizophrenia by a group of experienced psychiatrists responsible for altered enzyme activity with tissue speci- using DSM-IV criteria, including 294 men and 243 ficity [20-23]. Further, a case-control study by Gassó et women), were recruited from Xi’an Mental Health Cen- al. indicates that the G allele is a risk factor for develop- tre. Matched controls (n = 536, including 284 males and ing schizophrenia in a Spanish population [9]. 252 females) based on geographic origin, gender ratio Genetic polymorphisms associated with altered and age and without any family or personal history of enzyme activity may play a significant role in the etiol- neurological disorders, were recruited from hospital ogy of schizophrenia. Here, we investigated the associa- staff, students, and the general population. The patient tion of two representative functional polymorphisms, group had an age distribution of 12 and 72 years (mean rs6323 of MAOA and rs1799836 of MAOB,withthe ± SD: 29.95 ± 8.69 years), while the control population development of schizophrenia in Han Chinese. The full had an age distribution of 13 and 70 years (mean ± SD: list of genes and selected polymorphisms is outlined in 30.34 ± 11.63 years). A questionnaire was administered Table 1. These specific polymorphisms have been inves- to obtain demographic information from all of the sub- tigated in previous studies, however the results have not jects, including sex, age, ethnicity, personal medical his- been conclusive. Here, we investigate associations of tory, and family history of neurological disease. Clinical these polymorphisms utilizing a large sample size allow- data of all patients was obtained from hospital check-in ing generation of significant data. Additionally, as emer- records. ging reports indicate that MAOA and MAOB may have Whole blood samples were obtained from all patients, gender-specific roles in the development of several psy- and buccal swabs and blood spots were collected from chiatric disorders [9,12,17,19,24], we have included dif- healthy controls. This study was approved by the Xi’an ferences in gender in our statistical analysis. The MAO Jiaotong University Ethics Committee. Written informed genes are located on the X chromosome, therefore consent was obtained from all participants. Another pre- males are hemizygotes and haplotypes formed by rs6323 vious study using part of these samples has been pub- and rs1799836 can be explicitly assigned in male partici- lished [26]. pants. Finally, differences in allele frequency distribu- tions of rs6323 and rs1799836 have been identified Experimental procedures across multiple populations [25]. In general, such allele DNA was isolated from 1 ml of blood using the frequency differences can lead to association errors QIAamp DNA Blood Midi Kit and from saliva or (type I or II) if there is population stratification in the blood spot samples by MagAttract DNA Mini M48 samples. Thesameallelemayconfer adifferent risk for Kit. Genotypes of rs6323 were determined by sequen- disease in one population as compared to another due cing. The forward primer 5’ -GACCTTGACTGCCAA- GAT-3’ and reverse primer 5’ -CTTCTTCTTCCAG AAGGCC-3’ were used to amplify a 130 bp fragment. Table 1 Details of SNPs Genotype analysis of locus rs1799836 was performed by adopting the method of A/G-specific oligonucleotide dbSNP Position Gene symbol polymerase chain reaction, which was described pre- rs6323 chrX: 43591036 MAOA viously [9]. A- and G- specific oligonucleotides 5’- rs1799836 chrX: 43627999 MAOB CACTGGCAAATAGCAAAAGT-3’ and 5’-CACTGG- Map to Genome Build 37.1 in dbSNP. CAAATAGCAAAAGC-3’ were used as reverse primers Wei et al. Behavioral and Brain Functions 2011, 7:42 Page 3 of 6 http://www.behavioralandbrainfunctions.com/content/7/1/42 a a b Figure 1 Population distribution of rs6323 and rs1799836 . Data cited from Hapmap Database. CHB: Han Chinese in Beijing, China; JPT: Japanese in Tokyo, Japan; CEU: Utah residents with Northern and Western European ancestry from the CEPH collection; TSI: Tuscan in Italy. and 5’-GGATTTACTTTGCAGGCACC-3’ was used as a chain reaction were in complete concordance with the forward primer, the products’ size was 663 bp. For qual- re-sequencing results. ity control of this method, nearly 8% of samples (80 Results of single-locus analysis are shown in Table 2. samples) were randomly selected to take re-sequencing. No significant differences are observed in frequency distributions of rs6323 between total (male and female) Statistical analysis case and control groups (P = 0.919, Power = 100% Data were analyzed using the SPSS v15.0 software pack- when a = 0.05), or between each gender case and con- age (SPSS Inc., Chicago IL). Mean and standard devia- trol groups (male: P = 0.933, Power = 99.9% when a’ = tions were computed for continuous variables. For male 0.025; female: P = 0.787, Power = 99.9% when a’ = data, allelic frequency distributions between patients and 0.025). In contrast, allele frequency for the rs1799836 matched controls were analyzed using the c test and polymorphism displayed significant statistical differ- Fisher’s exact test. Hardy-Weinberg Equilibrium was ence between total case and control groups (P = examined by c test. Calculations of odds ratio and con- 0.00001), identifying the G allele as a risk factor for fidence limits for the risk alleles and haplotypes were schizophrenia (OR = 1.578, 95%CI = 1.284 - 1.938). implemented in the SPSS program. Haploview was used Stratification of the analysis by gender revealed that to analyze Hardy-Weinberg Equilibrium, linkage dise- the differences were significant in both female (P = quilibrium and disease association in females [27]. Test 0.0004; OR = 1.764, 95%CI = 1.285 - 2.421) and male power was estimated using G*Power 3.0 [28] at the sig- (P = 0.008; OR = 1.586, 95%CI = 1.121 - 2.245) groups. Odds ratios of female genotypes containing the nificant level of 0.05 (a = 0.05) and the effect size of 0.3 for all statistical tests, and Bonferroni correction (a’) G allele are listed in Table 3. was applied for multiple tests in comparison analysis. LD and risk haplotype analysis Results The MAOA and MAOB genes are located within 36.9 kb Single-locus frequency distribution and association of each other on the X chromosome. As risk haplotype analysis analysis displays an important role for genetic associa- Frequency of SNPs rs6323 and rs1799836 were analyzed tions in the etiology of complex diseases [29], we per- in case and control groups. Allelic frequency distribu- formed an analysis of rs6323 (G/T) and rs1799836 (A/ tions of markers are presented in Table 2. Each distribu- G). Using female data, the LD coefficient values of tion was in accordance with Hardy-Weinberg rs6323 and rs1799836 were tested in patients (D’ = Equilibrium, respectively, for males and females in both 0.387) and healthy controls (D’ = 0.198) respectively. case and control groups (MAF > 0.1, P >0.05).Results Bonferroni correction identified the rs6323T - obtained from A/G-specific oligonucleotide polymerase rs1799836G haplotype as a risk factor for developing Wei et al. Behavioral and Brain Functions 2011, 7:42 Page 4 of 6 http://www.behavioralandbrainfunctions.com/content/7/1/42 Table 2 Allelic frequencies of rs6323 and rs1799836 in schizophrenia patients and control subjects Allele Schizophrenia (n, %) Control (n, %) Male Female Total Male Female Total rs6323 G 167/294 (56.8) 262/486 (53.9) 429/780 (55.0) 160/284 (56.3) 276/504 (54.8) 436/788 (55.3) T 127/294 (43.2) 224/486 (46.1) 351/780 (45.0) 124/284 (43.7) 228/504 (45.2) 352/788 (44.7) a a P value 0.933 0.787 0.919 rs1799836 A 225/294 (76.5) 366/486 (75.3) 591/780 (75.8) 242/284 (85.2) 425/504 (84.3) 667/788 (84.6) G 69/294 (23.5) 120/486 (24.7) 189/780 (24.2) 42/284 (14.8) 79/504 (15.7) 121/788 (15.4) a a P value 0.008 0.0004 0.00001 P values are corrected for multiple testing, differences reaching statistical significance are P < 0.025. schizophrenia in female patients (Table 4). No associa- data, the T allele distributed almost equally among case tion was observed in male groups (P =0.235,Power = and control samples, suggesting that rs6323 is not asso- 99.9% when a = 0.05; OR = 1.359, 95% CI = 0.853 - ciated with schizophrenia. As such, our data contrast 2.165). withapreviousreportbyQiuet al., howeverweattri- bute this discrepancy to the difference in sample size Discussion between the two studies. Based upon our findings, we Complex disease may be caused by high-order risk suggest that focus be shifted to other polymorphisms, interactions between or within genes. Here, we investi- including those that distribute to coding regions and gated the association of rs6323 and rs1799836 poly- others that distribute to regulatory regions, both of morphisms with schizophrenia in a Han Chinese which can affect functional gene expression. population. Our data indicates that rs1799836 is a risk The rs72554632 mutation, in which glutamine is allele in the total population, and rs6323T - rs1799836G exchanged with a termination codon, has been indenti- is a risk haplotype in females. As all genetic samples fied in male patients with Brunner syndrome [33]. This were obtained from geography-matched Han Chinese, mutation significantly diminishes MAOA activity, and is these data are more definitive than results obtained by believed to contribute to the development of aggressive meta-analysis. The possibility of population stratifica- behavior characteristic of this syndrome. Previously, no association has been reported for rs72554632 in the tion, however, raises some possibility for the identifica- development of schizophrenia. The proximity of tion of false positive associations. Future studies that incorporate a genomic control for sample selection rs72554632 4 bp upstream of rs6323, however, warrants would further increase the reliability of results. As such, mention. As a side outcome of genotyping rs6323 in we recommend that prior to global analysis of the roles this study, we investigated the prevalence of rs72554632 of rs6323 and rs1799836 polymorphisms in schizophre- mutations in our cohort. We were unable to identify nia, genetic associations should be performed strictly any mutations at the rs72554632 site, suggesting that no within each of the major populations including Eur- association exists with schizophrenia. opean, African, and East Asian analyses. Although the A/G substitution of intron 13 The MAOA gene, also called the “warrior” or “vio- (rs1799836) of MAOB does not change the amino acid lence” gene [30], was identified as a candidate suscept- sequence, the G allele has been associated with lower ibility gene for schizophrenia and aggressive behavior enzyme activity in human brain [23]. In line with the [31], although the risk polymorphism has not been con- hypothesis of abnormal prefrontal dopamine signaling in firmed [32]. Similarly, the T allele of the functional schizophrenia, the association of rs1799836G allele with rs6323 locus was reported to be a risk factor in suscept- schizophrenia has been tested in a Spanish population ibility to schizophrenia in Chinese men [16]. In our [9,34]. Further, the G allele of rs1799836 was identified Table 3 Genotype distribution of rs1799836 in females Genotype Schizophrenia (n, %) Control (n, %) P value Odds Ratios (%95 Confidence Interval) AA 142/243 (58.4) 180/252 (71.4) 0.002 0.818 (0.717 - 0.933) AG 82/243 (33.7) 65/252 (25.8) 0.061 1.308 (0.995 - 1.720) GG 19/243 (7.8) 7/252 (2.8) 0.014 2.814 (1.204 - 6.575) Power for genotype distribution test is 99.9% when a = 0.05. Wei et al. Behavioral and Brain Functions 2011, 7:42 Page 5 of 6 http://www.behavioralandbrainfunctions.com/content/7/1/42 Table 4 Haplotype distribution in female patients and controls Haplotype Schizophrenia (n, %) Control (n, %) P value Odds Ratio (95% Confidence Interval) G-A 222.36/486 (45.8) 241.28/504 (47.9) 0.504 0.918 (0.715~1.179) G-G 39.64/486 (8.2) 34.72/504 (6.9) 0.449 1.200 (0.747~1.928) T-A 143.64/486 (29.6) 183.72/504 (36.5) 0.021 0.731 (0.560~0.955) T-G 80.36/486 (16.5) 44.28/504 (8.8) 0.0002 2.057 (1.392~3.039) P values are corrected for multiple testing, differences reaching statistical significance are P < 0.0125. Author details as a risk factor for developing schizophrenia in women. Department of Forensic Science, School of Medicine, Xi’an Jiaotong Our data confirms these results in a Han Chinese popu- University/Key Laboratory of Ministry of Public Health for Forensic Science, lation. The observed differences in G allele frequency Xi’an 710061, PR China. Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Ministry of Education, Xi’an 710061, PR are statistically significant in both male and female China. Institute of Forensic Science, Ministry of Public Security, Beijing patients compared to controls. The risk allele could be 100038, PR China. Key Laboratory of Forensic Genetics, Ministry of Public in LD with rs1799836. These data implicate MAOB in Security, Beijing 100038, PR China. the etiology of schizophrenia, and suggest that addi- Authors’ contributions tional polymorphisms of MAOB should be included in YLW performed the genotyping, analyzed the data and drafted the future studies [35]. manuscript, SBL offered the subjects and information, CXL analyzed the data and modified the manuscript, LH conducted experiments, and the Some variants that have no significant differences at corresponding author YL designed the study and finalized the manuscript. the single-locus levels may be associated with disease All authors have read and given final approval of the final manuscript. upon haplotype analysis [36]. Weak linkage disequili- Competing interests brium was found in controls between rs6323 and The authors declare that they have no competing interests. rs1799836, indicating frequent recombination in the Chinese population. A risk rs6323T - rs1799836G hap- Received: 31 March 2011 Accepted: 6 October 2011 Published: 6 October 2011 lotype was found in female groups, although rs6323 alone was not identified as a risk factor in our study. References Growing evidence indicates that gender-specific effects 1. Bhugra D: The global prevalence of schizophrenia. PLoS Med 2005, 2:e151, of MAOA and MAOB exist in various psychiatric dis- quiz e175. 2. Tandon R, Keshavan MS, Nasrallah HA: Schizophrenia, “just the facts” what eases [9,12,24], and haplotype analyses support this gen- we know in 2008. 2. Epidemiology and etiology. Schizophr Res 2008, der-specific hypothesis [12]. Inactivation of the × 102:1-18. chromosome in women during embryogenesis, however, 3. O’Donovan MC, Williams NM, Owen MJ: Recent advances in the genetics of schizophrenia. Hum Mol Genet 2003, 12(Spec No 2):R125-133. makes it difficult to predict an allele’s contribution to 4. 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Yu YW, Tsai SJ, Hong CJ, Chen TJ, Chen MC, Yang CW: Association study Acknowledgements of a monoamine oxidase a gene promoter polymorphism with major All authors would like to thank Zheng Tu, Bo-Wei Jiang and Rui-Fang Sun depressive disorder and antidepressant response. for their advices and technique assistance. This research was partially Neuropsychopharmacology 2005, 30:1719-1723. supported by Genetic resource of Chinese population (57004). The funding 12. Lin YM, Davamani F, Yang WC, Lai TJ, Sun HS: Association analysis of sources had input into the design of this study, the collection, analysis and monoamine oxidase A gene and bipolar affective disorder in Han interpretation of data, the writing of the report or the decision to submit Chinese. Behav Brain Funct 2008, 4:21. the paper for publication. Wei et al. Behavioral and Brain Functions 2011, 7:42 Page 6 of 6 http://www.behavioralandbrainfunctions.com/content/7/1/42 13. 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Kapur S: Psychosis as a state of aberrant salience: a framework linking • Immediate publication on acceptance biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry 2003, 160:13-23. • Inclusion in PubMed, CAS, Scopus and Google Scholar 35. Carrera N, Sanjuan J, Molto MD, Carracedo A, Costas J: Recent adaptive • Research which is freely available for redistribution selection at MAOB and ancestral susceptibility to schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2009, 150B:369-374. Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Behavioral and Brain Functions Springer Journals

Association study of monoamine oxidase A/B genes and schizophrenia in Han Chinese

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Copyright © 2011 by Wei et al; licensee BioMed Central Ltd.
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Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
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Abstract

Background: Monoamine oxidases (MAOs) catalyze the metabolism of dopaminergic neurotransmitters. Polymorphisms of isoforms MAOA and MAOB have been implicated in the etiology of mental disorders such as schizophrenia. Association studies detected these polymorphisms in several populations, however the data have not been conclusive to date. Here, we investigated the association of MAOA and MAOB polymorphisms with schizophrenia in a Han Chinese population. Methods: Two functional single nucleotide polymorphisms (SNPs), rs6323 of MAOA and rs1799836 of MAOB, were selected for association analysis in 537 unrelated schizophrenia patients and 536 healthy controls. Single-locus and Haplotype associations were calculated. Results: No differences were found in the allelic distribution of rs6323. The G allele of rs1799836 was identified as a risk factor in the development of schizophrenia (P = 0.00001). The risk haplotype rs6323T-rs1799836G was associated with schizophrenia in female patients (P = 0.0002), but the frequency difference was not significant among male groups. Conclusions: Our results suggest that MAOB is a susceptibility gene for schizophrenia. In contrast, no significant associations were observed for the MAOA functional polymorphism with schizophrenia in Han Chinese. These data support further investigation of the role of MAO genes in schizophrenia. Background often present with additional conditions such as major Schizophrenia is a chronic mental disorder characterized depression and anxiety disorders [6]. by abnormalities in the perception or expression of rea- Monoamine oxidase (MAO), a mitochondrial enzyme, lity. Onset of symptoms typically occurs in young adult- plays a vital role in the inactivation of neurotransmitters. hood. Global estimates for lifetime prevalence of MAOA and MAOB are two biochemically distinct forms schizophrenia are 4.0‰-7.0‰ [1,2]. The disease has of this enzyme that are encoded by distinct genes been ascertained with a high level of heritability by located adjacently on the X chromosome in opposite twins and adoption studies [3]. Many candidate genes direction [7]. While MAOA and MAOB are different in have been found, such as DAOA (G72), DTNBP1 (dys- metabolic substrates and inhibitor specificities, they bindin), COMT, with each having small effects in gen- equally contribute to the deamination of dopamine. ome-wide association studies. Many of these genes have According to the dopamine theory on the pathogenesis also been implicated in the etiology of bipolar disorder, of schizophrenia, low activity of MAO is a risk factor in as both diseases have some manifestations in common the development of the disorder [8,9]. [4,5]. Schizophrenic patients display increased dopamine Polymorphisms of the MAOA gene have been investi- activity in the mesolimbic pathway of the brain, and gated in several psychiatric illnesses including schizo- phrenia [10], major depressive disorder (MDD) [11] and * Correspondence: liuyao1123@yahoo.cn; hulan328@yahoo.com bipolar affective disorder (BPD) [12]. Examples of Department of Forensic Science, School of Medicine, Xi’an Jiaotong MAOA polymorphisms include rs6323, rs1800466, University/Key Laboratory of Ministry of Public Health for Forensic Science, rs1799835, and rs1465108. The functional polymorph- Xi’an 710061, PR China Institute of Forensic Science, Ministry of Public Security, Beijing 100038, PR ism (rs6323), located in exon 8, is associated with China altered enzyme activity and has been extensively Full list of author information is available at the end of the article © 2011 Wei et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Wei et al. Behavioral and Brain Functions 2011, 7:42 Page 2 of 6 http://www.behavioralandbrainfunctions.com/content/7/1/42 investigated in association studies. Synonymous substitu- to variations in genetic background or linkage disequili- tion of T to G at this location promotes MAOA activity brium (LD) patterns. As significant genetic difference [13,14]. MDD patients with genotype G or G/G at this between European and East Asian populations exist site have a significantly lower magnitude of placebo (Figure 1; δ = 0.225, δ =0.330), we have rs6323 rs1799836 response than those with T, G/T or T/T [15]. A recent limited our investigation to Han Chinese. Accounting study implied that the T allele was associated with schi- for these parameters, a case-control study was proposed zophrenia in Chinese males [16], however this associa- to investigate the associations of rs6323 and rs1799836 tion was not confirmed in a meta-study comprising polymorphisms with schizophrenia, and to generate a Caucasian, Japanese, and Han Chinese [17]. comparison of the relative contribution of each gene. MAOB, located adjacent to MAOA on the opposite Genetic association was examined simultaneously on strand at chromosome Xp11.23, is involved in the alleles, genotypes and haplotypes. breakdown of dopamine in the brain. A non-coding sin- gle nucleotide polymorphism (SNP) (rs1799836) in Material and methods intron 13 is associated with Parkinson’sdisease [18], Sample collection and is also significantly associated with reduced negative Han Chinese subjects (n = 537 patients diagnosed with emotionality [19]. This A/G (A644G) substitution is schizophrenia by a group of experienced psychiatrists responsible for altered enzyme activity with tissue speci- using DSM-IV criteria, including 294 men and 243 ficity [20-23]. Further, a case-control study by Gassó et women), were recruited from Xi’an Mental Health Cen- al. indicates that the G allele is a risk factor for develop- tre. Matched controls (n = 536, including 284 males and ing schizophrenia in a Spanish population [9]. 252 females) based on geographic origin, gender ratio Genetic polymorphisms associated with altered and age and without any family or personal history of enzyme activity may play a significant role in the etiol- neurological disorders, were recruited from hospital ogy of schizophrenia. Here, we investigated the associa- staff, students, and the general population. The patient tion of two representative functional polymorphisms, group had an age distribution of 12 and 72 years (mean rs6323 of MAOA and rs1799836 of MAOB,withthe ± SD: 29.95 ± 8.69 years), while the control population development of schizophrenia in Han Chinese. The full had an age distribution of 13 and 70 years (mean ± SD: list of genes and selected polymorphisms is outlined in 30.34 ± 11.63 years). A questionnaire was administered Table 1. These specific polymorphisms have been inves- to obtain demographic information from all of the sub- tigated in previous studies, however the results have not jects, including sex, age, ethnicity, personal medical his- been conclusive. Here, we investigate associations of tory, and family history of neurological disease. Clinical these polymorphisms utilizing a large sample size allow- data of all patients was obtained from hospital check-in ing generation of significant data. Additionally, as emer- records. ging reports indicate that MAOA and MAOB may have Whole blood samples were obtained from all patients, gender-specific roles in the development of several psy- and buccal swabs and blood spots were collected from chiatric disorders [9,12,17,19,24], we have included dif- healthy controls. This study was approved by the Xi’an ferences in gender in our statistical analysis. The MAO Jiaotong University Ethics Committee. Written informed genes are located on the X chromosome, therefore consent was obtained from all participants. Another pre- males are hemizygotes and haplotypes formed by rs6323 vious study using part of these samples has been pub- and rs1799836 can be explicitly assigned in male partici- lished [26]. pants. Finally, differences in allele frequency distribu- tions of rs6323 and rs1799836 have been identified Experimental procedures across multiple populations [25]. In general, such allele DNA was isolated from 1 ml of blood using the frequency differences can lead to association errors QIAamp DNA Blood Midi Kit and from saliva or (type I or II) if there is population stratification in the blood spot samples by MagAttract DNA Mini M48 samples. Thesameallelemayconfer adifferent risk for Kit. Genotypes of rs6323 were determined by sequen- disease in one population as compared to another due cing. The forward primer 5’ -GACCTTGACTGCCAA- GAT-3’ and reverse primer 5’ -CTTCTTCTTCCAG AAGGCC-3’ were used to amplify a 130 bp fragment. Table 1 Details of SNPs Genotype analysis of locus rs1799836 was performed by adopting the method of A/G-specific oligonucleotide dbSNP Position Gene symbol polymerase chain reaction, which was described pre- rs6323 chrX: 43591036 MAOA viously [9]. A- and G- specific oligonucleotides 5’- rs1799836 chrX: 43627999 MAOB CACTGGCAAATAGCAAAAGT-3’ and 5’-CACTGG- Map to Genome Build 37.1 in dbSNP. CAAATAGCAAAAGC-3’ were used as reverse primers Wei et al. Behavioral and Brain Functions 2011, 7:42 Page 3 of 6 http://www.behavioralandbrainfunctions.com/content/7/1/42 a a b Figure 1 Population distribution of rs6323 and rs1799836 . Data cited from Hapmap Database. CHB: Han Chinese in Beijing, China; JPT: Japanese in Tokyo, Japan; CEU: Utah residents with Northern and Western European ancestry from the CEPH collection; TSI: Tuscan in Italy. and 5’-GGATTTACTTTGCAGGCACC-3’ was used as a chain reaction were in complete concordance with the forward primer, the products’ size was 663 bp. For qual- re-sequencing results. ity control of this method, nearly 8% of samples (80 Results of single-locus analysis are shown in Table 2. samples) were randomly selected to take re-sequencing. No significant differences are observed in frequency distributions of rs6323 between total (male and female) Statistical analysis case and control groups (P = 0.919, Power = 100% Data were analyzed using the SPSS v15.0 software pack- when a = 0.05), or between each gender case and con- age (SPSS Inc., Chicago IL). Mean and standard devia- trol groups (male: P = 0.933, Power = 99.9% when a’ = tions were computed for continuous variables. For male 0.025; female: P = 0.787, Power = 99.9% when a’ = data, allelic frequency distributions between patients and 0.025). In contrast, allele frequency for the rs1799836 matched controls were analyzed using the c test and polymorphism displayed significant statistical differ- Fisher’s exact test. Hardy-Weinberg Equilibrium was ence between total case and control groups (P = examined by c test. Calculations of odds ratio and con- 0.00001), identifying the G allele as a risk factor for fidence limits for the risk alleles and haplotypes were schizophrenia (OR = 1.578, 95%CI = 1.284 - 1.938). implemented in the SPSS program. Haploview was used Stratification of the analysis by gender revealed that to analyze Hardy-Weinberg Equilibrium, linkage dise- the differences were significant in both female (P = quilibrium and disease association in females [27]. Test 0.0004; OR = 1.764, 95%CI = 1.285 - 2.421) and male power was estimated using G*Power 3.0 [28] at the sig- (P = 0.008; OR = 1.586, 95%CI = 1.121 - 2.245) groups. Odds ratios of female genotypes containing the nificant level of 0.05 (a = 0.05) and the effect size of 0.3 for all statistical tests, and Bonferroni correction (a’) G allele are listed in Table 3. was applied for multiple tests in comparison analysis. LD and risk haplotype analysis Results The MAOA and MAOB genes are located within 36.9 kb Single-locus frequency distribution and association of each other on the X chromosome. As risk haplotype analysis analysis displays an important role for genetic associa- Frequency of SNPs rs6323 and rs1799836 were analyzed tions in the etiology of complex diseases [29], we per- in case and control groups. Allelic frequency distribu- formed an analysis of rs6323 (G/T) and rs1799836 (A/ tions of markers are presented in Table 2. Each distribu- G). Using female data, the LD coefficient values of tion was in accordance with Hardy-Weinberg rs6323 and rs1799836 were tested in patients (D’ = Equilibrium, respectively, for males and females in both 0.387) and healthy controls (D’ = 0.198) respectively. case and control groups (MAF > 0.1, P >0.05).Results Bonferroni correction identified the rs6323T - obtained from A/G-specific oligonucleotide polymerase rs1799836G haplotype as a risk factor for developing Wei et al. Behavioral and Brain Functions 2011, 7:42 Page 4 of 6 http://www.behavioralandbrainfunctions.com/content/7/1/42 Table 2 Allelic frequencies of rs6323 and rs1799836 in schizophrenia patients and control subjects Allele Schizophrenia (n, %) Control (n, %) Male Female Total Male Female Total rs6323 G 167/294 (56.8) 262/486 (53.9) 429/780 (55.0) 160/284 (56.3) 276/504 (54.8) 436/788 (55.3) T 127/294 (43.2) 224/486 (46.1) 351/780 (45.0) 124/284 (43.7) 228/504 (45.2) 352/788 (44.7) a a P value 0.933 0.787 0.919 rs1799836 A 225/294 (76.5) 366/486 (75.3) 591/780 (75.8) 242/284 (85.2) 425/504 (84.3) 667/788 (84.6) G 69/294 (23.5) 120/486 (24.7) 189/780 (24.2) 42/284 (14.8) 79/504 (15.7) 121/788 (15.4) a a P value 0.008 0.0004 0.00001 P values are corrected for multiple testing, differences reaching statistical significance are P < 0.025. schizophrenia in female patients (Table 4). No associa- data, the T allele distributed almost equally among case tion was observed in male groups (P =0.235,Power = and control samples, suggesting that rs6323 is not asso- 99.9% when a = 0.05; OR = 1.359, 95% CI = 0.853 - ciated with schizophrenia. As such, our data contrast 2.165). withapreviousreportbyQiuet al., howeverweattri- bute this discrepancy to the difference in sample size Discussion between the two studies. Based upon our findings, we Complex disease may be caused by high-order risk suggest that focus be shifted to other polymorphisms, interactions between or within genes. Here, we investi- including those that distribute to coding regions and gated the association of rs6323 and rs1799836 poly- others that distribute to regulatory regions, both of morphisms with schizophrenia in a Han Chinese which can affect functional gene expression. population. Our data indicates that rs1799836 is a risk The rs72554632 mutation, in which glutamine is allele in the total population, and rs6323T - rs1799836G exchanged with a termination codon, has been indenti- is a risk haplotype in females. As all genetic samples fied in male patients with Brunner syndrome [33]. This were obtained from geography-matched Han Chinese, mutation significantly diminishes MAOA activity, and is these data are more definitive than results obtained by believed to contribute to the development of aggressive meta-analysis. The possibility of population stratifica- behavior characteristic of this syndrome. Previously, no association has been reported for rs72554632 in the tion, however, raises some possibility for the identifica- development of schizophrenia. The proximity of tion of false positive associations. Future studies that incorporate a genomic control for sample selection rs72554632 4 bp upstream of rs6323, however, warrants would further increase the reliability of results. As such, mention. As a side outcome of genotyping rs6323 in we recommend that prior to global analysis of the roles this study, we investigated the prevalence of rs72554632 of rs6323 and rs1799836 polymorphisms in schizophre- mutations in our cohort. We were unable to identify nia, genetic associations should be performed strictly any mutations at the rs72554632 site, suggesting that no within each of the major populations including Eur- association exists with schizophrenia. opean, African, and East Asian analyses. Although the A/G substitution of intron 13 The MAOA gene, also called the “warrior” or “vio- (rs1799836) of MAOB does not change the amino acid lence” gene [30], was identified as a candidate suscept- sequence, the G allele has been associated with lower ibility gene for schizophrenia and aggressive behavior enzyme activity in human brain [23]. In line with the [31], although the risk polymorphism has not been con- hypothesis of abnormal prefrontal dopamine signaling in firmed [32]. Similarly, the T allele of the functional schizophrenia, the association of rs1799836G allele with rs6323 locus was reported to be a risk factor in suscept- schizophrenia has been tested in a Spanish population ibility to schizophrenia in Chinese men [16]. In our [9,34]. Further, the G allele of rs1799836 was identified Table 3 Genotype distribution of rs1799836 in females Genotype Schizophrenia (n, %) Control (n, %) P value Odds Ratios (%95 Confidence Interval) AA 142/243 (58.4) 180/252 (71.4) 0.002 0.818 (0.717 - 0.933) AG 82/243 (33.7) 65/252 (25.8) 0.061 1.308 (0.995 - 1.720) GG 19/243 (7.8) 7/252 (2.8) 0.014 2.814 (1.204 - 6.575) Power for genotype distribution test is 99.9% when a = 0.05. Wei et al. Behavioral and Brain Functions 2011, 7:42 Page 5 of 6 http://www.behavioralandbrainfunctions.com/content/7/1/42 Table 4 Haplotype distribution in female patients and controls Haplotype Schizophrenia (n, %) Control (n, %) P value Odds Ratio (95% Confidence Interval) G-A 222.36/486 (45.8) 241.28/504 (47.9) 0.504 0.918 (0.715~1.179) G-G 39.64/486 (8.2) 34.72/504 (6.9) 0.449 1.200 (0.747~1.928) T-A 143.64/486 (29.6) 183.72/504 (36.5) 0.021 0.731 (0.560~0.955) T-G 80.36/486 (16.5) 44.28/504 (8.8) 0.0002 2.057 (1.392~3.039) P values are corrected for multiple testing, differences reaching statistical significance are P < 0.0125. Author details as a risk factor for developing schizophrenia in women. Department of Forensic Science, School of Medicine, Xi’an Jiaotong Our data confirms these results in a Han Chinese popu- University/Key Laboratory of Ministry of Public Health for Forensic Science, lation. The observed differences in G allele frequency Xi’an 710061, PR China. Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Ministry of Education, Xi’an 710061, PR are statistically significant in both male and female China. Institute of Forensic Science, Ministry of Public Security, Beijing patients compared to controls. The risk allele could be 100038, PR China. Key Laboratory of Forensic Genetics, Ministry of Public in LD with rs1799836. These data implicate MAOB in Security, Beijing 100038, PR China. the etiology of schizophrenia, and suggest that addi- Authors’ contributions tional polymorphisms of MAOB should be included in YLW performed the genotyping, analyzed the data and drafted the future studies [35]. manuscript, SBL offered the subjects and information, CXL analyzed the data and modified the manuscript, LH conducted experiments, and the Some variants that have no significant differences at corresponding author YL designed the study and finalized the manuscript. the single-locus levels may be associated with disease All authors have read and given final approval of the final manuscript. upon haplotype analysis [36]. Weak linkage disequili- Competing interests brium was found in controls between rs6323 and The authors declare that they have no competing interests. rs1799836, indicating frequent recombination in the Chinese population. 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